MLリソース:脳腫瘍治療薬





脳腫瘍治療薬,Brain tumor,星細胞腫,anaplastic astrocytoma,glioma,グリオーマ



■個別収録品目

●[1068]TEMODAR (Temozolomide) [Schering-Plough]テモゾロミド(テモダール)

 日本語版註)TEMODAR (Temozolomide) [Schering-Plough]テモゾロミド(テモダール)
 【別名】Methazolastone, CCRG81045, SCH52365, NSC362856, M&B 39831 【開発元】Schering-Plough Corporation  [DBR_ID]
 【化学名】3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide
 【承認】FDA申請=1998.8.2、FDA承認=1999.8.11,発売1999.9 ;【製剤】カプセル5 mg, 20 mg, 100 mg, or 250 mg 【適応】For the treatment of adult patients with refractory anaplastic astrocytoma, ie., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. 【用法用量】初回は28日間周期で、最初の5日間に1日1回150mg/m2経口投与する。 好中球と血小板数により用量を決定する 【作用】アルキル化剤 【特徴】 【製品情報】 【添付文書】http://www.fda.gov/cder/foi/label/1999/21029lbl.pdf 【EU】99.8.26付けEU 15カ国承認(星細胞腫; EMEA-CPMP答申99.5)、EUでは99.1 多形膠芽腫を承認済み。[http://www.sch-plough.com/news/business/1999/8-26-99.html] 【日本】テモダールカプセル[製造販売元/シェリング・プラウ株式会社]Temodal 申請2005.9.30 -06.9.15薬価収載 -06.9.15発売、2005.9.30優先審査品目に指定;2006.4.21薬食審医薬品第二部会審議通過。「テモダールカプセル20㎎、同100㎎」は、「悪性神経膠腫」を効能効果とする新有効成分医薬品。未承認薬使用問題検討会議において早期に承認申請を行うよう指示された薬剤で、優先審査品目に指定されている。原体・製剤は毒薬。再審査期間は10年。国内治験症例数が少ないため、承認条件として全例調査を行うよう指示された。  【製剤~日本】1カプセル テモゾロミド 50mg,100mg 【適応~日本】悪性神経膠腫 【用法用量~日本】[1. 初発の場合] 放射線照射との併用にて,通常,成人ではテモゾロミドとして1回75mg/m2(体表面積)を1日1回連日42日間,経口投与し,4週間休薬する。その後,本剤単独にて,テモゾロミドとして1回150mg/m2を1日1回連日5日間,経口投与し,23日間休薬する。この28日を1クールとし,次クールでは1回200mg/m2に増量することができる。 [2. 再発の場合] 通常,成人ではテモゾロミドとして1回150mg/m2(体表面積)を1日1回連日5日間,経口投与し,23日間休薬する。この28日を1クールとし,次クールで1回200mg/m2に増量することができる。 【製品情報~日本】 【添付文書~日本】テモダール添付文書 - [pdf] | インタビューフォーム 【その他】●Temozolomide Review ● ●1998年オーファン指定。臨床上利益評価のためのrandomized trialが承認条件。 既存薬無効の星細胞腫54例への臨床効果は完全反応9%,部分反応13%。[FDA APPROVES NEW DRUG FOR BRAIN CANCER] ●Oncologic Drugs Advisory Committee (ODAC) は、1999.1.12に11-0で承認勧告。 但し「星細胞腫」のみで「多形膠芽腫」は見送り。[Dr. Justice Response to temozolomide letters. FDA April 14, 1999]

●[1035]Gliadel Wafer (polifeprosan 20 with carmustine implant) [MGI Pharma]

 日本語版註)Gliadel Wafer (polifeprosan 20 with carmustine implant) [MGI Pharma]
 【別名】 【開発元】Guilford Pharmaceuticals Inc.→現MGI Pharma,Inc  [DBR_ID]
 【化学名】BCNUを含浸させた生分解性ポリマ-“薄シート”;carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. The copolymer, polifeprosan 20, consists of poly[bis(pcarboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine.
 【承認~多形性神経膠芽腫】FDA申請=、FDA承認=1996.9.23 ; 【承認~神経膠腫】FDA申請=2001.4.6、FDA承認=2003.2.25 ; 【製剤】GLIADEL Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine 【適応】1)[神経膠腫]GLIADEL Wafer is indicated in newly-diagnosed high grade malignant glioma patients as an adjunct to surgery and radiation. 2)[多形性神経膠芽腫]GLIADEL Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery. 【用法用量】10セント硬貨サイズの多無水物薄シートを、切除後に残った手術腔に植え込む。 【作用】腫瘍部位に直接アルキル化剤を放出するため、血液-脳関門を回避することができる。薄シートは、加水分解により分解され、約2-3 週間にわたって薬物を放出する。 【特徴】 【製品情報】http://www.gliadel.com/ 【添付文書】http://www.gliadel.com/pdf/211_029_Gliadel_PI.pdf 【EU】世界25か国で販売;英国Gliadel[Link Pharmaceuticals]2004.12発売 【日本】日本未開発 【その他】Drug Topics Red Book 1998年8 月改訂版の卸売価格(AWP) に基づく、薄シート8 枚のコストは12,480ドル



【日本語版コメント1068】
 脳腫瘍は,頭蓋内原発性と転移性に分類。病理別の頻度は髄膜腫,下垂体腫瘍,星細胞腫,膠芽腫,神経鞘腫の順(glioma全体では1/3を占める)。
 20年ぶりの脳腫瘍化学療法剤TemozolomideがFDA承認された。 これ迄有効な治療手段がなかったところへ、難治性脳腫瘍にも有効で副作用も少ないとされている。

【市場】Merck & Co
($ milllion)201020092008200720062005200420032002200120001999備考
 Temodar1,065(-1)1,0731,002(+16)861(+22)703(+20)588(+28)459(+42)324(+16)278(+54)180[+49]121[N/M]36temozolomide脳腫瘍
Guilford Pharmaceuticals Inc. ($ in millions) 2004 2003 2002 2001 GLIADEL Wafer 27.7 19.2 14.5 20.4 (polifeprosan w/carmustine) -制ガン剤 ●MGI Pharma,Inc
($ 000)2008予20072006200520042003200220012000特許期限備考
Gliadel Wafer42,000(+4)40,00035,836計33,700
[Q4]8,512(-)
#[Q1-Q3]25,200
#27,700#19,200---米国2006
国際2007
[BCNU polifeprosan 20 mplant]脳腫瘍Guilford製品
 註1)売上は米国内の販売によるもの 2)#印 Guilford社時代の売上 Sales of Gliadel(R) Wafer (polifeprosan 20 with carmustine implant) were $8.5 million for the fourth quarter of 2005. 2011年度売上予測:$50-70M  2008予/2007実積はエーザイ決算説明会資料から 初発の悪性神経膠腫における手術および放射線療法との併用 再発型の多形性神経膠芽腫における手術との併用 ■日本国内
製品(億円)0908070605040302010099備考
サイメリン[田辺三菱]2.52.6----55555[ラニムスチン]発売97.7;脳腫瘍(膠芽腫)ほか
ニドラン[第一三共]1.01.1---------[塩酸ニムスチン]発売80.2;脳腫瘍ほか
テモダール90.676.6---------[テモゾロミド]発売06.9.15;悪性神経膠腫
[]
テモダール:初年度売上予測 4.14億円(患者732人)       ピーク時(5年後)売上 15.67億円(患者1,046人) ■市場調査レポート ステイクホルダー・オピニオン:原発性脳腫瘍[Datamonitor,2007.7.2] - 2007年の主要7カ国市場全体における原発性脳腫瘍の発生は、47,000例と推測されてい ます。 症例の半数以上は多形性膠芽腫と考えられ、その生存の可能性は殆どありません。 この患者グループにおける生存期間の中央値は1.2年で、2年後に生存している患者は27% に過ぎません。 【開発中の新薬】開発中の新薬[<情報提供:日本製薬工業協会>] /2011.10.01
治験薬記号(一般名)
および剤型
予定される効能又は効果、
対象疾患名および症状名
開発段階その他
国内海外 (地域)
MLN0518 (tandutinib) 経口剤[武田薬品]神経膠腫
(受容体キナーゼ(FLT3、PDGFR、c-KIT)阻害薬)
米国第Ⅱ相自社品
【メモ】本薬は、低分子の受容体キナーゼ(RTK FLT3, PDGFR, c-KIT)阻害薬であり、細胞増殖に関係する複数のキナーゼを阻害することにより、効果的に癌細胞の増殖を抑制する。脳内移行性が良好であり、in vitroにおける試験においてAvastinとの併用で神経膠腫細胞に優れた効果を示している。
「アバスチン」R435(ベバシズマブ) 注[中外製薬]【適応拡大】結腸がん(アジュバント) ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体承認2009.9.18 EU承認2010.3.30
欧州承認2008.1.28転移性結腸・直腸がん
導入/ロシュ (ジェネンテック)
進行・再発の大腸がんで承認済み 世界80カ国で承認
【適応拡大】胃がん(アジュバント) ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体第Ⅲ相(多国籍共同治験)
【適応拡大】乳がん ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体申請2009.10.16米国承認2008.2.23局所再発・転移性乳がん
米国申請2006.5.26
欧州承認2007.3.29転移性乳がん
EU申請2006.7.10
【適応拡大】乳がん(アジュバント) ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体第Ⅲ相(国際共同治験)米国承認2008.2.23局所再発・転移性乳がん
欧州承認2009.7.29転移性乳がん
欧州承認2007.3.29転移性乳がん
欧州承認勧告2007.2.23
【適応拡大】転移性乳がんに対するXelodaの併用療法  EU承認勧告2011.4.15
【適応拡大】転移性乳がんに対するpaclitaxelの併用療法  EU承認2011.3.2
【適応拡大】非小細胞肺がん ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体承認2009.11.6
申請2008.11.26
EU承認2007.8.24
EU承認勧告2007.7.20
EU申請2006.8.8
米承認2006.10.12
米申請2006.4.12
【適応拡大】グリオブラストーマ ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体第Ⅲ相(多国籍共同治験)
【適応拡大】グリオブラストーマ(再発例) ヒト化抗VEGF(血管内皮細胞増殖因子)モノクローナル抗体第Ⅱ相米国発売2009
欧申請中
【適応拡大】インターフェロンα-2a との併用による進行・転移性腎細胞癌の一次治療 米承認2009.8.3
EU承認2007.12.19
EU承認勧告2007.11.16
【メモ】 「アバスチン(R)」は、腫瘍の増殖と転移に必要な血管の新生に重要な役割を果たすVEGFに特異的に結合し、その作用を阻害する抗体医薬。2004年2月に転移性の結腸・直腸がんの治療薬として米国で承認されて以来、治療ガイドラインで標準治療薬の一つに位置付けられている。 乳がんに対しては、欧州では2007年3月、米国では2008年2月の承認以降、進行・再発乳がんの一次治療として使用されている。国内では、2007年4月に「治癒切除不能な進行・再発の結腸・直腸癌」を効能・効果として承認された。承認後は特定使用成績調査を実施し、「アバスチン(R)」の適正使用の推進に努めてきた。 なお、中外製薬は2008年11月に扁平上皮がんを除く非小細胞肺がんを効能・効果とした追加承認申請を行い、現在、審査中。 用法・用量の追加承認2009.9.18

【乳がん】中外製薬株式会社は、抗VEGF(血管内皮増殖因子)ヒト化モノクローナル抗体ベバシズマブ(遺伝子組換え)-販売名『アバスチン(R)点滴静注用100mg/4mL、同400mg/16mL』の、乳がんに対する効能追加の承認申請を厚生労働省に行った。 海外で行われた第Ⅲ相臨床試験から、化学療法未治療の進行・再発の乳がん患者において、化学療法に「アバスチン(R)」を併用することで、主要評価項目である無増悪生存期間の統計学的に有意な延長が認められた。海外では、欧州において2007年3月、また、米国では2008年2月の承認以降、化学療法未治療の進行・再発乳がんにおいて化学療法との併用により使用されている。 国内で実施した化学療法未治療の進行・再発乳がん患者を対象とする第Ⅱ相臨床試験においても、日本人の患者における「アバスチン(R)」の有効性が確認されるとともに、忍容性も海外臨床試験と同等の水準にあることが示唆された。 日本において乳がんの新規罹患者数は年々増加しており、2010年の年間新規乳がん罹患患者数は45,000人強と推計されている。 from [記事2009.10.16]

一次治療としての化学療法による治療歴のあるHER2陰性の進行性乳がん女性を対象としたAvastin(bevacizumab)の第Ⅲ相臨床試験(RIBBON-2試験:684名)では、Avastinと二次治療として標準的に用いられる化学療法の併用投与を受けた女性の無増悪生存期間(PFS)が化学療法単独に比べ28%改善することが示された。有害事象は以前にAvastinで報告されたものと一致し、新たな安全性シグナルは観察されなかった。 FROM [記事2009.12.21]

NICE 「ベバシズマブ」転移性乳がんでの推奨せずとガイダンス草案発出
英国国立医療技術評価機構(NICE)は7月9日、ロシュの血管新生阻害剤「ベバシズマブ」について、タキサンとの併用による転移性乳がん患者への使用は推奨できないとのガイダンス草案を発出した。ベバシズマブ製造者からNICEに提出されたエビデンスでは、転移した乳がん患者の生存期間の有意な改善は認められないとしており、臨床的ベネフィットの不確実性と相まって英国国民保健機関(NHS)が支払いを請求される金額も高額であることから、転移性乳がんにおける同剤(タキサン併用)ファーストライン療法は推奨できないとした。(訳:薬事ニュース社)  from Bevacizumab rejected by NICE in draft guidance due to uncertain evidence base[NICE 2010.7.9]

ロシュ社のAvastin、転移性乳がん女性における用法・用量が拡大される[2011.7.4]
ロシュ社は転移性乳がんへのAvastinの使用に関するFDA公聴会の最新情報を提供[2011.6.30]

【卵巣がん】
ロシュは2011年2月8日、前治療歴があり白金製剤に感受性の再発卵巣がんの女性患者を対象に、化学療法(carboplatinとgemcitabine)とAvastin(bevacizumab)の併用療法後に病勢進行までAvastinの単独投与を継続した第Ⅲ相臨床試験(OCEANS試験)で、主要評価項目が達成されたことを発表しました。

試験では、Avastinと化学療法の併用療法を受けた後にAvastin単独投与を継続した女性の患者で、化学療法単独のみの治療を受けた女性と比較して、疾患を悪化させることなく生存する期間(無増悪生存期間、PFS)が延長することが示されました。新たな安全上の所見は認められず、有害事象はこれまでに実施されたAvastinの主要な試験でみられたものと同様でした。OCEANS試験の全てのデータは、今後開催される学会で発表される予定です。
[Avastinについて]
・日本での効能・効果は「治癒切除不能な進行・再発の結腸・直腸癌」、「扁平上皮癌を除く切除不能な進行・再発の非小細胞肺癌」、販売名は「アバスチン®点滴静注用100mg/4mL、同400mg/16mL」です。
・国内では胃がん、乳がん術後補助療法、グリオブラストーマを対象とした多国籍第Ⅲ相臨床試験に参加、また、グリオブラストーマ(再発例)を対象とした臨床試験を実施中です。
・乳がんに対する効能追加の承認申請を、2009年10月に厚生労働省に行っています。
・卵巣がんに対する開発要請を受け、公知申請への該当性に係る企業見解を提出しています。 from 卵巣がんに対するAvastinの3番目の第Ⅲ相臨床試験で主要評価項目を達成[2011.2.16] 

SHL562BB(gadobutrol) 静注/GADOVIST[バイエル薬品]転移性脳腫瘍のMRI造影申請承認自社
【適応追加】脳・脊髄のMRI造影第Ⅲ相EU承認
FDA承認2011.3.15
FDA申請受理2010.8.4
自社/Muitinational trial
【適応追加】躯幹部・四肢のMRI造影第Ⅲ相承認自社/Muitinational trial
【メモ】Gadovist/Gadografは“Contrast enhancement in cranial and spinal(脳および脊髄) magnetic resonance imaging”として2000.1にドイツで承認後、相互承認により欧州とノルウェイで2000.6承認。 2003.11に追加適応"Contrast-enhanced Magnetic resonance angiography"(CE-MRA) from [EMEA-Referrals - Gadovist INN: gadobutrol ]
[Referral procedures concluded] The Committee finalised referral procedures for Gadovist/Gadograf (gadobutrol) from Schering AG, recommending to extend the marketing authorization to contrast enhanced magnetic resonance imaging (MRI) of liver or kidneys in patients over 18 years of age with high suspicion or evidence of having focal lesions to classify these lesions as benign or malignant. The referrals were triggered by Spain in accordance with Article 36(1) of the Community code on human medicinal products (Directive 2001/83/EC as amended), with a view to restrict the indication applied for by the marketing authorization holder in the context of the mutual recognition procedure. The scope of the application for extension of indication originally applied for was contrast enhanced MRI of liver and kidneys. Article 36(1) procedures are initiated where a Member State considers that there are public health issues relating to a product that may require regulatory action. from [記事2006.12.15 Meeting highlights from the CHMP 11-14 Dec 2006]

Gadovistが世界初の充填済みMRI造影剤としてスエーデン・デンマークで2008夏に発売。from [記事2008.3.10]Bayer to launch world’s first pre-filled cartridges for MRI contrast media

Gadovist(R)1.0の追加適応for use in Magnetic Resonance Angiography (MRA)のドイツ承認。 from [記事2003.11.28]Schering receives EU approval for Gadovist(R)1.0 in Magnetic Resonance Angiography; www.gadovist.com

バイエル社、脳・脊髄造影を効能・効果として、MRI用造影剤Gadobutrol注射液の製造販売承認を米国食品医薬品局より取得[2011.3.16]
~バイエル ヘルスケア・ファーマシューティカルズは、本日、米国食品医薬品庁(FDA)より、「GadavistTM/ガダビスト」(gadobutrol/ガドブトロール注射液)の製造販売承認を取得したことを発表しました。「GadavistTM」は、マクロ環構造を有する1.0mol(モル)濃度のガドリニウム造影剤です。静脈内へ注射することで、成人及び2歳以上の小児のMRI(磁気共鳴コンピューター断層撮影)において、血液脳関門の破綻及び/或いは中枢神経系の血流異常を描出します。「GadavistTM」は、米国外では、「Gadovist®/ガドビスト」の製品名で60カ国以上において製造販売承認を取得しています。

●リスト除外品目~承認
テモダールカプセル(一般名:テモゾロミド)
カプセル剤[MSD株式会社][旧シェリング・プラウ株式会社]
悪性神経膠腫申請2005.9.30
06.9.15薬価収載
06.9.15発売
発売(米・欧)自社
「テモダール(R)点滴静注用100mg」(TEMODAL(R) Injection 100mg 一般名:テモゾロミド)静注[旧シェリング・プラウ株式会社]【新剤型】悪性神経膠腫発売2010.5.12
承認2010.1.20
申請(米・欧)自社
【メモ】テモダール(R)は旧シェリング・プラウ・コーポレーション(現:Merck & Co., Inc., Whitehouse Station, N.J., U.S.A:米国ニュージャージー州)が1991年に欧州連合(EU)で承認を受けて以降、カプセル剤と点滴静注剤を合わせ、現在90カ国以上で承認されており、点滴静注剤は33カ国で承認されています。

日本においては、2005年7月22日、厚生労働省の「未承認薬使用問題検討会議」により「テモダール(R)カプセル20mg/100mg」(TEMODAL(R)Capsule 20mg/100mg)が早期承認申請の要請を受け、申請後、同年9月30日付で「優先審査品目」に指定されました。その後2006年9月、悪性神経膠腫*1の適応を有する日本で19年ぶりの新規薬剤として発売されています。

初発の膠芽腫に対するテモダール(R)カプセルと放射線治療による併用療法は、放射線単独療法に比べ生存率の有意な改善を示すことが立証されています。放射線単独治療による5年生存率が1.9%であるのに対して、テモダール(R)カプセルと放射線との併用療法では9.8%であることが2009年3月に発表されました。*2

テモダール(R)点滴静注用100mgは、頭蓋内圧上昇に伴う悪心、嘔吐によりカプセル剤が飲み込めない患者、脳幹への腫瘍の浸潤などによりカプセル剤の嚥下が困難な状態にある患者など、悪性神経膠腫の限られた患者に対する治療選択肢として静脈内投与が有益であると考え、開発された製剤です。

●表から除去~開発中止など
NK408(シントレデキン・ベスドトクス/Cintredekin besudotox)[日本化薬]脳腫瘍(Glioblastoma multiforme)第Ⅰ相欧米第Ⅲ相(ネオファーム社)起原:ネオファーム社(米);2008.5期H1除外
【メモ】Cintredekin besudotox is an immunotoxin at NeoPharm (US) in phase III trials for the treatment of glioblastoma multiforme, in phase I/II trials for the treatment of malignant glioma in children, and in phase I trials for the treatment of anaplastic astrocytoma in combination with radiation therapy with or without temozolomide. Preclinical studies are under way at NeoPharm for the treatment of idiopathic pulmonary fibrosis (IPF). An IND was filed for this indication in 2010. No recent development has been reported for preclinical studies for the treatment of asthma.

The drug is a recombinant protein consisting of the tumor targeting molecule interleukin-13 (IL-13) and the cytotoxic agent Pseudomonas exotoxin (PE). It has been shown to demonstrate potent cytotoxicity against malignant glioma cells expressing the IL-13 receptor. Healthy brain cells appear to be unharmed since they do not have this receptor. Convection enhanced delivery (CED) of cintredekin besudotox has shown evidence of a selective antitumor effect in the tumor-infiltrated white matter of the brain.

Originally developed at the National Institutes of Health and the University of Pennsylvania, NeoPharm obtained an exclusive, worldwide license to the compound in October 1997. In January 2004, Nippon Kayaku signed an exclusive license agreement with NeoPharm for the Japanese development rights to cintredekin besudotox. Diosynth was chosen by NeoPharm to manufacture clinical quantities of the drug candidate for their phase III trials in April 2004. In 2007, this licensing agreement was terminated. Cintredekin besudotox was granted orphan drug status from the FDA in November 2001 for the treatment of malignant glioma and from the EMEA in late April 2002. Fast track status was also received from the FDA in May 2002. In 2010, orphan drug designation was assigned by the FDA for the treatment of idiopathic pulmonary fibrosis. The compound has also been studied for the treatment of renal cell carcinoma.

New Medicines Database[PhRMA 米製薬協]
131I-TM-601TransMolecularrecurrent gliomaPhase II(Orphan Drug)
AP23573ARIAD PharmaceuticalsglioblastomaPhase I(mTOR inhibitor) (see also cervical, leukemia,lymphoma, multiple myeloma,prostate, sarcoma, solid tumors)
CC 8490CelgeneglioblastomaPhase II
Cervene(TM)(TP-38)IVAXrecurrent glioblastomaPhase II
cintredekin
besudotox(IL13-PE38QQR)
NeoPharmglioblastoma multiformePhase III(Orphan Drug)
Cloretazine(TM)
VNP40101M
Vion Pharmaceuticalsrecurrent adult gliomaPhase II(see also leukemia)(Orphan Drug)
Cotara(R)
TNT-tumor necrosis therapy
Peregrine Pharmaceuticals(see also colon)Phase II/III
DCVax(R)-BrainNorthwest Biotherapeuticsglioblastoma multiformePhase II
depsipeptide
(FK228)
Gloucester Pharmaceuticals Phase I/II(see also bladder, colon, head/neck, leukemia, lung, lymphoma, ovarian, skin, solid tumors, stomach, other)
DTI 015/carmustine (BCNU) for intratumoral injectionDirect Therapeuticsrecurrent glioblastoma multiformePhase I/II completed
Efaproxyn(TM)
efaproxiral
Allos Therapeuticsbrain metastases from breast cancerapplication submitted(see also cervical)
glioblastoma multiformePhase II
EMD 121974Merck KGaA(see also prostate, skin, solid tumors)Phase I/II
epothilone B analog(BMS 247550)Bristol-Myers Squibb(see also breast, kidney, liver, lymphoma, prostate, solid tumors, other)Phase I/II
fenretinide(4-HPR)National Cancer InstituteglioblastomaPhase II(see also prostate, solid tumors)
GW572016GlaxoSmithKline(see also breast, cervical, head/neck, liver, prostate, stomach)Phase I/II
Hemopure(R)
hemoglobin glutamer-250(bovine)
Biopuretreatment of patients with glioblastoma as an adjunct to radiotherapy by increasing oxygen perfusion in hypoxic tumorsPhase I
Hycamtin(R)
topotecan
GlaxoSmithKline(see also lung, ovarian)Phase II
irofulvenMGI Pharmarecurrent malignant gliomaPhase II(see also liver, ovarian, prostate)
MPC-6827Myriad Geneticsmetastatic brain cancerPhase I
O6-benzylguanine(O6-BG)National Cancer Institute(see also lymphoma, solid tumors, cancer/chemotherapy)Phase I/III
pyrazoloacridinePfizerglioblastoma multiforme, gliomaPhase I
SDX-102
(l-alanosine)
Salmedixpreviously treated brain tumorsPhase I/II(see also lung, pancreatic, sarcoma)
Xcytrin(R)
motexafin gadolinium
Pharmacyclicsbrain metastases from non-small-cell lung cancer in combination with radiotherapyPhase III(see also kidney, leukemia, lung,lymphoma, multiple myeloma,solid tumors)
brain metastases in combination with whole brain radiation therapy and stereotactic radiosurgeryPhase II
malignant glioma in combination with Temodar(R)Phase I
Xerecept(TM)
corticotropin-releasing factor(CRF)
Neurobiological Technologiesreduction of brain edema associated with brain tumors (peritumoral brain edema)Phase III
Xinlay
atrasentan
Abbott Laboratories(see also kidney, lung,Phase II
(INDICATIONCHILD = ‘Astrocytoma’ OR INDICATIONCHILD = ‘Glioma’ OR INDICATIONCHILD = ‘Glioblastoma’ OR INDICATIONCHILD = ‘Germ cell and embryonal neoplasms’ OR INDICATIONCHILD = ‘Ependymoma’ OR INDICATIONCHILD = ‘Meningioma’ OR INDICATIONCHILD = ‘Medulloblastoma’ OR INDICATIONCHILD = ‘Brain cancer’ OR INDICATIONCHILD = ‘Brain metastases’)=272
163 filter active

■開発パイプライン(Glioma,Glioblastoma,Brain tumor)	/2011.10.1 by R&D Insight
製品名開発会社開発段階作用適応症備考
AC 480
(AC 480, AC480, BMS-599626, panHER )
Ambit Biosciences Corporation(Licensee World)
/Bristol-Myers Squibb(ORIGINATOR)
Phase-IIEpidermal growth factor inhibitors, ERBB4 protein inhibitors, HER2 inhibitors, HER3 inhibitorsBreast cancer(P1), Glioma(P1), Non-small cell lung cancer(P1), Solid tumours(P2) 
【メモ】Ambit Biosciences Corporation is developing AC 480 for the treatment of cancer. The pyrrolotriazine compound is a pan-HER inhibitor with activity against epidermal growth factor receptor (EGFR/ErbB1/HER1), as well as HER2 (ErbB2/neu), HER3, and HER4 (ErbB4) protein tyrosine kinases. EGFR and HER2 have been found to be frequently overexpressed in a variety of tumour types. AC 480 emerged from a collaborative research programme between Bristol-Myers Squibb (BMS) and Ambit Biosciences which was originally signed in January 2005; the kinase inhibitor was identified using Ambit's proprietary kinase profiling technology (KinomeScan™). KinomeScan™ is an innovative, high-throughput method for screening small molecule libraries against a large number of human kinases. Bristol-Myers Squibb, the originator of the compound, conducted several clinical trials of AC 480 in solid tumours. Ambit Biosciences is conducting clinical trials of intravenous and oral formulations in the US.
AEE 788
(AEE 788, AEE788, NVP AEE 788, NVP-AEE788 )
NovartisPhase-I/IIEpidermal growth factor receptor antagonists, HER2 inhibitors, Protein tyrosine kinase inhibitors, Vascular endothelial growth factor receptor-2 antagonistsGlioblastoma(P1/2), Solid tumours 
【メモ】AEE 788 is an orally available anticancer agent that is being developed by Novartis in collaboration with the University of Texas M. D. Anderson Cancer Center, USA. This small molecule acts as a reversible inhibitor of multiple tyrosine kinases, including EGFR (Epidermal growth factor receptor), HER2 (human epidermal growth factor receptor 2) and VEGFR2 (Vascular endothelial growth factor receptor 2). These receptor tyrosine kinases are involved in a number of processes contributing to the cancer cell phenotype, such as cell cycle deregulation and the establishment of tumour vasculature. Aberrant expression of these kinases is associated with advanced cancer and poor prognosis for a number of tumour types, such as breast, lung, ovarian, prostate and glioma. Clinical trials with AEE 788 have been completed in the US.

Glioblastoma: Novartis commenced a dose escalation phase I/II study (NCT00107237) to evaluate continuous oral dosing regimes of AEE 788 plus everolimus among patients with recurrent or relapsing glioblastoma multiforme (GBM) in the US. The study was discontinued due to safety data arising from dosing regimens of AEE 788 plus everolimus 1.

Afatinib
(Afatinib, BIBW 2992, BIBW2992, Tomtovok™, Tovok® )
Boehringer IngelheimPhase-IIIEpidermal growth factor receptor antagonists, HER2 inhibitorsBreast cancer(P3), Colorectal cancer, Glioblastoma(P1/2), Head and neck cancer(P2), Non-small cell lung cancer(P3), Prostate cancer, Solid tumours(P1) 
【メモ】
Aminolevulinic acid - DUSA
( ALA, 5-Aminolaevulinic acid, 5-Aminolevulinic acid, Aminolevulinic acid - DUSA, Delta-aminolevulinic acid, Levulan PDT, Levulan® PDT, Levulan®/Kerastick® )
DUSA Pharmaceuticals(Licensee World )
/PARTEQ Innovations(orignator)
MarketedPhotosensitisersActinic keratosis(米国発売), Brain cancer(米P2), Warts(米P1/2) 
【メモ】
Aminolevulinic acid - Medac
(Aminolevulinic acid - Medac, Gliolan )
MedacGlioma(EU承認2007)PhotosensitisersGlioma 
【メモ】Aminolevulinic acid hydrochloride was initially launched in 2000 in the U.S. as Levulan(TM) Kerastick for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp, used in conjunction with photodynamic therapy (PDT). In 2007, the product was approved in the E.U. for the visualization of malignant tissue during surgery for malignant glioma (WHO grade III and IV). Early clinical studies are ongoing at the University of Arkansas for the treatment of premalignant oral and/or oropharynx lesions and at Dusa for the oral treatment of leukoplakia. The National Cancer National Cancer Institute (NCI) is evaluating the product for imaging procedures used in finding residual tumor in patients with grade IV malignant astrocytoma who are undergoing surgery. Dusa is also conducting phase II clinical trials for the treatment of actinic keratosis in chronically immunosuppressed solid organ transplant recipients at high risk of developing non-melanoma skin cancer and for the reduction of non-melanoma skin cancer in chronically immunosuppressed solid organ transplant recipients.

When exposed to an appropriate light source, the compound is activated to destroy targeted cells via PDT with relatively minimal damage to surrounding tissue. Currently, aminolevulinic acid is in phase II clinical development at Dusa for the treatment of various conditions, including mild to moderate acne, high-grade dysplasia in Barrett's esophagus and facial photodamage. Phase I/II trials had been under way for the detection of bladder cancer, however, no recent development has been reported for this indication. Dusa had been developing aminolevulinic acid for the treatment of fungal infection and arterial restenosis. In 2006, the product was licensed to Stiefel for marketing in Central and South America as photodynamic therapy for the treatment of dermatology conditions. In 2007, the compound was granted orphan drug designation in the U.S. for the treatment of high-grade dysplasia in Barrett's esophagus patients. Orphan drug designation has also been received in the E.U. for the intra-operative photodynamic diagnosis of residual glioma.

Aminolevulinic acid - Nobelpharma
(5-ALA - Nobelpharma, Aminolevulinic acid - Nobelpharma, NPC 07, NPC-07 )
NobelpharmaPhase-IIIPhotosensitisersGlioma 
【メモ】
Amuvatinib
(Amuvatinib, HPK 56, HPK56, MP 470, MP470 )
Astex Pharmaceuticals, Inc(旧SuperGen,Inc)
/※2011.9.12社名変更
Phase-IIProtein tyrosine kinase inhibitors, Rad51 recombinase inhibitorsGlioblastoma(前臨床), Lymphoma(P1), Small cell lung cancer(P2), Solid tumours(P1) 
【メモ】
Antibody guided radioimmunotherapy - sigma-tau
(Antibody guided radioimmunotherapy - sigma-tau, Pre-targeted antibody guided radioimmunotherapy )
sigma-tau SpAPhase-IImmunomodulatorsGlioma, Non-Hodgkin's lymphoma 
【メモ】
Antineoplaston AS2-1
(Antineoplaston AS2-1, Antineoplastons therapy, AS2-1, Astugenal )
Burzynski Research InstitutePhase-IIApoptosis stimulants, Cell cycle inhibitorsCancer(P2), Glioma(P2) 
【メモ】The Burzynski Research Institute is developing certain compounds called antineoplastons for the treatment of cancer. Antineoplastons are naturally occurring peptides and amino acid derivatives originally isolated from human blood and urine by Dr Stanislaw Burzynski. It is hypothesised that these substances counteract the development of cancerous growth through a biochemical process which does not inhibit the growth of normal tissues. Injection formulation of a synthetic antineoplaston, called AS2-1 is in phase II clinical development in the US.

Phenylacetate (PN) and phenylacetylglutaminate (PG) are two major components of the antineoplaston AS2 1 and are metabolites of phenylbutyrate (PB). PN and PG are known to cause G1 arrest and apoptosis in several tumour cell lines. The effect is enhanced when PG and PN are used in combination, as in AS2 1.

In January 2009, the Burzynski Research Institute reached an agreement with the US FDA to enable the company to conduct a phase III trial of combination antineoplaston therapy plus radiation therapy in patients with newly-diagnosed, diffuse, intrinsic brainstem glioma. The agreement was made under the FDA's Special Protocol Assessment (SPA) procedure and means that the design and planned analysis of the phase III study is acceptable to support a regulatory submission seeking new drug approval. The primary objective of this study is to compare overall survival of children with newly-diagnosed diffuse intrinsic brainstem glioma (DBSG) who receive combination antineoplaston therapy (antineoplastons A10 and AS2-1) plus radiation therapy (RT) versus RT alone 1 2. However, as of May 2011, the trial had still not started.

A phase II clinical trial (BC-BT-23, NCT00003477) with antineoplaston A10 and antineoplaston AS2-1 therapy in children with optic pathway glioma has been conducted and positive results have been reported 3.

The Burzynski Research Institute is sponsoring several phase II clinical trials of different formulations of synthetic antineoplastons A10 and AS2-1 in capsules and injections. Positive results of the combination of A10 and AS2 1 in patients with malignant glioma have been reported 4 5 6.

Antineoplaston AS2-1 received orphan drug status in September 2004 from the FDA for the treatment of brain stem glioma. In 2008, US orphan drug designation was extended to include all gliomas 7 8.

APG 101
(APG 101, APG101, CD95-Fc fusion protein )
ApogenixPhase-IIApoptosis inhibitors, CD95 antigen inhibitorsGlioblastoma, Graft-versus-host disease, Myocardial infarction, Stroke 
【メモ】
AR 67
((20S)-7-t-Butyldimethylsilyl-10-hydroxycamptothecin, AR 67, AR-67, D 67, DB-67, DB67 )
University of PittsburghPhase-IIDNA topoisomerase I inhibitorsGlioblastoma, Myelodysplastic syndromes, Solid tumours 
【メモ】
ARC 100
(ARC 100, NBT 287, TPI 287, TPI-287 )
Tapestry PharmaceuticalsPhase-IITubulin polymerisation inhibitorsBreast cancer, Cancer, Glioblastoma, Malignant melanoma, Medulloblastoma, Neuroblastoma, Pancreatic cancer, Prostate cancer 
【メモ】
Arsenic trioxide
(Arsenic trioxide, Trisenox® )
CephalonMarketedApoptosis stimulantsAcute lymphoblastic leukaemia(欧発売), Acute myeloid leukaemia(米加P3), Acute promyelocytic leukaemia(日米欧発売), Glioma(米P1), Multiple myeloma(米P2), Myelodysplastic syndromes(伊P1) 
【メモ】
AT 101
((-)-gossypol, AT 101, AT-101, R-(-)-gossypol acetic acid )
National Institutes of Health (USA)Phase-IIApoptosis stimulants, Proto-oncogene protein c-bcl-2 inhibitorsChronic lymphocytic leukaemia, Glioblastoma, Non-Hodgkin's lymphoma, Non-small cell lung cancer, Oesophageal cancer, Prostate cancer, Small cell lung cancer 
【メモ】
AT 9283Astex TherapeuticsPhase-IIAurora kinase A inhibitors, Aurora kinase B inhibitors, Bcr-abl tyrosine kinase inhibitors, Janus kinase-2 inhibitors, Mitosis inhibitors, STAT3 transcription factor inhibitorsAcute myeloid leukaemia, Medulloblastoma, Multiple myeloma, Myelofibrosis, Non-Hodgkin's lymphoma, Solid tumours 
【メモ】AT9283 is a small molecule inhibitor of kinases including aurora A and B, and JAK2. Initial clinical trials have demonstrated early signals of efficacy in patients with hematological malignancies.

AT9283 has been investigated as monotherapy in patients with advanced solid tumors in two phase 1, open-label, dose-escalation trials at centers in the UK, USA and Canada. The two trials confirmed AT9283 is safe and well tolerated in patients with advanced solid malignancies. Oral bioavailability of AT9283 in humans has also been demonstrated. In conjunction with Cancer Research UK, Astex Pharmaceuticals™ is also investigating the activity of single agent AT9283 in pediatric patients with solid tumors in a trial being conducted at multiple sites in the UK.

Atrasentan
(A 147627, A 147627-1, A-1476271, Abbott 147627, ABT 147627, ABT 627, Atrasentan, Atrasentan hydrochloride, Xinlay™ )
Abbott LaboratoriesPhase-IIEndothelin A receptor antagonistsDiabetic nephropathies 
【メモ】
Bafetinib
(Bafetinib, BCR-ABL/Lyn Kinase Inhibitors, INNO 406, INNO-406, NS 187, NS-187 )
Nippon ShinyakuPhase-IIApoptosis stimulants, Bcr-abl tyrosine kinase inhibitors, Lyn protein-tyrosine kinase inhibitors, Osteoclast inhibitorsAcute lymphoblastic leukaemia, Bone resorption, Brain cancer, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia, Prostate cancer 
【メモ】
Bavituximab
(3G4, Anti-PS MAb 3G4, Bavituximab, Tarvacin™)
Peregrine PharmaceuticalsPhase-IIAngiogenesis inhibitors, Immunostimulants, Phosphatidylserine receptor antagonistsBrain cancer, Breast cancer, Hepatitis C, HIV infections, Liver cancer, Non-small cell lung cancer, Pancreatic cancer, Prostate cancer, Solid tumours, Viral haemorrhagic fevers 
【メモ】Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.

Research has shown that chemotherapy and radiation increase the exposure of PS on the surface of the tumor blood vessels, increasing the availability of bavituximab's target molecule, and potentially enhancing bavituximab's anti-tumor activity.

Belagenpumatucel-L
(Belagenpumatucel-L, Glionix, Lucanix®)
Sidney Kimmel Comprehensive Cancer Center
at Johns Hopkins
Phase-IIIImmunostimulantsGlioma, Non-small cell lung cancer 
【メモ】
Berubicin
(Berubicin, Berubicin (B), Berubicin hydrochloride, Reata 744, RTA 744, RTA744, WP744 )
Reata PharmaceuticalsPhase-IIType II DNA topoisomerase inhibitorsBrain cancer, Glioma, Neoplastic meningitis 
【メモ】
Bevacizumab
(Avastin®, Bevacizumab, R 435, R435, RG435, rhuMAb-VEGF )
GenentechMarketedVascular endothelial growth factor A inhibitorsBrain metastases, Breast cancer(EU承認2007;日本発売2011), Cancer, Carcinoid tumour, Cervical cancer, Colorectal cancer(EU承認2005;日本発売2007), Diffuse large B cell lymphoma, Gastric cancer, Glioblastoma(米国発売2009;EU申請中), Haemangiosarcoma, Head and neck cancer, Liver cancer, Malignant melanoma, Mesothelioma, Multiple myeloma, Non-Hodgkin's lymphoma, Non-small cell lung cancer(EU承認2007;日本発売2009), Ovarian cancer, Rectal cancer, Renal cancer(EU発売2007), Solid tumours 
【メモ】Brain cancer and brain metastases: bevacizumab was evaluated in a phase II clinical trial in combination with first- or second-line therapy in subjects with metastatic non-squamous NSCLC with previously treated CNS metastases. One-hundred and fifteen patients were enrolled in the US (PASSPORT; NCT00312728) 42.

In March 2009, the EMA removed the restriction in the product label of bevacizumab which prevented the use of the drug in patients with untreated brain metastases 43.

BEZ 235
(BEZ 235, BEZ235, NVP BEZ-235, NVP BEZ235, NVP-BEZ-235, NVP-BEZ235 )
NovartisPhase-I/II1 Phosphatidylinositol 3 kinase inhibitors, 3 phosphoinositide dependent protein kinase 1 inhibitors, 3-phosphoinositide dependent-protein-kinase-inhibitors, Apoptosis stimulants, MTOR protein inhibitorsGlioblastoma, Haematological malignancies, Non-small cell lung cancer, Renal cancer, Solid tumours 
【メモ】
Brain cancer vaccine - Northwest Biotherapeutics
(Brain cancer vaccine - Northwest Biotherapeutics, DCVax®-Brain, DCVax-Brain, DCVax-Brain personalised immune therapy - Northwest Biotherapeutics )
Northwest BiotherapeuticsPreregistrationDendritic cell stimulants, ImmunostimulantsGlioblastoma 
【メモ】DCVax(R)-Brain is an autologous cellular therapy developed by Northwest Biotherapeutics which had been filed for regulatory approval in Switzerland for the treatment of newly diagnosed glioblastoma multiforme (GBM). However, no recent development has been reported for this filing. The company is conducting phase II clinical trials for GBM in the U.S. Delivered as an injection, the dendritic cell-based immunotherapy is designed to create a specific immune response against a patient's cancer. Orphan drug designation was assigned to the therapy in the U.S. in 2002.
Brain Cancer Vaccine - Stemline Therapeutics
(Brain Cancer Vaccine - Stemline Therapeutics, SL 701, SL-701 )
University of PittsburghPhase-I/IIImmunostimulantsGlioma 
【メモ】
Cabozantinib
(BMS 907351, BMS-907351, Cabozantinib, XL 184, XL184 )
ExelixisPhase-IIIProto oncogene protein c met inhibitors, Proto oncogene protein c ret inhibitors, Proto oncogene protein c-kit inhibitors, Vascular endothelial growth factor receptor-2 antagonistsCancer, Non-small cell lung cancer(P1/2), Ovarian cancer(P2), Prostate cancer(P2), Renal cancer, Solid tumours(P1), Thyroid cancer(P3), Glioblastoma(P2中断) 
【メモ】
Cancer gene therapy - Advantagene
(Cancer gene therapy - Advantagene, Gene Mediated Cytotoxic Immunotherapy, GliAtak™, PancAtak™, ProstAtak™, TKR therapy - Advantagene )
AdvantagenePhase-IIIThymidine kinase stimulantsBrain cancer(P1), Glioma(P2), Pancreatic cancer(P1), Prostate cancer(P3) 
【メモ】Advantagene, a US based company, is developing a proprietary method of administering cancer-suicide gene-therapy for the treatment of primary and metastatic disease. The therapy, named Gene Mediated Cytotoxic Immunotherapy™ (GMCI™) involves the local delivery of an adenoviral vector with the Herpes thymidine kinase gene (AdV-tk) in combination with radiation therapy, and an oral anti-herpetic prodrug. The orally administered prodrug is self administered on an outpatient basis. The therapy is given different names: ProstAtak™ for prostate cancer, GliAtak™ for malignant glioma, and PancAtak™ for pancreatic cancer. ProstAtak™ is in a pivotal phase III study in the US. GliAtak™ is in phase II and PancAtak™ is in phase I development.

Preclinical studies evaluating the use of AdV-tk in conjunction with radiotherapy have led to the discovery of their synergistic effects with standard anti-cancer therapy. Among the discoveries were the increased local and systemic anti-tumour effects when HSV-tk gene therapy is combined with radiation therapy.

Cancer vaccine - GreenPeptide
()
GreenPeptide(Collaborator World )/Kurume University(Originator)Phase-I/IIImmunostimulantsBrain cancer(P1/2), Prostate cancer(P1/2) 
【メモ】GreenPeptide of Fukuoka (Japan) is developing a personalised peptide vaccine for human leucocyte antigens (HLA)-A2-positive advanced cancer. The vaccine was originated by researchers at Kurume University in Fukuoka, and is administered by subcutaneous injection. Phase I/II clinical trials are in progress in Japan for the treatment of HLA-A24-positive malignant brain tumour and advanced hormone-refractory prostate cancer.

The personalised vaccine process involves selecting high-response peptides for each patient by determining the specific immune response to all the available peptide vaccine candidates. A personalised vaccine is thereby optimised for each patient; the therapy can be performed in an outpatient clinic.

The results of a phase I/II clinical trial of GreenPeptide's personalised peptide vaccine in patients with advanced cancer who were HLA-A2 positive were reported at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO-2008) 1.

Cancer vaccine - Trimed Biotech GmbH
()
Trimed BiotechPhase-IIImmunostimulantsGlioblastoma, Renal cancer 
【メモ】
Capecitabine
(Capecitabine, R340, RG 340, RG340, RO 091978, Xeloda®)
RocheMarketedThymidylate synthase inhibitorsBiliary cancer(米P2), Breast cancer(米欧発売), Cervical cancer, Colorectal cancer(日米欧発売), Gastric cancer(日欧承認), Glioma(米P1), Nasopharyngeal cancer, Oesophageal cancer, Pancreatic cancer(韓国承認), Rectal cancer 
【メモ】
Carmustine polifeprosan 20 wafer
(BCNU, BIODEL carmustine, Carmustine BIODEL, Carmustine polifeprosan 20 wafer, Gliadel®, Gliadel® Wafer, NPC-08, NSC 409962, WR 139021 )
Eisai Co Ltd(Licensee World)
/Massachusetts Institute of Technology(Originator)
MarketedDNA inhibitorsGlioma 
【メモ】
CC 8490Celgene CorporationPhase-IIUndefined mechanismGlioblastoma 
【メモ】
Cediranib
(AZD 2171, AZD2171, Cediranib, Recentin™ )
AstraZenecaPhase-IIIVascular endothelial growth factor receptor 3 antagonists, Vascular endothelial growth factor receptor-1 antagonists, Vascular endothelial growth factor receptor-2 antagonistsAcute myeloid leukaemia(P2), Biliary cancer(P2), Breast cancer(P2), Cervical cancer(P2), Non-small cell lung cancer(P2/3), Ovarian cancer(P3), Renal cancer(P2), Soft tissue sarcoma(P2), Solid tumours(P1) 
【メモ】
Cilengitide
(EMD 121974, EMD 85189 )
Merck KGaA
/The Scripps Research Institute
Phase-IIIIntegrin alphaVbeta3 antagonists, Integrin alphaVbeta5 antagonistsGlioblastoma(P3), Head and neck cancer(P2), Non-small cell lung cancer(P2) 
【メモ】Cilengitide, an angiogenesis inhibitor targeting alpha-v integrins, was initially developed at Merck KGaA in collaboration with the Technical University of Munich. EMD Pharmaceuticals, an affiliate of Merck KGaA, is currently conducting phase III clinical trials of cilengitide in the treatment of glioblastoma multiforme in collaboration with the National Cancer Institute (NCI). The NCI is also sponsoring several clinical trials for the treatment of lymphoma (phase I), and prostate cancer (phase II) under a Cooperative Research & Development Agreement (CRADA) for the compound's development. Merck KGaA is conducting phase II clinical studies for the treatment of non-small cell lung cancer and for the treatment of cancer, head and neck (squamous cell carcinoma). Cilengitide received orphan drug designation in the E.U. and the U.S. for the treatment of glioma in 2004 and 2005, respectively.
Cintredekin besudotox
(hIL13-PE38QQR, IL13-PE38, IL13-PE38QQR, Interleukin-13-PE38QQR, NK 408, NK408 )
NeoPharm(Licensee)/National Institutes of Health (USA)(originator)Phase-IApoptosis stimulantsGlioblastoma multiforme(P3), Glioma(P1/II),Astrocytoma, anaplastic(P1), Pulmonary fibrosis(IND Filed) 
【メモ】Cintredekin besudotox is an immunotoxin at NeoPharm (US) in phase III trials for the treatment of glioblastoma multiforme, in phase I/II trials for the treatment of malignant glioma in children, and in phase I trials for the treatment of anaplastic astrocytoma in combination with radiation therapy with or without temozolomide. Preclinical studies are under way at NeoPharm for the treatment of idiopathic pulmonary fibrosis (IPF). An IND was filed for this indication in 2010. No recent development has been reported for preclinical studies for the treatment of asthma.

The drug is a recombinant protein consisting of the tumor targeting molecule interleukin-13 (IL-13) and the cytotoxic agent Pseudomonas exotoxin (PE). It has been shown to demonstrate potent cytotoxicity against malignant glioma cells expressing the IL-13 receptor. Healthy brain cells appear to be unharmed since they do not have this receptor. Convection enhanced delivery (CED) of cintredekin besudotox has shown evidence of a selective antitumor effect in the tumor-infiltrated white matter of the brain.

Originally developed at the National Institutes of Health and the University of Pennsylvania, NeoPharm obtained an exclusive, worldwide license to the compound in October 1997. In January 2004, Nippon Kayaku signed an exclusive license agreement with NeoPharm for the Japanese development rights to cintredekin besudotox→日本化薬はP1開発中止. Diosynth was chosen by NeoPharm to manufacture clinical quantities of the drug candidate for their phase III trials in April 2004. In 2007, this licensing agreement was terminated. Cintredekin besudotox was granted orphan drug status from the FDA in November 2001 for the treatment of malignant glioma and from the EMEA in late April 2002. Fast track status was also received from the FDA in May 2002. In 2010, orphan drug designation was assigned by the FDA for the treatment of idiopathic pulmonary fibrosis. The compound has also been studied for the treatment of renal cell carcinoma.

Cositecan
(BNP Karenitecin, BNP1350, Cositecan, Karenitecin®)
BioNumerik PharmaceuticalsPhase-IIIDNA topoisomerase inhibitorsBrain cancer(P2), Malignant melanoma(P2), Non-small cell lung cancer(P1/2), Ovarian cancer(P3), Solid tumours(P1) 
【メモ】
Crenolanib
(ARO 002, ARO-002, CP 868, 596, CP 868-596, CP 868596, CP-868, 596, CP-868-596, CP-868596, Crenolanib, Crenolanib besylate )
PfizerPhase-IIPlatelet-derived growth factor inhibitors, Platelet-derived growth factor receptor antagonists, Signal transduction pathway inhibitorsCancer, Gastrointestinal stromal tumours, Glioma 
【メモ】
CVA 21
(Cavatak™, Coxsackievirus A21)
ViroTargPhase-ICD55 antigen inhibitors, Cell death stimulants, Intercellular adhesion molecule 1 antagonistsBladder cancer, Breast cancer, Glioma, Head and neck cancer, Lung cancer, Malignant melanoma, Multiple myeloma, Pancreatic cancer, Prostate cancer 
【メモ】
Cytosine deaminase gene therapy - Tocagen
(Toca 511, Toca-511 )
TocagenPhase-I/IIGene transferenceGlioblastoma 
【メモ】Tocagen is developing a cytosine deaminase gene therapy, called Toca 511, for the treatment of brain cancer. Toca 511 is a modified live virus-based replication-competent retroviral vector engineered to deliver a modified cytosine deaminase (CD) prodrug activating gene to glioma cells. CD converts prodrug flucytosine to anticancer 5-fluorouracil intratumourally. A phase I/II trial of Toca 511 is in progress in the US.

Tocagen used its Controlled Active Gene Transfer Technology (CAGT™) platform to develop Toca 511. The CAGT virus selectively multiplies in cancer cells sparing the healthy ones.

Key Development Milestones Tocagen initiated a phase I/II trial to assess the safety and tolerability of single, ascending doses of Toca 511 in patients with recurrent glioblastoma multiforme (GBM) who have undergone surgery, radiation therapy and chemotherapy with temozolomide (NCT01156584). The trial will enrol 30 patients in the US. The study comprises two parts: in the first part, subjects will receive a single, transcranial, intratumoural injection of Toca 511, followed by cyclic treatment with 5-flucytosine; in the second part, additional subjects will receive Toca 511 at the maximum tolerated dose determined in the first part, followed by cyclic treatment with 5-flucytosine.
In June 2011, Tocagen reported that the trial would include patients with recurrent high grade glioma, such as those with glioblastoma multiforme grade IV 1.

Tocagen also plans to develop the gene therapy in primary GBM and inoperable brain tumours. Positive results from a preclinical study of Toca 511 were reported in June 2010 2.

DA 3607Dong-A PharmaceuticalPhase-ITNF related apoptosis inducing ligand stimulantsBrain cancer 
【メモ】
Dabrafenib
(2118436, B-RafV600E inhibitor, Dabrafenib, GSK 2118436, GSK2118436, GSK2118436A )
GlaxoSmithKlinePhase-IIIProto oncogene protein b raf inhibitorsBrain metastases(P2), Malignant melanoma(P3), Non-small cell lung cancer(P2), Solid tumours(P1/2) 
【メモ】GlaxoSmithKline is developing dabrafenib, an orally-administered compound that emerged from a research programme focussed on discovering selective inhibitors of B-raf kinase activity based on the mutant BRAF kinase gene as a target for the treatment of solid tumours, particularly malignant melanoma and non-small cell lung cancer. Mutations in the BRAF gene are associated with increased growth and proliferation of cancer cells. GlaxoSmithKline is focussing on malignant melanoma as BRAF mutations are present in 50% of these cancers. Phase III development is underway in the treatment of malignant melanoma, and phase II development is underway in the treatment of malignant melanoma that has metastasised to the brain. Phase II development is planned in non-small cell lung cancer.

Brain metastases: a phase II trial (Break MB) in patients with BRAF mutant melanoma that has metastasised to the brain was initiated in February 2011 (NCT01266967). Enrolment of approximately 142 patients has been completed in the US, Canada, Australia, France, Germany and Italy 4.

Dasatinib
(BMS 354825, BMS-354825, Dasatinib, Sprycel® )
Bristol-Myers SquibbMarketedBcr-abl tyrosine kinase inhibitors, EphA2 receptor antagonists, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c-kit inhibitors, Src-Family kinase inhibitorsAcute lymphoblastic leukaemia(米欧発売), Breast cancer(P2), Chronic lymphocytic leukaemia(P2), Chronic myeloid leukaemia(日米欧発売), Colorectal cancer, Glioblastoma(P1/2), Leukaemia, Malignant melanoma, Mesothelioma, Multiple myeloma, Myelodysplastic syndromes(P2), Non-Hodgkin's lymphoma, Non-small cell lung cancer(P2), Pancreatic cancer(P2), Prostate cancer(P3), Scleroderma 
【メモ】
Dendritic cell vaccines/immunotherapies (CreaVax) - CreaGene
(CreaVax-HCC Inj., CreaVax-HCC®, CreaVax-PC Inj., CreaVax-PC®, CreaVax-RA Inj., CreaVax-RCC Inj., CreaVax-RCC®, Dendritic cell vaccine for glioblastoma multiforme - CreaGene, Dendritic cell vaccines/immunotherapies (CreaVax) - CreaGene, Renal cell carcinoma vaccine - CreaGene/Dong-A )
Creagene[韓国]MarketedImmunomodulatorsGlioblastoma(韓国Preclinical), Liver cancer(韓国P2), Prostate cancer(韓国P1/2), Renal cancer(韓国発売), Rheumatoid arthritis(韓国P1) 
【メモ】
E 7016MGI GPPhase-IPoly(ADP-ribose) polymerase inhibitorsGlioma, Solid tumours 
【メモ】
EGEN 001
(IL-12 gene therapy - Expression Genetics, Interleukin-12 gene therapy - Expression Genetics, phIL-12-005/PPC)
Expression GeneticsPhase-IIImmunostimulants, Interleukin 12 stimulantsColorectal cancer(P1/2), Fallopian tube cancer(P2), Glioblastoma(前臨床), Ovarian cancer(P2), Peritoneal cancer(P2) 
【メモ】EGEN is developing EGEN 001, an anticancer immunotherapy product composed of an interleukin-12 (IL-12) gene expression plasmid and a biocompatible delivery polymer, for the treatment of various tumour types. EGEN 001 is designed for intraperitoneal delivery into the local tumour environment. Ovarian cancer will be the indication of initial focus and development is at the phase II stage in the US. Preclinical evaluation is ongoing for other solid tumour indications.

EGEN 001 utilises the company's proprietary TheraPlas™ delivery technology and is designed to increase the local concentration of IL-12, a potent anticancer cytokine. The TheraPlas™ technology platform is a non-viral polymeric-based system for delivery of nucleic acids to cells. Preclinical studies have shown that this strategy is safe for repeated administration as a monotherapy and also in combination with standard chemotherapy.

Glioblastoma: in September 2011, EGEN entered into a colaboration with the National Cancer Institute′s Nanotechnology Characterization Laboratory to characterise the behaviour of EGEN 001 in preclinical models of brain cancer. Following characterisation, EGEN plans to initiate phase I development in glioblastoma 2 3.

Enzastaurin
(LY 317615, LY-317615 )
Eli LillyPhase-III1 Phosphatidylinositol 3 kinase inhibitors, Protein kinase C beta inhibitorsBrain cancer(P2), Breast cancer(P2), Colorectal cancer(P2), Diffuse large B cell lymphoma(P3), Follicular lymphoma(P2), Glioblastoma(P2), Lung cancer prevention(P2), Multiple myeloma(P2), Non-Hodgkin's lymphoma(P2), Non-small cell lung cancer(P2), Ovarian cancer(P2), Prostate cancer(P2), Renal cancer(P2), Waldenstrom's macroglobulinaemia(P2) 
【メモ】Enzastaurin is an oral serine-threonine kinase inhibitor that appears to attack tumours in three ways: by reducing tumour cell proliferation, increasing apoptosis of tumour cells, and inhibiting angiogenesis in the tumour. Data have suggested enzastaurin achieves this via inhibiting the PKC-β and PI3K/AKT signaling pathways. Eli Lilly is conducting a phase III trial of enzastaurin as a maintenance therapy to prevent relapse in patients with diffuse large B-cell lymphoma, the most common form of non-Hodgkin's lymphoma. The drug is also in a phase III clinical trial in patients with glioblastoma. In addition, Eli Lilly is supporting phase II trials with enzastaurin, either alone or in combination with other therapeutics, for the treatment of various cancers.

Brain metastases: in January 2011, Eli Lilly completed a phase II trial (NCT00415363) to investigate enzastaurin in patients with brain metastases from lung cancer. This randomised, double-blind placebo controlled trial enrolled 107 patients who had completed whole brain radiotherapy, in Europe. The primary endpoint was time to worsening of brain metastases 1.

Erlotinib
(CP 358774, Erlotinib, NSC 718781, OSI 774, R1415, RG 1415, RG1415, Tarceva® )
OSI Pharmaceuticals(Originator)
/Roche(Licensee World)
MarketedEpidermal growth factor receptor antagonistsBladder cancer(P2), Brain metastases(P2), Breast cancer(P2), Cancer metastases, Colorectal cancer(P3), Ependymoma(P2), Glioblastoma(P2), Gynaecological cancer, Head and neck cancer(P2), Liver cancer(P3), Myelodysplastic syndromes(P2), Non-small cell lung cancer(日米欧発売), Pancreatic cancer(日米欧発売), Squamous cell cancer 
【メモ】Glioma, glioblastoma and ependymoma: a phase I/II trial of erlotinib in patients with recurrent/residual glioblastoma multiforme and anaplastic astrocytoma was initiated in the US in March 2006 (NCT00301418). The open-label trial, conducted by Genentech in collaboration with the Weill Medical College of Cornell University, will assess the safety and efficacy of twice daily erlotinib 150 mg, for 12 months.

Genentech is conducting phase II trials evaluating erlotinib and temozolomide in combination with radiation therapy in patients with glioblastoma multiforme (NCT00535249, NCT00720356). OSI Pharmaceuticals and Genentech have initiated a phase II clinical trial of erlotinib in combination with sirolimus (NCT00672243). Genentech has also initiated a phase II trial of erlotinib in combination with bevacizumab (NCT00671970).

OSI Pharmaceuticals is evaluating erlotinib versus etoposide in a phase II trial in patients with recurrent or refractory paediatric ependymoma (NCT01032070). Approximately 40 subjects will be randomised 1:1 to receive single-agent erlotinib or oral etoposide. Patient recruitment is ongoing in the US, Canada, and the UK. An extension trial is enrolling patients who were assigned to the etoposide arm in the previous study by invitation (NCT01247922). The open-label study aims to assess the safety profile of single-agent erlotinib in patients with recurrent or refractory paediatric ependymoma 53.

The US FDA has granted erlotinib orphan drug status for the treatment of malignant glioma 54.

Everolimus
(Absorb™, Afinitor®, Certican®, Everolimus, Promus Element™, Promus™, RAD, RAD 001, RAD001, SDZ RAD, Votubia™, Xience Nano™, Xience Prime™, Xience V®, Zortress™)
NovartisMarketedB cell inhibitors, MTOR protein inhibitors, T lymphocyte inhibitorsAngiomyolipoma, Astrocytoma[米国発売2010,EU承認2011], Breast cancer, Colorectal cancer, Coronary artery restenosis, Diffuse large B cell lymphoma, Gastric cancer, Gastrointestinal stromal tumours, Head and neck cancer, Heart transplant rejection(発売2004), Hodgkin's disease, Liver cancer, Liver transplant rejection, Lung transplant rejection, Mantle-cell lymphoma, Neuroendocrine tumours, Pancreatic cancer(発売2011), Polycystic kidney disease, Renal cancer(発売2009), Renal transplant rejection(発売2004), Urogenital cancer 
【メモ】Astrocytomas: everolimus was approved and launched in the US for the treatment of subependymal giant cell astrocytomas (SEGAs) in patients (children and adults) with tuberous sclerosis in October 2010, following priority review by the US FDA 79 80 81. The product was approved in Canada in this indication in patients aged 3 years and older in September 2011 82.

In September 2011, the European Commission approved everolimus for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) 83. Novartis submitted an MAA to the EMA for approval in this indication in July 2010. The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion with a recommendation for approval in June 2011 84. A submission for TS complex angiomyolipoma is planned for 2011 81. Submissions were based on results from a phase II trial in patients aged three years and above, in which a meaningful reduction in tumour size was observed in 75% of patients with subependymal giant cell astrocytomas (SEGAs) associated with TS after treatment with everolimus 85 86. These results were published in the New England Journal of Medicine in November 2010 87.

In May 2011, the Swiss Agency for Therapeutic Products approved everolimus for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS), for whom surgery is not a suitable option. The submission was based on results from a phase II trial in patients aged 3 years and above, in which a meaningful reduction in tumour size was observed in 75% of patients with SEGAs associated with TS after treatment with everolimus 88.

Regulatory approvals have also been granted in this disease setting in Brazil, Guatemala and the Philippines 88.

Everolimus has received orphan drug status in the US and EU for use in patients with SEGA associated with TS 81.

The phase III EXIST-1 trial evaluated everolimus in patients with SEGAs associated with TS (NCT00789828) 89. The primary endpoint was met 90.

F-18-fluorothymidine - National Cancer InstituteNational Cancer Institute (USA)Phase-IIBreast cancer, Glioma 
【メモ】
Ficlatuzumab
(AV-299, AV299, Ficlatuzumab, SCH 900105, SCH-900105 )
AVEO PharmaceuticalsPhase-IIHepatocyte growth factor inhibitors, Proto oncogene protein c met inhibitorsGlioblastoma(P1), Lymphoma(P1), Multiple myeloma(P1), Non-small cell lung cancer(P2), Solid tumours(P1) 
【メモ】
Gefitinib
(Gefitinib, Iressa®, ZD 1839, ZD1839 )
AstraZenecaMarketedEpidermal growth factor receptor antagonistsBladder cancer(P2), Glioblastoma(P2), Head and neck cancer(P1), Non-small cell lung cancer(日米欧発売) 
【メモ】
Glembatumumab vedotin
(CDX 011, CDX-011, CR 011 ADC, CR 011-vcMMAE, CR011, CR011 ADC)
Celldex Therapeutics(旧CuraGen Corporation)Phase-IIApoptosis stimulants, Tubulin polymerisation inhibitorsBrain cancer(前臨床), Breast cancer(P2), Malignant melanoma(P2) 
【メモ】Glembatumumab vedotin is an antibody-drug conjugate (ADC) being developed by Celldex Therapeutics (formerly CuraGen Corporation), for the treatment of cancers; particularly breast cancer, melanoma and brain cancer. Glembatumumab vedotin consists of a fully human monoclonal antibody (CR 011) conjugated to the highly cytotoxic agent, monomethyl auristatin E (MMAE), via a valine-citrulline dipeptide linker. MMAE is a derivative of the tubulin modifying agent, auristatin E. Following intravenous (IV) administration, glembatumumab targets and binds to GPNMB, a membrane glycoprotein predominantly expressed on the surface of melanoma cells. After internalisation into the target cell, intracellular enzymes cleave MMAE from the IgG2 antibody releasing the activated cytotoxic auristatin E. Release of MMAE into the cytosol induces G2/M-phase growth arrest and apoptosis. Glembatumumab vedotin is in phase II development in the US for the treatment of melanoma and breast cancer. Preclinical studies are ongoing for glembatumumab vedotin in the treatment of brain cancer.

In October 2009, CuraGen Corporation was acquired by Celldex Therapeutics 1.

Glembatumumab vedotin was developed under a research programme between CuraGen and Amgen (formerly Abgenix) [see separate profile]. The fully-human monoclonal antibody was generated using Xenomouse® technology from Abgenix. ADC technology was licensed from Seattle Genetics covering the MMAE component with a stable linker system for attaching it to CR011 2.

In June 2004, CuraGen licensed Seattle Genetics' proprietary ADC technology for use with one of its antibodies, CR 011, in cancer treatment. Seattle Genetics received an upfront technology access fee of $US2.0 million and CuraGen will pay ongoing technology access and material supply fees. In addition, CuraGen has also agreed to make progress-dependent milestone payments and pay royalties on net sales of ADC products 3 4.

Glioblast-13TargepeuticsPreclinicalUndefined mechanismColorectal cancer, Glioma, Head and neck cancer, Malignant melanoma 
【メモ】
Glioma stem cell therapy - Cellonis BiotechnologiesCellonis BiotechnologiesPhase-IImmunostimulantsGlioma 
【メモ】
GRN 1005
(ANG 1005, ANG-1005, ANG1005, AngioPep1)
AngioChemPhase-I/IIMitosis inhibitors, Tubulin inhibitors, Tubulin polymerisation promotersBrain cancer, Glioma 
【メモ】カナダAngioChem社は、2008年10月22日、同社の製品候補のなかで最も開発が進んでいるANG1005の前臨床試験結果と臨床試験の予備的な結果をスイスで開催された第20回EORTC-NCI-AACRシンポジウムで発表した。いずれも、この薬剤の有用性と安全性、忍容性を示唆したという。

 通常は、95%を越える薬剤が血液脳関門により脳への侵入を阻害される。ゆえに、これまでは脳への薬剤送達は難しかった。そこで同社はペプチドベクターAngiopepを開発。このベクターは、薬剤の血液脳関門通過を容易にする。ANG1005は、Angiopepとパクリタキセルを結合した薬剤だ。Angiopepを利用した送達技術は、ぺプチドやモノクローナル抗体、siRNA、その他の生物製剤など、様々な薬剤の脳への送達に適用できると期待されている。

 学会発表された前臨床試験結果は2件だ。

 1件めは、マウスとラットを使った実験の結果で、ANG1005が血液脳関門を通過すること、脳内の濃度はフリーのパクリタキセルを投与した場合に比べ約100倍、グリオーマ治療薬として2006年に日本でも承認されたテモゾロミド(現時点では唯一の原発性脳腫瘍治療薬)に比べ約10倍高いことを示した。ANG1005はマウスのグリオブラストーマ・モデルの生存期間を27%延長し、ラットの腫瘍に有意な縮小をもたらしたという。

 2件めは、癌細胞株とマウス・モデルを用いて行った前臨床試験の結果だ。ANG1005はパクリタキセルと同様の抗腫瘍効果を示すこと、脳腫瘍の増殖を有意に遅らせることを示した。

 米国で現在進行中の2件のフェーズ1/2用量漸増試験の予備的な結果も報告された。どちらの試験も30人の患者を登録、ANG1005を21日ごとに1時間かけて注入している。

 両試験ともに主要エンドポイントは、安全性、忍容性の評価と、最大耐用量の決定にある。2次エンドポイントは薬物動態学的特性の分析、予備的な有効性評価などに設定されている。主な結果は2008年末に得られる見込みだ。

 1件めは、再発性グリオブラストーマの治療を目指す試験で、これまでに治療を受けた12人の患者においてANG1005の安全性と忍容性が示されているという。治療後に切除された腫瘍組織を対象にANG1005の濃度測定も行われる予定だ。

 2件めは、固形癌の脳転移の治療を目的とするもの。これまでに治療が行われた22人の患者に関するデータが報告された。500mg/m2までは安全で忍容性が高いことが示されている。 from ペプチドベクターを使う脳腫瘍治療薬ANG1005の開発が進展【EORTC-NCI-AACR2008】[癌Expertsニュース2008. 10. 24]

HSV 1716
(Herpes simplex virus 1716 - Crusade, Herpes simplex virus-1 - Crusade, HSV 1716, HSV1716, Seprehvir )
英国Crusade LaboratoriesPhase-IIIImmunomodulatorsGlioblastoma(P3), Head and neck cancer(P1), Malignant melanoma(P1) 
【メモ】Crusade Laboratories in Glasgow, Scotland is developing a modified herpes simplex virus, HSV 1716, for the potential treatment of cancer, in particular CNS tumours. The company has conducted phase I trials that have revealed that the virus was completely non-toxic in patients with glioblastomas and HSV 1716 prolonged patient survival. Phase I studies in patients with advanced melanoma and squamous cell carcinoma of the head and neck have also been completed. HSV 1716 is undergoing phase III development in Europe.

The HSV1 virus is well-known for causing cold sores and, when it infects the brain, it replicates rapidly and can cause encephalitis. Crusade has removed a single gene from HSV1, ICP34.5, which is responsible for virus replication, to create HSV 1716. Removal of this gene ensures that HSV 1716 is unable to replicate in healthy cells and is only able to replicate in rapidly dividing tumour cells. The explosive replication of the virus in these cells results in tumour cell death in preclinical animal model systems, and prompted Crusade to test HSV 1716 in the clinic in patients with glioma. Crusade has evaluated HSV 1716 in 45 patients with glioblastomas.

A phase I trial (NCT00931931) of HSV 1716 is being conducted by the Children's Hospital Medical Center, Cincinnati, in collaboration with the US FDA Office of Orphan Products Development. This trial was initiated in March 2010 and aims to investigate the safety of a single HSV 1716 injection in adolescents and young adults with non-central nervous system solid tumours. This study will enrol approximately 18 adolescents and young adults (aged 13 to 30 years) in the US. The expected completion date of the trial is October 2012 1.

ICT 107
()
ImmunoCellular TherapeuticsPhase-IIImmunostimulants, T lymphocyte stimulantsGlioblastoma 
【メモ】
ICT 111
(Cancer stem cell antigen vaccine)
ImmunoCellular TherapeuticsPreclinicalImmunostimulants, Stem cell inhibitorsGlioblastoma 
【メモ】
Iniparib
(BSI 201, BSI-201, BSI201, Iniparib, SAR 240550, SAR240550 )
BiPar SciencesPhase-IIIPoly(ADP-ribose) polymerase inhibitorsBrain metastases(米P2), Breast cancer(米P3), Fallopian tube cancer(米P2), Glioblastoma(米P1/2), Non-small cell lung cancer(米欧P3), Ovarian cancer(米P2), Peritoneal cancer(米P2), Solid tumours(日米P1), Uterine cancer(米P2) 
【メモ】Iniparib is being developed by BiPar Sciences (a subsidiary of Sanofi) as a treatment for a variety of solid tumour malignancies. The drug has reached phase III clinical development for metastatic triple negative breast cancer in the US and non-small cell lung cancer in several countries including the US and the EU. Phase II trials of iniparib as a neoadjuvant therapy for breast cancer are underway in certain European Union countries. There are also ongoing phase II trials in gynaecological cancers and brain metastases resulting from breast cancer in the US. Iniparib is also in phase I clinical trials in solid tumours in the US and Japan.

Iniparib is an inhibitor of poly-ADP-ribose polymerase (PARP), which is an important regulator of gene transcription and DNA repair. The drug has been shown to cross the blood-brain barrier. Based on data generated by BiPar/Sanofi, it is concluded that iniparib does not have typical characteristics of the PARP inhibitor cass; however, the exact mechanism of action has not been fully elucidated.

BiPar used the Gene Logic Inc. Bioexpress® System to identify cancer types that have an over-expression of the PARP protein. Expression on PARP was above the 95% upper confidence limit for normal tissue in ovarian cancer, intraductal breast cancer, lung cancer and uterine cancer. However, prostate tumour tissue showed minimal PARP overexpression. These results will be used to focus the development plan for iniparib by targeting certain tumour types 1 2.

In April 2009, BiPar Sciences was acquired by sanofi-aventis 1. The latter was subsequently renamed as Sanofi in May 2011 3.

Glioblastoma multiforme (GBM): in April 2008, BiPar expanded the clinical programme for iniparib into GBM. This phase I/II study (NCT00687765) is being conducted by investigators from the New Approaches to Brain Tumour Therapy (NABTT) consortium, an NCI-funded research group. The initial study phase will evaluate the safety and tolerability of iniparib in combination with temozolomide, given at standard doses. The phase II component will assess iniparib combined with temozolomide plus radiation therapy in newly diagnosed patients with GBM, where the primary endpoint is overall survival. Approximately 100 patients will be enrolled into this trial 20. As of June 2011, recruitment into the study was continuing 21.

Interferon-beta-1b - Toray/Daiichi Sankyo
(DL 8234, DL-8234, Feron®)
Daiichi Sankyo Company(Licensee)
/Toray(Originator)
MarketedImmunomodulators, Interferon beta stimulantsBrain cancer(日本発売), Glioblastoma(日本発売), Hepatitis B(日本発売), Hepatitis C(日本発売), Liver cirrhosis(日本承認), Malignant melanoma(日本発売) 
【メモ】Toray has developed interferon-β-1b, a natural human interferon, for the treatment of hepatitis C and B virus infections and tumours such as glioblastoma, medulloblastoma, astrocytoma, and malignant skin melanoma. Interferon-β-1b was launched in Japan in 1985. This product is described by Daiichi Sankyo as a natural interferon-β preparation with reduced adverse reactions (e.g. depression, alopecia), compared with interferon-α. Interferon-β-1b has subsequently been launched for an additional indication, inactive hepatitis C. The drug has also been approved in Japan for use in combination with ribavirin for the treatment of hepatitis C.
L19 131I
(131 I-L19-small immunoprotein, 131I-L19-SIP, 131I-L19SIP, I-131-L19-SIP, I-L19-SIP, L19 131I, L19-131 I, L19-131I, L19-SIP )
PhilogenPhase-IIAngiogenesis inhibitorsBrain cancer, Haematological malignancies, Non-small cell lung cancer, Solid tumours 
【メモ】
Lapatinib
(572016, GW2016, GW572016, GW572016F, Lapatinib, Tycerb, Tykerb®, Tyverb® )
GlaxoSmithKlineMarketedEpidermal growth factor receptor antagonists, HER2 inhibitorsBrain cancer(欧P3), Breast cancer(日米欧発売), Colorectal cancer(米P2), Gastric cancer(日米欧P3), Head and neck cancer(米欧P3) 
【メモ】Brain metastases (arising from breast cancer): GlaxoSmithKline has initiated a phase III clinical trial to evaluate the effect of lapatinib on the incidence of brain metastases in ErbB2 (HER2)-positive metastatic breast cancer patients exposed to prior taxanes of anthracyclines (NCT00820222). This trial will enrol approximately 650 patients from the US and Europe.

Previously, the company initiated a global phase II trial to assess lapatinib in the treatment of brain metastases associated with HER2-positive breast cancer in patients who had prior trastuzumab-based therapy (EGF105084). The trial, which enrolled 220 patients, evaluated the activity of lapatinib by monitoring brain lesions using magnetic resonance imaging (MRI); results were modest and target response rates were not reached. Thus, the company initiated further phase II studies to investigate the potential of the drug, with or without chemotherapeutics, in this indication 25 36.

Interim results from the extension arm of a phase II trial of lapatinib in patients with HER2-positive breast cancer brain metastases demonstrated that 20% of the 49 patients who received a combination of lapatinib plus capecitabine experienced at least a 50% volumetric reduction in measurable brain metastases (NCT00437073). Additionally, 37% of patients experienced a volumetric decrease of at least 20%. Enrolment into the extension arm of the study commenced in March 2007; however, the trial was subsequently terminated due to operational issues 37.

Leflunomide
(Arava®, HWA 486, SU 101)
sanofi-aventisMarketedDihydroorotate dehydrogenase inhibitors, Dihydropteroate synthase inhibitors, Epidermal growth factor receptor antagonists, Immunomodulators, Immunosuppressants, Protein tyrosine kinase inhibitorsAnaplastic astrocytoma(米P2), Psoriatic arthritis(EU発売), Rheumatoid arthritis(発売) 
【メモ】Cancer: SUGEN has completed enrolment of 60 patients with anaplastic astrocytoma for a phase II trial of leflunomide. This trial is being conducted in the US and Canada.

SUGEN, originally a subsidiary of Pharmacia Corporation, was a licensee for leflunomide in North America. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. It appears that SUGEN was subsequently integrated into Pfizer during 2003.

Esteve has marketing rights for leflunomide in Spain and Portugal for glioblastoma but has not been involved in development.

Leflunomide was licensed to Roche Bioscience for the US, but the joint development agreement was terminated. Sanofi-Aventis (formerly Aventis) plans to undertake independent marketing of leflunomide in the USA.

Aventis (now Sanofi-Aventis) had licensed leflunomide to Kyorin for co-marketing in Japan. However, Kyorin no longer has any involvement with leflunomide.

Lenalidomide
(CC 5013, CC-5013, CDC 5013, ENMD 0997, IMiD3, Lenalidomide, Revlimid® )
Celgene CorporationMarketedAngiogenesis inhibitors, Immunomodulators, Interleukin 1 beta inhibitors, Interleukin 10 stimulants, Tumour necrosis factor inhibitorsAcute myeloid leukaemia, Cancer, Chronic lymphocytic leukaemia, Cutaneous T cell lymphoma, Diffuse large B cell lymphoma, Eye neoplasms, Glioblastoma, Liver cancer, Mantle-cell lymphoma, Multiple myeloma, Myelodysplastic syndromes, Myelofibrosis, Non-Hodgkin's lymphoma, Pancreatic cancer, Peripheral T-cell lymphoma, Prostate cancer, Solid tumours 
【メモ】
Lenvatinib
(E 7080, E-7080, E7080, ER 20349200, ER-203492-00)
Eisai Co LtdPhase-IIIFibroblast growth factor receptor antagonists, Proto oncogene protein c ret inhibitors, Vascular endothelial growth factor receptor antagonistsEndometrial cancer(米P2), Glioma(米P2), Liver cancer, Lymphoma(米欧P1), Malignant melanoma(米欧P2), Non-small cell lung cancer, Ovarian cancer(米P1/2), Renal cancer(米P1/2), Solid tumours(日米欧P1), Thyroid cancer(米P3欧P2) 
【メモ】Glioma: Eisai initiated a phase II trial to investigate the safety and efficacy of lenvatinib compared with bevacizumab (NCT01137604). This open-label, three cohort trial will recruit approximately 170 patients with recurrent malignant glioma at multiple centres in the US 4.
Lexibulin
(CYT 997)
Cytopia LimitedPhase-I/IITubulin polymerisation inhibitors, Vascular disrupting agentsGlioblastoma, Solid tumours 
【メモ】
Lonafarnib
(MK 6336, MK-6336, Sarasar™, SCH 066336, SCH 66336 )
Schering-PloughPhase-IIFarnesyl transferase inhibitorsBreast cancer, Glioblastoma, Glioma, Progeria 
【メモ】
LucanthoneAlbert Einstein College of MedicinePreclinicalApoptosis stimulants, Cathepsin D modulators, Type II DNA topoisomerase inhibitorsBreast cancer 
【メモ】
LY 2157299Eli LillyPhase-IITransforming growth factor beta1 inhibitorsGlioma, Liver cancer 
【メモ】
MEDI 575
(Anti-PDGFRa MAb - MedImmune)
Cambridge Antibody TechnologyPhase-IIPlatelet-derived growth factor alpha receptor modulatorsGlioblastoma, Non-small cell lung cancer, Solid tumours 
【メモ】
Monoclonal antibody 8H9 I-131
(8H9 MAb, Monoclonal antibody 8H9 I-131)
Memorial Sloan-Kettering Cancer CenterPhase-IImmunostimulantsBrain cancer, Peritoneal cancer, Soft tissue sarcoma 
【メモ】
Monoclonal antibody ch14.18
(Anti-GD2 monoclonal antibody ch14.18, Chimeric anti-GD2 monoclonal antibody, Monoclonal antibody ch14.18)
United Therapeutics Corporation(Collaborator)
/National Cancer Institute (USA)(Originator)
Phase-III Neuroblastoma 
【メモ】United Therapeutics Corporation, in collaboration with the National Cancer Institute (NCI), is developing ch14.18, a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Ch14.18, an IgG3 human/mouse chimeric switch variant of murine MAb 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. United Therapeutics is evaluating the clinical development plan for ch14.18, with the aim of filing a BLA.

Key Development Milestones

In July 2010, United Therapeutics entered into a Cooperative Research and Development Agreement (CRADA) with the NCI to collaborate on the late-stage development and commercialisation of ch14.18 for the treatment of neuroblastoma.

Results from a phase III clinical trial to assess the efficacy of MAb-3F8 in combination with interleukin-2 and sargramostim being conducted by the NCI were published in the New England Journal of Medicine in September 2010 (ANBL0032; NCT00026312). The trial showed that administration of immunotherapy consisting of ch14.18 in combination with other agents increased the percentage of children with neuroblastoma who were alive and free of disease progression after two years from 46% for children receiving a standard therapy to 66% for children receiving immunotherapy plus standard therapy.

The Children's Oncology Group, with the NCI, are conducting a phase III clinical trial of ch14.18, in combination with sargramostim, aldesleukin, and isotretinoin after autologous stem cell transplantation in 105 paediatric patients with neuroblastoma (NCT01041638).

Monoclonal antibody ch14.18 - Apeiron
(APN 311, APN311, ch14.18/CHO, Monoclonal antibody ch14.18 - Apeiron)
Apeiron BiologicsPhase-IIIGD2 ganglioside inhibitors, ImmunostimulantsNeuroblastoma 
【メモ】Apeiron Biologics is developing an unconjugated ch14.18 monoclonal antibody produced in Chinese hamster ovary (CHO) cells that targets GD2 for the treatment of neuroblastoma and other GD2-positive tumours. GD2 is a glycosphingolipid found on the surface of tumour cells, which is uniformly expressed in many tumour types. Ch14.18 targets GD2, selectively inducing an immune reaction against tumour cells. The antibody-based treatment is in phase III development in Europe for high-risk neuroblastoma.

Apeiron is working with the European Medicines Agency (EMA) for fast approval of monoclonal antibody ch14.18 for high-risk neuroblastoma, an agressive form of infant cancer with high medical need and few treatment options.

Company Agreements

In June 2011, Apeiron concluded an agreement with the Children's Cancer Research Institute (CCRI) and the International Society of Paediatric Oncology European Neuroblastoma Research Network (SIOPEN) to support the clinical development of monoclonal antibody ch14.18. Under the agreement, Apeiron obtained the exclusive, worldwide rights to further develop, file for regulatory approval and market the final product. Apeiron also commissioned Polymun Scientific to continue production for CCRI/SIOPEN sponsored studies and to prepare for manufacture of material at market standard 1.

Key Development Milestones

Neuroblastoma: Apeiron is supporting the clinical development of monoclonal antibody ch14.18 for paediatric high-risk neuroblastoma. A phase III trial in the minimal residual disease setting is being conducted by the CCRI and SIOPEN in various European clinical centres. More than 100 patients are enrolled in this ongoing, randomised trial 1.

In 2007, SIOPEN initiated a phase III trial investigating the effects of monoclonal antibody ch14.18 and isotretinoin, with or without subcutaneous interleukin-2, on event-free and overall survival.

In a phase I trial, monoclonal antibody ch14.18 demonstrated remission in relapsed/refractory patients.

Monoclonal antibody ch14.18 interleukin-2 fusion protein
(APN 301, APN301, ch14.18-IL2, EMD 273063, hu14.18-IL2, Monoclonal antibody ch14.18 interleukin-2 fusion protein)
Apeiron Biologics(Licensee World )
/Lexigen Pharmaceuticals(Originator)
Phase-IIImmunostimulantsMalignant melanoma(米P2), Neuroblastoma(米P2) 
【メモ】Monoclonal antibody ch14.18 interleukin-2 fusion protein is an intravenously administered immunocytokine under development as an anticancer agent by Apeiron Biologics. It is a recombinant protein which comprises the ch14.18 monoclonal antibody against the GD2 antigen (which is expressed on neuroblastoma, melanoma, and other malignant tissues) fused to the cytokine interleukin-2 (IL2). Monoclonal antibody ch14.18 interleukin-2 fusion protein was originally under development by EMD Lexigen (now part of Merck KGaA). The compound reached phase II development with Merck KGaA in malignant melanoma and neuroblastoma, and Apeiron plans to continue clinical development.

Company Agreements

In February 2011, Apeiron acquired rights to further develop and commercialise monoclonal antibody ch14.18 interleukin-2 fusion protein from Merck KGaA 1.

Key Development Milestones

Neuroblastoma: Apeiron plans to continue the clinical development of monoclonal antibody ch14.18 interleukin-2 fusion protein in paediatric neuroblastoma in 2011. Study data from a phase II trial provided drug development checkpoints to proceed to phase III in certain paediatric neuroblastoma patients 1.

A phase II trial of monoclonal antibody ch14.18 interleukin-2 fusion protein in children with recurrent or refractory neuroblastoma was conducted in the US and Canada by the Children's Oncology Group and the US National Cancer Institute (NCT00082758). Results have been reported 2 3.

Monoclonal antibody TNT-1
(131-I chTNT 1/B, 131-I-chTNT-1/B mAb, Cotara®, Iodine-131 radiolabeled TNT monoclonal antibody, Monoclonal antibody TNT-1, TNT-1, Tumour necrosis therapy-1)
米国Peregrine PharmaceuticalsMarketedIonising agentsGlioblastoma(米P2), Lung cancer(中国発売) 
【メモ】Peregrine Pharmaceuticals is developing monoclonal antibody TNT-1 as a treatment for solid tumours, in particular recurrent glioblastoma multiforme. This radioimmunotherapeutic was developed using Peregrine's Tumour Necrosis Therapy (TNT) technology and consists of a chimeric monoclonal antibody conjugated to the radioisotope iodine-131. It specifically targets DNA and associated histone proteins accessible in dead and dying cells found at the core of solid tumours, where the radioactive iodine-131 can kill neighbouring tumour cells. The nuclear and cellular membranes in necrotic cancer cells become porous, which exposes the DNA making it an abundant and selective target. The DNA target may also be more stable and reliable than conventional targets, since it is not believed to modulate, as is commonly seen with tumour-specific cell surface antigens that are used with other antibody-based therapeutics. In addition, monoclonal antibody TNT-1 can be easily tracked by scanning devices to be sure it is entering the tumour and is not dispersing in healthy tissues. Another potential advantage is that each successive treatment with monoclonal antibody TNT-1 potentially kills more cancer cells, expanding the necrotic area of the tumour, thus the therapy becomes more effective upon subsequent doses. Under a license from Peregrine to Shanghai Medipharm Biotech, a product similar to monoclonal antibody TNT-1 has been developed and launched in China for the treatment of lung cancer. Phase II development is underway in the US and India for monoclonal antibody TNT-1 in recurrent glioblastoma multiforme.

Monoclonal antibody TNT-1 is available for licensing or partnering worldwide, except in China.

Company Agreements

Peregrine acquired rights to Tumour Necrosis Therapy (TNT) technology in July 1994 after it merged with Cancer Biologics. The assets acquired from Cancer Biologics primarily consisted of patent rights to the TNT technology.

During September 1995, Peregrine granted Cancer Therapeutics Laboratories the exclusive right to sublicense its TNT technology platform to a major pharmaceutical company in China. During March 2001, Peregrine extended the exclusive licensing period granted to Cancer Therapeutics, which is set to expire on 31 December 2016. Cancer Therapeutics subsequently sublicensed the technology to Shanghai MediPharm Biotech (formerly Shanghai Brilliance Pharmaceuticals). Peregrine has filed a US lawsuit against Cancer Therapeutics alleging various breaches of contract following repeated attempts by Peregrine to obtain adequate information concerning the agreement with Shanghai MediPharm Biotech in China; Cancer Therapeutics has subsequently filed a cross-complaint. Peregrine is exploring alternative avenues for commercialisation of its TNT technology platform in China 1 2.

Peregrine entered into an agreement with Cambridge Antibody Technology (CAT) in February 1996. CAT's antibody technology was to be used create a humanised monoclonal antibody for TNT. CAT is no longer involved with development, but will receive royalties on any future sales. In June 2006, Cambridge Antibody Technology was acquired by AstraZeneca 3.

In November 2003, Avid Bioservices (a wholly-owned subsidiary of Peregrine Pharmaceuticals) announced it had signed a product development agreement with MediPharm Biotech of China for the process and product development of TNT under current Good Manufacturing Practices (cGMP). Avid will provide the process development and manufacturing services to assist MediPharm in preparing for commercial launch of their radiolabelled TNT antibody in China.

Peregrine entered a worldwide non-exclusive license agreement with Lonza Biologics in October 2004. The agreement is in regards to intellectual property and materials relating to the expression of recombinant monoclonal antibodies for use in the manufacture of TNT-1. Peregrine will pay royalties on net sales of products that utilise the underlying technology. Lonza will be owed £300,000 per year if Peregrine or Lonza do not manufacture monoclonal antibody TNT-1.

Key Development Milestones

Glioblastoma multiforme (GBM): Peregrine Pharmaceuticals is conducting a phase II trial (Study PPHM 0503; NCT00677716) in the US and India investigating of the tolerability and efficacy of monoclonal antibody TNT-1 in 40 patients with glioblastoma multiforme in first relapse. Monoclonal antibody TNT-1 will be administered as a single infusion by convection-enhanced delivery, an intratumoural delivery technique that bypasses the blood brain barrier. The primary endpoint of the study is the maximum tolerated dose. The trial was initiated in June 2007, with the first patient dosed in August 2007. Enrolment was completed in December 2010 4. Interim data showed a median survival ranging from 38 to 41 weeks 5 6 7 8 9. Final results from this trial are expected to be released in mid 2011. Data from this trial will be combined with data gathered from the ongoing US-based phase I study and should provide the safety, dosimetry and efficacy data to the final design of a larger phase III study. The company plans to meet with the FDA in the second half of 2011 to discuss the optimal registration pathway for the drug 10.

A phase I, dose confirmation and dosimetry trial (Study PPHM 0602; NCT00509301) of monoclonal antibody TNT-1 is being conducted in patients with recurrent GBM. This non-randomised, open-label, uncontrolled, single group study began in November 2006, and completed enrolment of 12 subjects at sites in the US in December 2009 11. The trial is evaluating the efficacy and safety of the product administered via convection-enhanced delivery (CED), a technique developed by the US National Institutes of Health (NIH). The trial is also assessing the maximum tolerated dose, radiation dosimetry, overall patient survival, progression-free survival and the proportion of patients alive at six months following product administration. As of May 2009, screening for the anticipated final patient in this study is underway and patient follow-up is continuing. Preliminary results have been reported 12 8 13.

Peregrine has completed a US-based, phase I, dose confirmation and dosimetry trial (NCT00128635) of a single intratumoral infusion of monoclonal antibody TNT-1 in patients with first or second recurrence of GBM. This trial was conducted in collaboration with New Approaches to Brain Tumor Therapy (NABTT), a brain tumour treatment consortium funded by the National Cancer Institute 14.

In February 2003, the FDA granted Peregrine approval to start a phase III trial of monoclonal antibody TNT-1 for the treatment of recurrent GBM comparing chimeric monoclonal antibody TNT-1 with temozolomide 15. However, it appears this trial was never undertaken. Peregrine was seeking a strategic partner before commencing this trial.

A phase II study of monoclonal antibody TNT-1 was previously conducted at nine US centres in patients with recurrent malignant glioma (GBM or anaplastic astrocytoma) or newly diagnosed GBM. Preliminary results from the trial were reported for 13 of approximately 60 patients 16.

In November 2010, Peregrine Pharmaceuticals was awarded a $US977 917 grant under the US Internal Revenue Service's Qualifying Therapeutic Discovery Project tax credit programme. The grant will be used to support the development of monoclonal antibody TNT-1 for the treatment of GBM, and also the bavituximab programme [see separate profile for Bavituximab] 17.

In August 2001, Image-Guided Neurologics (IGN) and Peregrine agreed to co-sponsor a phase I/II pilot study of TNT-1 utilising IGN's Navigus® Array multi-lumen intracranial catheter to deliver the agent to the tumour of patients with brain cancer.

In the US, monoclonal antibody TNT-1 has orphan drug and fast track status for GBM and anaplastic astrocytoma. Monoclonal antibody TNT-1 also has orphan drug status in the EU for the treatment of glioma.

Motexafin gadolinium
(API-GP3, FP-GP1, Gadolinium (III) texaphyrin, Gadolinium texaphyrin, Gd-Tex, Gd-texaphyrin, GdT2B2, MGd, Motexafin gadolinium, PCI 0120, PCI-0120, Xcytrin® )
PharmacyclicsPhase-IIApoptosis stimulants, Reactive oxygen species stimulants, Thioredoxin reductase inhibitorsGlioblastoma 
【メモ】
Nimotuzumab
(Anti-EGFR mAb hR3, BIOMAb EGFR™, DE-766, DE766, h-R3, hR3, Nimotuzumab, OSAG101, TheraCIM hR3, TheraCIM®, Theraloc®, VECTHIX®)
Center of Molecular Immunology, CIMYMMarketed(インドBiocon Biopharmaceuticalsが頭頸部癌で2006年発売;アジアInnogene社が商品名TheraCIMでグリオーマで発売 )Epidermal growth factor inhibitorsAnaplastic astrocytoma(ウクライナ承認), Brain cancer(米P2), Breast cancer, Cervical cancer, Colorectal cancer, Gastric cancer, Glioblastoma(独P3), Glioma(欧P3米P2), Head and neck cancer(印発売), Nasopharyngeal cancer, Non-small cell lung cancer, Oesophageal cancer, Pancreatic cancer, Prostate cancer 
【メモ】・Epidermal Growth Factor Receptor(EGFR、上皮細胞成長因子受容体)に対するヒト化モノクローナル抗体。 ・皮膚毒性に関する安全性と他のEGFR抗体に匹敵する有効性から、ベストインクラスのEGFR抗体として期待される。 キューバでは頭頸部癌で2006年発売(Biocon Biopharmaceuticals)。 頭頸部癌、脳腫瘍などが主適応。 ハバナのCentre for Molecular Immunology (CIM)が創製。 米Oncoscienceはライセンスを受け、脳腫瘍P3、膵臓がんP2/3。 日本では胃がんでP2(第一三共)、第一三共がキューバ・シマブ社から2006.7導入、DE-766としてP2。

1995.05.03 加YM Bioscience, IncはキューバCIMAB社からnimotuzumabのライセンス獲得(米国と欧州の独占権)。
1995.11 YM社とCIMABは、CIMYM (現CIMYM BioSciences Inc.)を設立。
2003.11.12 YM BioSciences Incの子会社は、独Oncoscience AGにTheraCIM hR3(nimotuzumab)をサブライセンス。
 地域はECおよび隣接国で40ヵ国以上を含む。
 from YM Bioscience Annual Report 2010
 - Embargoに関する説明は、22p,26p参照。

2006.07.20 インドでnimotuzumab承認(頭頸部癌)。Biocon Biopharmaceuticals Ltd( Biocon社とキューバCIMAB SAの合弁)
2006.07.31 YM Biosciences子会社CIMYMは第一三共にnimotuzumabをサブライセンス(日本)。
2007.04.16 第一三共がIND認可獲得。
(各種固形癌を予定:小児脳腫瘍、NSCLC、頭頸部癌、乳癌、子宮頸癌、前立腺癌、食道癌)
上咽頭癌(nasopharyngeal carcinoma)は、India, China, Cuba, Argentina and Columbiaで承認
2007.05.24 Health CanadaはCIMYM BioSciences Incのnimotuzumabの臨床試験用500㍑製造設備を承認
2007.06.04 Nimotuzumabの大腸癌のP2試験をHealth Canadaが認可
2007.08.21 独Oncoscience AGがADULT GLIOMA AND PANCREATIC CANCERのP3試験開始
2008.12.04 独Oncoscience AGがEMEA申請取下げ(脳腫瘍)

Brain metastases: nimotuzumab, in combination with radiation therapy, was undergoing a phase II trial in Canada and the US in patients with brain metastases from non-small cell lung cancer (NCT00872482; see also section on Non-small cell lung cancer) 12. The trial was terminated because of low enrolment numbers.

Glioma: in September 2009, nimotuzumab was approved in Mexico for the treatment of adult and paediatric glioma. The drug will be marketed by Laboratorios PiSA as VECTHIX® 21.

Nimotuzumab has been approved in the Philippines and Indonesia for the treatment of adult and paediatric glioma, triggering a milestone payment to CIMYM BioSciences from IGK. IGK has also initiated a special access programme in its territories where a broad development programme is underway 22 23.

Nimotuzumab has been approved in the Ukraine for the treatment of grade III and IV brain tumours of adult patients as well as for the treatment of children with recurrent anaplastic astrocytoma grade III, glioblastoma grade IV, and with diffuse intrinsic pontine glioma 24.

Oncoscience withdrew its MAA for nimotuzumab (5 mg/mL concentrate for infusion solution) to treat children and adolescents with resistant or recurrent high-grade glioma. The withdrawal was due to the company not being able to address the concerns of CHMP regarding the quality and efficacy of nimotuzumab within the required timeframe. The submission was based on phase II data 25 26.

Eurofarma is planning a phase II trial of nimotuzumab in combination with radiotherapy in paediatric patients with diffuse intrinsic brainstem glioma (NCT01145170). This open-label trial will enrol approximately 40 patients in Brazil and Cuba. The study will investigate the change in tumour volume and progression free survival.

Oncoscience AG completed a phase III study in November 2008 assessing nimotuzumab plus radiation in children and adolescents with inoperable diffuse intrinsic pontine glioma (DIPG) (NCT00561691). Positive results were released in October 2009. The trial was conducted in the EU and Russia, enrolling 41 evaluable patients. The trial's primary endpoint was progression-free survival. Oncoscience expects to submit the phase III data for EU approval in 2009. This would be a type II variation if its earlier submission is approved 27 23 28.

In August 2008, Oncoscience AG initiated a randomised, multicentre, phase III trial that is comparing nimotuzumab plus the current standard of care (radiotherapy with concomitant and adjuvant temozolomide) with that of the current standard care alone in patients with glioblastoma multiforme (GBM) (NCT00753246). Enrolment of 150 patients in this European trial was completed in June 2011. Patients will be treated for a 24 month period, with the primary end-point being progression free survival with response rate and symptom control being secondary endpoints. Interim tolerability data have been reported 29 30 31.

In a phase II/III trial in Cuba, CIMYM is evaluating the safety and efficacy of nimotuzumab in combination with radiotherapy in 80 patients with newly diagnosed high-grade glioma. In this randomized, double-blind, multi-centre trial, patients are treated with placebo or nimotuzumab (200mg, six weekly infusions) plus radiotherapy, followed by a maintenance dose of nimotuzumab or placebo every 21 days for a year. As of November 2008, 30 patients with glioblastoma and 35 with anaplastic astrocytomas have been enrolled. Positive preliminary data have been released 32.

YM BioSciences has completed a phase II trial that investigated nimotuzumab as second-line therapy in paediatric patients with recurrent diffuse intrinsic pontine glioma (DIPG) (NCT00600054). Completion of the trial was reported by YM BioSciences in July 2011. The study was conducted in the US, Canada and Israel and enrolled 44 patients with DIPG who were treated with nimotuzumab monotherapy. The primary endpoint of the trial was response rate, with a target of 15% 33. Additionally, nimotuzumab is available in the US on a compassionate use basis for children with DIPG 11 23 23 34.

Biocon Biopharmaceuticals is conducting a phase II trial in India for the treatment of glioma in adults.

Early success for nimotuzumab was seen in a phase I/II trial in paediatric pontine glioma that was conducted in 28 hospitals of the Berlin-Frankfurt-Münster Cooperative Group in Germany and Austria. The trial reached a clinical milestone when at least three patients responded to the treatment; this allowed for early conversion into a pivotal trial 35 36.

Nimotuzumab has orphan drug status in the US and the EU for adult and paediatric glioma.

Olaratumab
(Anti-PDGFRα mAb 3G3, IMC 3G3, IMC-3G3, LY 3012207, LY3012207, Olaratumab )
ImClone SystemsPhase-IIPlatelet derived growth factor alpha receptor antagonistsGastrointestinal stromal tumours, Glioblastoma, Non-small cell lung cancer, Ovarian cancer, Prostate cancer, Soft tissue sarcoma, Solid tumours 
【メモ】
Paclitaxel poliglumex
(CHC 12103, CHC12103, CT 2103, CT-2103, Opaxio™, Paclitaxel poliglumex, PG - paclitaxel Cell Therapeutics, Poly(L-glutamic acid)-paclitaxel conjugate, Polyglutamate - Taxol, Polyglutamate-paclitaxel conjugate, Polyglutamic acid paclitaxel, PPX, Xyotax™ )
Cell Therapeutics(Licensee World)
/University of Texas M. D. Anderson Cancer Center(Originator)
Phase-IIIApoptosis stimulants, Mitosis inhibitors, Tubulin inhibitors, Tubulin polymerisation promotersFallopian tube cancer(米P3), Glioma(米P2), Non-small cell lung cancer(米P3), Oesophageal cancer(米P2), Ovarian cancer(米P3), Peritoneal cancer(米P3) 
【メモ】Glioma: preliminary results from an investigator-initiated (Brown University) phase II trial (BrUOG-Brain-223) of concurrent chemoradiotherapy with paclitaxel poliglumex in combination with temozolomide in approximately 25 patients have been reported by CTI (NCT00763750) 5 6. Enrolment in this trial has been completed and the study is due for completion in December 2011. CTI plans on working with the Brown University Oncology Group to conduct an additional study in a subset of patients with high-grade glioma with specific genetic markers. The company believes that paclitaxel poliglumex and radiotherapy might be more beneficial than temozolomide and radiotherapy (standard therapy) in this patient population.

In August 2011, Cell Therapeutics reported that enrolment had been initiated in a randomised phase II investigator-sponsored (Brown University) trial comparing paclitaxel poliglumex with temozolomide, both in combination with radiotherapy, in approximately 60 patients with newly diagnosed glioblastoma (NCT01402063) 7 8. If positive, results from the study may be used to plan a phase III study of paclitaxel poliglumex in combination with radiotherapy for approval in this disease.

Panobinostat
(DACi - Novartis, LBH 589, LBH589, LBH589A, LBH589B, NVP-LBH-589, NVP-LBH589, Panobinostat )
NovartisPhase-IIIHistone deacetylase inhibitorsAcute lymphoblastic leukaemia(米P2), Acute myeloid leukaemia(米P2), Breast cancer, Chronic lymphocytic leukaemia(米P2), Chronic myeloid leukaemia(米欧P2/3), Colorectal cancer(米P2), Gastrointestinal stromal tumours, Glioma(米P2), Graft-versus-host disease, Head and neck cancer, Mantle-cell lymphoma, Multiple myeloma(米欧P3), Myelodysplastic syndromes, Neuroendocrine tumours, Pancreatic cancer, Prostate cancer, Renal cancer, Small cell lung cancer, Solid tumours, Waldenstrom's macroglobulinaemia 
【メモ】Glioma: Novartis commenced a phase II trial of panobinostat as neoadjuvant therapy in patients with recurrent glioblastoma in March 2009 (NCT01115036). Approximately 24 patients will be enrolled at the Duke University Medical Center in the US.

Novartis has initiated a phase I/II clinical trial to determine the amount of panobinostat that can be administered in combination with bevacizumab (NCT00859222). This trial will enrol approximately 67 patients with recurrent high-grade glioma from sites in the US.

Pasireotide
(SOM 230, SOM-230, SOM230, SOM230C )
NovartisPreregistrationGrowth hormone releasing factor antagonists, Insulin-like growth factor I inhibitorsAcromegaly(米欧P3), Meningioma(米P2), Neuroendocrine tumours(米P3), Pancreatic disorders(米P3), Pituitary ACTH hypersecretion(欧申請中,米P3), Prostate cancer(米P2), Radiation injuries 
【メモ】Meningioma: an open-label phase II clinical trial is assessing the efficacy and safety of monthly pasireotide LAR in the treatment of recurrent meningioma in 40 patients from the US (NCT00859040). Interim results for 26 patients have been reported 10. Another phase II study of pasireotide twice daily is ongoing (NCT00813592). Recruitment of patients has been completed 11.
Patupilone
(EPO 906, EPO906, Epothilone B)
NovartisPhase-IIMitosis inhibitors, Tubulin modulators, Tubulin polymerisation promotersBrain cancer, Breast cancer, Colorectal cancer, Liver cancer, Non-small cell lung cancer, Prostate cancer 
【メモ】
Pazopanib
(786034, GW 786034, GW786034B, Pazopanib, SB 786034, Votrient®, Votrient™ )
GlaxoSmithKlineMarketedAngiogenesis inhibitors, Platelet-derived growth factor receptor antagonists, Proto oncogene protein b raf inhibitors, Proto oncogene protein c-kit inhibitors, Vascular endothelial growth factor receptor-2 antagonistsAge-related macular degeneration(米欧P2), Bladder cancer(米P2), Breast cancer(米欧P3), Cervical cancer(米欧P2), Chondrosarcoma(米P2), Colorectal cancer, Fallopian tube cancer(日米欧P3), Glioma(米欧P2), Liver cancer, Non-small cell lung cancer, Ovarian cancer(日米欧P3), Peritoneal cancer(日米欧P3), Renal cancer(米欧発売), Sarcoma(米欧承認、日P3), Small cell lung cancer, Solid tumours 
【メモ】Glioma: a phase II clinical trial has been initiated to assess the safety and tolerability of pazopanib and lapatinib when administered in combination with enzyme-inducing anticonvulsants in patients with recurrent Grade III or IV malignant glioma (NCT00350727). The trial enrolled 75 patients and was completed in December 2009.
PD 332991Onyx Pharmaceuticals, PfizerPhase-IICyclin-dependent kinase 4 inhibitors, Cyclin-dependent kinase 6 inhibitorsBreast cancer, Cancer, Glioblastoma, Liposarcoma, Mantle-cell lymphoma, Multiple myeloma 
【メモ】
PEG arginine deiminase
(AD-PEG, ADI PEG 20, ADI PEG20, ADI-PEG, ADI-PEG 20, ADI-PEG20, ADI-SS PEG, Arginine deiminase-PEG, Hepacid®, Melanocid®, PEG arginine deiminase, Peglyated arginine deiminase - Phoenix Pharmacologics, Pegylated arginine deiminase - Polaris Group )
Phoenix PharmacologicsPhase-IIIEnzyme stimulantsAcute myeloid leukaemia, Bladder cancer, Glioblastoma(前臨床), Liver cancer(米欧P3), Lymphoma, Malignant melanoma(米P2), Mesothelioma(米P2), Pancreatic cancer, Prostate cancer, Renal cancer, Sarcoma, Small cell lung cancer, Viral infections 
【メモ】
Pegdinetanib
(Adnectin™ BMS-844203, Angiocept™, BMS-844203, CT 322, CT-322, Pegdinetanib )
Adnexus TherapeuticsPhase-IIVascular endothelial growth factor receptor-2 antagonistsColorectal cancer, Glioblastoma, Non-small cell lung cancer 
【メモ】
Perifosine
(D 21266, KRX 0401, KRX-0401)
AEterna ZentarisPhase-IIIProto oncogene protein c-akt inhibitors, Signal transduction pathway inhibitorsChronic lymphocytic leukaemia, Colorectal cancer(米P3), Gastrointestinal stromal tumours, Glioma(米P2), Leukaemia, Lymphoma, Multiple myeloma(米P3), Neuroblastoma(前臨床), Renal cancer, Sarcoma, Solid tumours, Waldenstrom's macroglobulinaemia 
【メモ】
PHA 848125Nerviano Medical SciencesPhase-IICDC2 protein kinase inhibitors, Cyclin-dependent kinase 2 inhibitors, TrkA receptor antagonistsGlioma, Mesothelioma, Thymoma 
【メモ】
Poly ICLC
(Hiltonol®, P.I.C.L.C., Poly ICLC, Poly-ICLC, Polyinosinic polycytidylic acid, Polyriboinosinic-polyribocytidylic acid )
OncovirPhase-II2', 5' oligoadenylate synthetase modulators, Proto oncogene protein c rel modulators, Toll-like receptor 3 agonistsAnaplastic astrocytoma, Glioblastoma, Smallpox 
【メモ】
PX 866The Burnham Institute
, University of Arizona
, University of Pittsburgh
Phase-II1 Phosphatidylinositol 3 kinase inhibitors, Signal transduction pathway modulatorsGlioblastoma, Idiopathic pulmonary fibrosis, Prostate cancer, Solid tumours 
【メモ】
Ranpirnase
(Amphibian ribonuclease A, Onconase®, P-30 protein - Alfacell, P-30 ribonuclease)
Alfacell CorporationPhase-IIApoptosis stimulants, Mitosis inhibitors, Protein synthesis inhibitors, Ribonuclease stimulants, Tubulin inhibitorsAcute myeloid leukaemia, Chronic lymphocytic leukaemia, Neuroblastoma, Non-small cell lung cancer 
【メモ】
Recombinant human endostatin - Simcere
(Endostar, Endu, Recombinant human endostatin - Simcere, YH 16, YH-16 )
中国Simcere Pharmaceutical GroupMarketedAngiogenesis inhibitorsBrain metastases(中国P2), Colorectal cancer(中国P2), Malignant ascites(中国P2), Malignant melanoma(中国P2), Malignant pleural effusion(中国P2), Non-small cell lung cancer(中国発売), Oesophageal cancer(中国P2), Osteosarcoma(中国P2), Small cell lung cancer(中国P2) 
【メモ】Simcere Pharmaceutical Group has developed a recombinant human (rh) endostatin for the treatment of cancer. Endostatin is an angiogenesis inhibitor that may also inhibit endothelial cell proliferation. It has been launched in China for the treatment of stage III/IV non-small cell lung cancer (NSCLC). The company is conducting phase II clinical trials of the product in combination with approved anticancer drugs for the treatment of various cancers in China.

Brain metastases: a phase II clinical trial is taking place in China in patients with brain metastases (NCT01410370). The trial, which is expected to enrol 80 subjects, is assessing continuous infusion of endostatin combined with radiotherapy 1.

Reovirus - Oncolytics Biotech
(Reolysin®, Reovirus - Oncolytics Biotech, Reovirus serotype 3 - Oncolytics Biotech, Respiratory Enteric Orphan virus )
Oncolytics BiotechPhase-IIIApoptosis stimulants, ImmunomodulatorsColorectal cancer(英P2), Glioma(米P1/2), Head and neck cancer(米欧P3), Lung cancer(米P2), Malignant melanoma(米P2), Multiple myeloma(加前臨床), Non-small cell lung cancer(米P2), Ovarian cancer(米P2), Pancreatic cancer(米P2), Sarcoma(米P2), Solid tumours(英P1/2,米P1) 
【メモ】Oncolytics Biotech is developing a type 3 reovirus (acronym for Respiratory Enteric Orphan virus), based on the naturally occurring reovirus, as a therapeutic for solid tumours that have an activated Ras pathway. Human reovirus is a ubiquitous, non-enveloped, double-stranded RNA virus that infects the upper respiratory and gastrointestinal tract but does not have any clinical symptoms. It appears that the virus can selectively target and replicate inside tumour cells that have an activated Ras pathway, thereby killing these cells. Published results from phase I trials suggest that reovirus may stimulate the immune system to mount a dynamic immune response to the presence of virus, increasing the potential to enhance the efficacy of oncolytic virotherapy. Oncolytics Biotech is pursuing a three-pronged approach to develop reovirus: intratumoural administration of reovirus; systemic intravenous (IV) administration of reovirus as a monotherapy; and IV reovirus given in combination with radiation and/or chemotherapy. Clinical trials for various cancer indications are underway, including a phase III trial for head and neck cancers in the US, the UK, Canada, and Belgium.

Company Agreements

Oncolytics Biotech has entered into a collaborative agreement with the Cancer Therapy & Research Center at the University of Texas Health Science Center, the National Cancer Institute, and University of Leeds to conduct clinical trials 1. The agreement includes up to five trials of reovirus in combination with chemotherapy for expected cancer indications including malignant melanoma, pancreatic cancer, squamous cell lung, liver and K-ras mutated colorectal cancers. These five trials are in addition to those already being conducted.

Glioma: Oncolytics Biotech completed a US-based, open-label phase I/II trial (REO 007; NCT00528684) of intratumourally administered reovirus in 18 patients with recurrent malignant gliomas. The primary objectives were to determine the maximum tolerated dose, dose limiting toxicity, and safety profile of single, escalating doses 12 13 14. Enrolment of the phase I portion was completed in April 2010; the treatment was shown to be well-tolerated and the maximum tolerated dose was not reached, according to results for 15 patients 15 16.

Research programme: antiviral and anticancer ribonucleases - Tamir Biotechnology
(AC 03-636, AC 03636, AC CJ-001, AC-03-636, Amphinase 3, Natural P31 - Tamir, rAmphinase 2 - Tamir, Recombinant amphinase 2 - Tamir, Research programme: antiviral and anticancer ribonucleases - Tamir Biotechnology )
Alfacell CorporationPreclinicalMitosis inhibitorsCytomegalovirus infections, Dengue, Human papillomavirus infections, Severe acute respiratory syndrome, Yellow fever 
【メモ】
Research programme: brain cancer therapeutics - Agios PharmaceuticalsAgios PharmaceuticalsResearchIsocitrate dehydrogenase inhibitorsBrain cancer 
【メモ】
Research programme: Brain-related disorder therapeutics - Angiochem
(ANG 1007, ANG 1009, ANG 1011, ANG 2002, ANG 2004, ANG 2008, ANG1007, ANG1009, ANG1011, ANG2002, ANG2004, ANG2008, ANG3101, ANG3201, Research programme: Brain-related disorder therapeutics - Angiochem )
AngioChemPreclinicalBrain derived neurotrophic factor modulators, DNA intercalators, Glucagon like peptide 1 receptor agonists, Immunomodulators, Leptin receptor modulators, Neurotensin receptor modulators, RNA interference, Type II DNA topoisomerase inhibitorsBrain cancer, Obesity, Pain, Parkinson's disease 
【メモ】
Research programme: cancer therapeutics - Avicenna
(DAV0602)
Avicenna Pharma DevelopmentPreclinicalGlioblastoma 
【メモ】
Research programme: cancer vaccines - ColbyJuvaris BioTherapeuticsPreclinicalImmunostimulants, Toll-like receptor agonistsCancer, Glioblastoma 
【メモ】
Research programme: cancer vaccines - Targepeutics
(Cancer vaccines research programme - Targepeutics, gliovax)
TargepeuticsPreclinicalImmunostimulantsBrain cancer 
【メモ】
Research programme: cell movement inhibitors - Pharmaxon
(PR 22G, PR-22G)
CNRS
, Schafer-N
, Universite de la Mediterranee
, University Medical Center Hamburg-Eppendorf
PreclinicalCell movement inhibitorsGlioblastoma 
【メモ】
Research programme: central nervous system therapeutics - ArmaGen
(AGT 110, AGT 115, AGT 120, AGT 160, AGT 185, AGT 190, AGT-110, AGT-115, AGT-120, AGT-160, AGT-185, AGT-190)
ArmaGen TechnologiesPreclinicalAcetylcholinesterase inhibitors, Amyloid beta-protein inhibitors, Tumour necrosis factor alpha inhibitorsAlzheimer's disease, Brain cancer, Brain disorders, Major depressive disorder, Neurodegenerative disorders, Neuroprotection, Poisoning, Spinal cord injuries 
【メモ】
Research programme: CNS cancer therapeutics - Angiochem/Geron CorporationAngioChem, Geron CorporationPreclinicalTelomerase inhibitors, Tubulin polymerisation promotersBrain cancer 
【メモ】
Research programme: CNS disorders therapeutics - MedGenesis TherapeutixMedGenesis TherapeutixPreclinicalUndefined mechanismAlzheimer's disease, Glioblastoma, Parkinson's disease 
【メモ】
Research programme: DP 71 - D-PharmD-PharmPreclinicalUndefined mechanismPsoriasis 
【メモ】
Research programme: glioma diagnostics and therapeutics - Arch BiopartnersArch BiopartnersPreclinicalDiagnostic imaging enhancers, Magnetic resonance imaging enhancers, Stem cell inhibitorsGlioma 
【メモ】
Research programme: glutathione-pegylated liposome therapeutics - to-BBBto-BBB technologies, VIBResearchUndefined mechanismAlzheimer's disease, Brain cancer, CNS disorders 
【メモ】
Research programme: glycolysis inhibitors - Oncolin Therapeutics
(ONC 127)
University of Texas M. D. Anderson Cancer CenterPreclinicalGlycolysis inhibitorsBrain cancer 
【メモ】
Research programme: Hedgehog pathway inhibitors - Curis/GenentechCurisPreclinicalHedgehog cell-signalling pathway inhibitorsBrain cancer, Pancreatic cancer, Solid tumours 
【メモ】
Research programme: leuprorelin-based cancer therapy - CuraxisCuraxis Pharmaceutical CorporationPreclinicalGonadotropin releasing hormone stimulantsGlioblastoma, Non-small cell lung cancer, Pancreatic cancer, Prostate cancer, Renal cancer 
【メモ】
Research programme: matrix metalloproteinase inhibitors - EpitomicsEpitomicsPreclinicalMatrix metalloproteinase 2 inhibitors, Matrix metalloproteinase 9 inhibitorsBrain cancer 
【メモ】
Research programme: microRNA-targeted therapeutics - Rosetta Genomics
(miR-451)
Rosetta GenomicsPreclinicalRNA inhibitorsGlioblastoma 
【メモ】
Research programme: nerve-targeted gene therapy - Diamyd Medical
(NC 3, NC3, NE 2, NE2 Endomorphin, NG 2, NG2, NG2 GAD)
Diamyd MedicalPreclinicalGABA modulators, Glutamate decarboxylase stimulants, Nerve growth factor stimulants, Opioid receptor agonists, Opioid receptor modulatorsErectile dysfunction, Glioma, Neuropathic pain, Peripheral nervous system diseases 
【メモ】
Research programme: peptide-based immunotherapies - ImmunoCellular Therapeutics
(ICT-121, Notch and numb pathway immunotherapies - ImmunoCellular Therapeutics)
Cedars-Sinai Health SystemPreclinicalImmunostimulantsGlioblastoma 
【メモ】
Research programme: protein/lipid nanovesicle therapeutics - Bexion Pharmaceuticals
(SapC-DOPS, SapC-DOPS nanovesicles, Saposin C coupled-dioleoylphosphatidylserine )
Bexion PharmaceuticalsPreclinicalApoptosis stimulantsGlioblastoma, Pancreatic cancer 
【メモ】
Research programme: Proto oncogene proteins c-akt inhibitors - ProlX
(Protein kinase B inhibitors - ProlX, PX 316, PX-316, Research programme: Proto oncogene proteins c-akt inhibitors - ProlX )
ProlX PharmaceuticalsPreclinicalProto oncogene protein c-akt inhibitorsBrain cancer 
【メモ】
Research programme: ras protein inhibitors - Concordia PharmaceuticalsConcordia PharmaceuticalsPreclinicalRas protein inhibitors, Signal transduction pathway inhibitorsGlioma 
【メモ】
Research programme: ribonuclease conjugates and fusion proteins - Tamir Biotechnology
(AC RN-321, AC-CJ-002, AC-RD-3002, AC-RD-3003, Ranpirnase-antibody conjugates, Research programme: ribonuclease conjugates and fusion proteins - Tamir Biotechnology, RN-321, rRNP-EGF )
Alfacell Corporation
, National Cancer Institute (USA)
, National Institutes of Health (USA)
PreclinicalMitosis inhibitors, Protein synthesis inhibitorsNon-Hodgkin's lymphoma 
【メモ】
Research programme: RNA interference-based therapeutics - SenetekPolish-Academy-of-SciencesResearchRNA interferenceBrain cancer, Cancer 
【メモ】
Research programme: RNA polymerase I inhibitors - Cylene
(CX 3773, CX 3800 series - Cylene, CX 5461, CX-3773, CX-3800 series - Cylene, CX-5461, Oral Pol I complex inhibitor - Cylene, Research programme: RNA polymerase I inhibitors - Cylene )
Cylene PharmaceuticalsPreclinicalRNA polymerase I inhibitorsBrain cancer, Solid tumours 
【メモ】
Research programme: SeV-based gene therapies - DNAVEC
(Research programme: SeV-based gene therapies - DNAVEC, SeV 10102, SeV 10401, SeV 10501, SeV 20201, SeV 20202, SeV 20301, SeV 20302, SeV1 0102, SeV1 0401, SeV1 0501, SeV2 0201, SeV2 0202, SeV2 0301, SeV2 0302, SeV2 0401)
DNAVEC CorporationPreclinicalUndefined mechanismBrain cancer, Cystic fibrosis, Ischaemic heart disorders, Malignant melanoma, Rheumatoid arthritis 
【メモ】
Research programme: siRNA therapeutics - Sirnaomics
(siRNA nanoparticles - Sirnaomics, STP 601, STP 702, STP 801, STP-601, STP-702, STP-801, STP601, STP702, STP801)
SirnaomicsPreclinicalRNA interferenceAge-related macular degeneration, Eye disorders, Glioblastoma, Influenza virus infections, Lung cancer, Transplantation 
【メモ】
Research programme: sodium channel antagonists - Unibioscreen
(UNBS 5200, UNBS5200 )
UnibioscreenPreclinicalSodium channel antagonistsCancer, Glioblastoma 
【メモ】
Research programme: solid tumour therapeutics - PhytoMedical Technologies
(D11B, Research programme: solid tumour therapeutics - PhytoMedical Technologies )
Dartmouth CollegePreclinicalDNA intercalatorsGlioblastoma, Solid tumours 
【メモ】
Research programme: Src kinase inhibitors - Kinex Pharmaceuticals
(KX 02, KX 2377, KX-02, KX-2377, KX02, KX2-377)
Kinex PharmaceuticalsPreclinicalSrc-Family kinase inhibitorsBrain cancer, Sensorineural hearing loss 
【メモ】
Research programme: temozolomide analogues - Merck & Co./Pharminox
(DC 010116, DC-010-116, Research programme: temozolomide analogues - Merck & Co./Pharminox )
Merck & Co, PharminoxResearchAlkylating agentsGlioblastoma 
【メモ】
Research programme: TGF-beta RI kinase inhibitors - Scios
(SX 007, SX-007, SX007, TGF-beta RI kinase inhibitors, TGF-beta RI kinase inhibitors research programme - Scios )
SciosPreclinicalTransforming growth factor beta 1 antagonistsGlioblastoma 
【メモ】
Research programme: polysaccharide inhibitors - Zacharon Pharmaceuticals/PfizerZacharon PharmaceuticalsPreclinicalPolysaccharide inhibitorsBrain cancer, Lysosomal storage diseases 
【メモ】
Rindopepimut
(ALT-110, CDX 110, CDX-110, PF 4948568, PF-04948568, PF-04948569, PF-4948568, PF-4948569, Rindopepimut, SPX-110 )
Duke University, Johns Hopkins UniversityPhase-IIEpidermal growth factor inhibitors, ImmunostimulantsGlioblastoma, Solid tumours 
【メモ】
Sagopilone
(BAY86-5302, Sagopilone, SH Y03757A, SHY-03757, SHY-03757A, SHY03757, ZK 219477, ZK epothilone, ZK-EPO, ZK219477, ZKEPO )
Bayer Schering PharmaPhase-IIMitosis inhibitors, Tubulin modulators, Tubulin polymerisation promotersBreast cancer, Glioblastoma, Non-small cell lung cancer, Ovarian cancer, Prostate cancer, Small cell lung cancer 
【メモ】
SAR 245408
(XL-147)
ExelixisPhase-II1 Phosphatidylinositol 3 kinase inhibitorsBreast cancer, Endometrial cancer, Glioblastoma, Lymphoma, Non-small cell lung cancer, Solid tumours 
【メモ】
SAR 245409
(XL765)
ExelixisPhase-II1 Phosphatidylinositol 3 kinase inhibitors, MTOR protein inhibitorsBreast cancer, Glioblastoma, Solid tumours 
【メモ】
SB-313-xTZ
(SB-313, SB-313-xTZ, Zetakine engineered T-cell therapy - Sangamo )
City of Hope National Medical CenterPhase-IT-cell receptor gene stimulantsGlioblastoma 
【メモ】
Sorafenib
(BAY 43-9006, BAY 439006, BAY43-9006, Nexavar®)
Onyx PharmaceuticalsMarketedAngiogenesis inhibitors, Fms-like tyrosine kinase 3 inhibitors, Mitogen-activated protein kinase inhibitors, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c ret inhibitors, Proto oncogene protein c-kit inhibitors, Raf kinase inhibitors, Vascular endothelial growth factor receptor 3 antagonists, Vascular endothelial growth factor receptor-2 antagonistsAcute myeloid leukaemia(独P2,米P1/2), Breast cancer(日米欧P3), Colorectal cancer(米欧P2), Gastric cancer(日米欧P2), Germ cell and embryonal neoplasms(ポーランドP2), Glioma(米P2), Head and neck cancer(米P2), Liver cancer(日米欧発売), Multiple myeloma(米P1/2), Myelodysplastic syndromes(米P1/2), Neuroendocrine tumours(米P1), Neurofibromatoses(米P2), Non-small cell lung cancer(米欧P3), Ovarian cancer(日米欧P2), Renal cancer(日米欧発売), Thyroid cancer(日米欧P3) 
【メモ】Germ cell cancer: Bayer sponsored a phase II trial which evaluated sorafenib in patients with inoperable/recurrent germ cell carcinoma that was refractory to chemotherapy. The open-label study involved 20 patients and was completed in Poland 49.

Glioma/Astrocytoma: enrolment has been initiated in a phase II trial investigating the tolerability and efficacy of sorafenib in children and young adults with recurrent of progressive optic pathway glioma, low grade astrocytoma and neurofibromatoses (NCT01338857). The primary endpoint is the objective response at 1 year. Approximately 68 patients are expected to be enrolled at multiple centres in the US 50. A phase I trial, which began in March 2009 and estimated to complete in December 2011, is evaluating sorafenib in combination with temozolomide and radiation therapy in ≤ 18 patients aged ≥ 18 years with newly diagnosed malignant glioma 51.

Syn 2001Synt:emPhase-IUndefined mechanismBrain cancer 
【メモ】
Talaporfin
(Aptocine™, Laserphyrin®, Leserfin®, Litx™, LS 11, ME 2906, Mono-L-aspartyl chlorin e6, NP e6, NPE 6, Talaporfin, Taporfin sodium)
Meiji Seika KaishaMarketedPhotosensitisersBenign prostatic hyperplasia(米P1), Cardiovascular disorders, Colorectal cancer(米欧P3), Glioma(セルビアP2), Liver cancer(亜P3), Lung cancer(日発売), Neurofibromatoses, Prostate cancer 
【メモ】
Tandutinib
(CT53518, MLN 518, MLN0518, MLN518)
Millennium PharmaceuticalsPhase-IIFms-like tyrosine kinase 3 inhibitors, Platelet-derived growth factor receptor antagonists, Proto oncogene protein c-kit inhibitorsGlioblastoma, Glioma 
【メモ】
TB 403
(αPlGF, Anti-PlGF, R7334, RG 7334, RG7334, RO5323441)
BioInvent International, ThromboGenicsPhase-IAngiogenesis inhibitors, Placenta growth factor inhibitorsGlioblastoma, Liver cancer, Solid tumours 
【メモ】
Temozolomide
(CCRG 81045, MB 39831, NSC 362856, RP 46161, Temodal®, Temodar, Temodar®)
Merck & Co(Licensee World)/Cancer Research UK(Originator)MarketedAlkylating agents, DNA cross linking agents, DNA synthesis inhibitorsAcute myeloid leukaemia(米P2), Anaplastic astrocytoma(米欧発売), Glioma(日米欧発売), Malignant melanoma(米P1), Non-small cell lung cancer(米P2), Small cell lung cancer(米P2) 
【メモ】
Temsirolimus
(CCI 779, CCI-779, Cell cycle inhibitor-779, Temsirolimus, Torisel®)
WyethMarketedMTOR protein inhibitorsCNS cancer, Colorectal cancer, Follicular lymphoma, Glioblastoma(デンマークP2), Head and neck cancer, Hodgkin's disease, Mantle-cell lymphoma(欧承認,米P3), Multiple myeloma, Pancreatic cancer, Prostate cancer, Renal cancer(日米欧発売), Soft tissue sarcoma 
【メモ】
Terameprocol
(CINelim™, EM-1421, EM1421, M4N, NSC 136955, Terameprocol, Tetra-O-methyl nordihydroguaiaretic acid, Tetra-O-methyl-NDGA, Tetramethoxynordihydroguaiaretic acid )
Johns Hopkins UniversityPhase-IIApoptosis stimulants, BIRC5 protein inhibitors, Cdc2 kinase inhibitors, Mitosis inhibitors, Transcription factor inhibitorsCervical intraepithelial neoplasia, Glioma, Haematological malignancies, Head and neck cancer, Herpes simplex virus infections, HIV infections, Human papillomavirus infections, Influenza virus infections, Solid tumours 
【メモ】
TH 302
(HAP-302)
Threshold PharmaceuticalsPhase-IIAlkylating agentsAstrocytoma(米P3), Leukaemia(米P1), Multiple myeloma(米前臨床), Pancreatic cancer(米P2), Soft tissue sarcoma(米P3), Solid tumours(米P1/2) 
【メモ】Threshold Pharmaceuticals is developing TH 302, an intravenously administered, cytotoxic, hypoxia-activated prodrug (HAP), for the treatment of cancer, including solid tumours and soft tissue sarcoma. The drug is a nitroimidazole-linked prodrug of a brominated derivative of an isophosphoramide mustard previously used in currently available cancer therapies such as ifosfamide, cyclophosphamide and glufosfamide. The candidate consists of two components, a toxic portion and an attached trigger molecule. To prevent general toxicity, the trigger molecule keeps the toxin inactive until the prodrug is in the hypoxic region of the tumour, where it is then activated by the low oxygen concentration, thus killing the cells in its vicinity. A phase III trial of TH 302 is underway in the US for soft tissue sarcoma, and the compound is in clinical development in the US for the treatment of leukaemias, astrocytoma, pancreatic cancer and other solid tumours. Preclinical studies for the treatment of multiple myeloma are also underway.

Threshold plans to seek a partner or external funding for further development of TH 302.

Company Agreements

In July 2008, the company initiated private equity financing and anticipates raising gross proceeds of $US18.3 million. The offering is expected to close in the third quarter of 2008 and the proceeds will be used to complete the company's ongoing phase I/II trial of TH 302 for the treatment of various solid tumours, to complete at least one other phase I/II trial in a new indication and to begin at least one phase II trial of TH 302 alone or in combination with chemotherapy 1.

Key Development Milestones

Astrocytoma: in July 2011, Threshold Pharmaceuticals initiated a dose-escalation phase II trial investigating the safety and preliminary efficacy of adjuvant TH 302 + bevacizumab in 28 patients with recurrent high-grade astrocytoma (NCT01403610). A single dose of TH 302 will be administered preoperatively to assess the effects of this agent on tumour hypoxia; TH 302 + bevacizumab combination therapy will be initiated postoperatively to determine the maximum tolerated dose. The main efficacy endpoint is progression-free survival following debulking craniotomy. This trial will be conducted at the University of Texas Health Science Center 2 3.

x●Tipifarnib
(R 115777, R115777, Tipifarnib, Zarnestra™ )
Janssen L.P.
, Janssen-Cilag
, Johnson & Johnson
Phase-IIApoptosis stimulants, Farnesyl transferase inhibitorsAcute myeloid leukaemia, Glioma 
【メモ】Tipifarnib (R-115777), discovered and developed at Johnson & Johnson, is an oral inhibitor of farnesyl transferase, an enzyme required for activation of multiple tumor-growth pathways. Johnson & Johnson is exploring with the National Cancer Institute (NCI) potential uses of tipafirnib in solid and hematological malignances. Compound is evaluating in phase III clinical trials in patients with acute myeloid leukemia and early clinical trials are ongoing for the treatment of metastatic melanoma, breast cancer, glioblastoma multiforme, glioma, pancreatic cancer, neurofibromatosis, lymphoma and T-cell large granular lymphocytic leukemia. No recent development has been reported for research into the treatment of multiple myeloma which had been ongoing at the National Cancer Institute (NCI).

Johnson & Johnson received a not approvable letter from the FDA in June 2005 for the treatment of patients 65 years of age and older with newly diagnosed acute AML, although the drug had been granted orphan drug designation by the FDA for the treatment of AML in 2004. In 2005, the Committee for Orphan Medicinal Products of the European Medicines Agency (EMEA) adopted a positive opinion on orphan medicinal product designation for the drug.

T-lymphocyte cell therapy - Innocell
(Activated T-lymphocytes - Innocell, Immuncell-LC®, Inno-LC-01)
韓国Innocell CorporationMarketedT lymphocyte stimulantsCervical cancer(韓国前臨床), Colorectal cancer(韓国前臨床), Gastric cancer(韓国前臨床), Glioblastoma(韓国P3), Liver cancer(韓国発売), Malignant melanoma(韓国前臨床), Non-small cell lung cancer(韓国前臨床), Ovarian cancer(韓国前臨床), Pancreatic cancer(韓国P2), Prostate cancer(韓国前臨床), Renal cancer(韓国前臨床) 
【メモ】Innocell Corporation has developed a cell therapy, which involves the collection of immune cells from the patients' own blood, for the treatment of various cancers. Immuncell-LC® amplifies the response of T-lymphocytes collected from patients, which are then re-introduced into the patient via intravenous injection. These activated T-lymphocytes use information obtained from antigen-presenting cells to identify cancer cells and kill them. Immuncell-LC® is designed to remove residual cancer cells, following removal by surgery, embolisation or other methods. The product is available in South Korea for the treatment of liver cancer, and is in clinical development of the treatment of pancreatic cancer and glioblastoma.

Glioblastoma: a phase III clinical trial is underway to assess the efficacy and safety of Immuncell-LC® administered with temozolomide in patients with glioblastoma (NCT00807027). This trial will enrol approximately 180 subjects from South Korea. Preliminary results suggested that Immuncell-LC® improved the survival of patients in this trial 3 4.

TM 601
(Chlorotoxin)
TransMolecularPhase-IAngiogenesis inhibitorsEye disorders, Glioma 
【メモ】
TM-601-I-131TransMolecularPhase-IIAngiogenesis inhibitors, Apoptosis stimulants, Ionising agentsGlioma, Malignant melanoma, Solid tumours 
【メモ】
Topotecan
(Hycamtin, Hycamtin®, NK 211, NK-211, NK211, Nogitecan, NSC 609699, SKF 104864)
GlaxoSmithKlineMarketedDNA topoisomerase I inhibitorsBrain cancer(米欧P3), Cervical cancer(米欧発売), Ovarian cancer(米欧発売,日申請), Small cell lung cancer(日米欧発売) 
【メモ】Brain metastases from non-small cell lung cancer: topotecan is being investigated in a phase III trial for the treatment of brain metastases from non-small cell lung cancer (NSCLC) (NCT00390806). This trial has completed target enrolment of 473 patients from sites in the US, Canada, Hungary, Poland, Russia and Slovakia.
Trabedersen
(AP 12009, AP 2/09-DS, AP-2/09)
Antisense PharmaPhase-III
Phase-II
Phase-I/II
Phase-I/II
Phase-I/II
Transforming growth factor beta2 inhibitorsAnaplastic astrocytoma
, Glioblastoma
, Colorectal cancer
, Malignant melanoma
, Pancreatic cancer
 
【メモ】Trabedersen is an antisense oligonucleotide that specifically targets mRNA encoding transforming growth factor-β2 (TGFβ2). TGF-beta2 is responsible for growth and metastasis of tumours. In addition, TGF-beta2 builds up a protective shield surrounding the tumour. This shield results in an inactivation of immune cells and protects the tumour against the immune system. Studies have shown that trabedersen addresses these mechanisms of tumour progression by reversing tumour induced immuno-blockade, reactivating the immune response, inhibiting tumour cell growth, and reducing migration and metastases. Antisense Pharma is conducting clinical trials of trabedersen for high-grade glioma and anaplastic astrocytoma, as well as for colorectal cancer, pancreatic cancer and malignant melanoma.

Antisense Pharma is seeking to out-license the clinical development, supply and marketing of trabedersen for high-grade glioma and pancreatic cancer in the USA, Europe and Japan. Agreements for further territories and indications are optional.

【Key Development Milestones】

Anaplastic astrocytoma: trabedersen is in a phase III clinical trial (SAPPHIRE; NCT00761280) in patients with confirmed recurrent or refractory anaplastic astrocytoma. The study is expected to enrol 132 patients from sites in Europe, Canada, Mexico, and Asia. Trabedersen will be compared with standard chemotherapy (temozolomide or BCNU) in the trial. The primary endpoint will be the survival rate at 24 months. In October 2009, Health Canada approved the pivotal phase III study 1 2.

Antisense is targeting approval of trabedersen in this indication in the EU where the product candidate has orphan drug status. The Scientific Advice Working Party of the EMEA has accepted the 24 month survival rate as the primary study endpoint for the phase III study. Given the rarity of the disease, the surrogate endpoint of 14 month progression rate will be accepted as the endpoint for conditional approval in anaplastic astrocytoma by the EMEA, provided this is supported by the survival data 3.

Glioblastoma: results from a phase IIb study (NCT00431561) in 145 patients with recurrent or refractory glioblastoma demonstrated trabedersen administered intratumourally was well tolerated and equivalent to chemotherapy with temozolomide or PCV (combination therapy of procarbazine, lomustine and vincristine). In addition, a subpopulation analysis demonstrated trabedersen improved overall response rate and survival in 39 patients with anaplastic astrocytoma. Results from a 24-month follow-up were reported in April 2010. The European study began in April 2003, and finished accruing patients in April 2005 2 4 5 3 6 7.

A good safety and tolerability profile was reported for trabedersen following a phase I/II clinical trial in Germany and Europe in mid-2002. There were no drug related clinically relevant adverse events and six of eighteen patients showed stabilisation or response 8.

In April 2002, Antisense Pharma received orphan drug status for the treatment of high-grade glioma in the EU. Orphan drug status was granted by the US FDA in July 2002 for the same indication.

Trans-sodium crocetinate
(Sodium crocetinate, Trans-sodium crocetinate, TSC )
University of VirginiaPhase-I/IIUndefined mechanismGlioblastoma, Hypoxia 
【メモ】
TVAX cancer vaccine - TVAX Biomedical
(TVAX, TVAX cancer vaccine - TVAX Biomedical, TVI-Brain-1, TVI-Breast-1, TVI-Colon-1, TVI-Kidney-1, TVI-Lung-1, TVI-Melanoma-1, TVI-Ovary-1, TVI-Prostate-1)
TVAX BiomedicalPhase-IIImmunostimulantsBreast cancer, Colorectal cancer, Glioma, Lung cancer, Malignant melanoma, Ovarian cancer, Prostate cancer, Renal cancer 
【メモ】
VAL 083Del Mar PharmaceuticalsRegisteredAlkylating agentsBrain cancer(米臨床), Haematological malignancies(米臨床), Leukaemia(中国承認), Lung cancer(中国承認), Solid tumours(米臨床) 
【メモ】DelMar Pharmaceuticals is developing a first-in-class small molecule chemotherapeutic, known as VAL 083, for the treatment of cancer. The compound, which has been approved in China for the treatment of leukaemia and lung cancer since the late 1980s, has demonstrated anti-cancer activity in previous clinical studies sponsored by the National Cancer Institute in the US. An IND application has been submitted to the US FDA for a phase II trial in glioblastoma multiforme. The company is initially going to target this indication, as well as acute myeloid leukaemia and non-small cell lung cancer.

DelMar Pharmaceuticals is leveraging previous clinical trial data of VAL 083 from studies sponsored by the US National Cancer Institute to rapidly develop and commercialise the product.

In September 2011, the US FDA approved DelMar's IND application to evaluate VAL 083 in a phase I/II trial in patients with recurrent glioblastoma multiforme who have failed both front- and second-line therapies. The study will be an open-label, single arm dose-escalation study and is designed to test the safety, tolerability, pharmacokinetics and efficacy of VAL 083 1 2 3.

VB 111Vascular BiogenicsPhase-IIAngiogenesis inhibitors, Vascular disrupting agentsGlioblastoma, Lung cancer, Solid tumours, Thyroid cancer 
【メモ】
Veliparib
(ABT 888, ABT-888)
Abbott LaboratoriesPhase-IIPoly(ADP-ribose) polymerase inhibitorsBrain cancer, Breast cancer, Colorectal cancer, Fallopian tube cancer, Malignant melanoma, Ovarian cancer, Prostate cancer, Solid tumours 
【メモ】
Vemurafenib
(PLX4032, R 7204, R7204, RG 7204, RG7204, RO 5185426, RO5185426, Vemurafenib, Zelboraf™)
Roche(Licensee World)
/Plexxikon(Originator)
RegisteredProto oncogene protein b raf inhibitorsBrain metastases(米P2), Colorectal cancer(米P1), Malignant melanoma(米承認、欧申請中), Thyroid cancer(米欧P2) 
【メモ】Plexxikon (Daiichi Sankyo subsidiary) and Roche are developing vemurafenib, an orally-administered small molecule that selectively inhibits oncogenic BRAFV600E kinase, as a treatment for solid tumours, including malignant melanoma, thyroid cancer and colorectal cancer. The BRAFV600E gene, a mutated form of the BRAF kinase gene, is associated with increased tumour aggressiveness, decreased survival, and is found in approximately 70% of malignant melanomas and a large number of colorectal and thyroid tumours. Interim data from a phase III trial show that vemurafenib may represent a new standard of care in patients with BRAFV600E mutant-positive malignant melanoma. The product has been approved for the treatment of BRAFV600E mutation-positive, inoperable or metastatic melanoma in the US. Regulatory applications for the treatment of metastatic melanoma have been submitted in the EU, Switzerland, Australia, New Zealand, Brazil, India, Mexico and Canada. Development as a second-line therapy is in phase II in the US, Australia, and Switzerland for the same indication. A phase II trial in patients with refractory papillary thyroid cancer is underway in the US and Europe. Development is in phase I for colorectal cancer in the US and Australia.

Plexxikon uses a diagnostic test developed in collaboration with Roche Molecular Systems to identify patients with the BRAFV600E gene mutation 1 2 3.

In April 2011, Plexxikon was acquired by Daiichi Sankyo 4.

In June 2011, Roche announced it had registered the trademark Zelboraf™ for vemurafenib in both metastatic melanoma and papillary thyroid cancer.

Company Agreements

In August 2011, Roche granted Chugai Pharmaceutical the exclusive development and marketing rights for vemurafenib in Japan. Under the terms of the agreement, Chugai will make milestone payments to Roche. Chugai will initially focus its efforts in metastatic melanoma, with development for other BRAF tumour types dependent on the progress and results of the clinical trials conducted by Roche 5.

Plexxikon signed an agreement with Genentech in January 2011 to co-promote vemurafenib in the US 6.

In October 2006, Plexxikon and Roche signed an agreement to develop and commercialise vemurafenib and follow-up compounds. Roche obtained exclusive worldwide development and commercialisation rights to vemurafenib and other compounds for the treatment of cancer resulting from the partnership, while Plexxikon retained co-promotional rights for any product from the collaboration in the US. Under the terms of the agreement, Roche paid Plexxikon an upfront payment of $US40 million and this will be followed by a further $US6 million in research funding over two years. Additionally, Plexxikon may receive up to $US660 million over the term of collaboration, including development and commercial milestones, and royalties on potential sales 3. Roche is conducting all clinical trials phase II and beyond 7.

Key Development Milestones

Brain metastases (malignant melanoma): Roche is conducting a phase II trial of vemurafenib in patients with treated or untreated malignant melanoma with brain metastases (NCT01378975). The primary endpoint of the trial is the overall response of previously untreated brain metastases. Approximately 132 patients will be enrolled in the US with expected expansion into the Netherlands, Italy, and Spain 39.

Another phase II trial in patients with brain metastases is being planned by Roche. This trial will involve patients who have BRAFV600 mutation-positive malignant melanoma 19 40.

A phase II trial evaluating the tolerability of vemurafenib for the treatment of melanoma patients with brain metastases was initiated in November 2010 (NCT01253564). Approximately 20 patients from Switzerland will be enrolled and treated with vemurafenib (960mg; twice-daily) 41.

Vismodegib
(GDC 0449, GDC-0449, GDC0449, R 3616, R3616, RG 3616, RG3616)
Roche(Licensee World )
/Curis(Originator)
Preregistration
Phase-II
Phase-II
Phase-II
Phase-II
Phase-II
Phase-II
Phase-I/II
Phase-I/II
Hedgehog cell-signalling pathway inhibitorsBasal cell cancer
, Basal cell nevus syndrome
, Gastric cancer,
Glioblastoma,
Medulloblastoma,
Pancreatic cancer,
Prostate cancer,
Sarcoma,
Small cell lung cancer
 
【メモ】Vismodegib is a first-in-class, orally-administered, small molecule Hedgehog pathway antagonist that was originated by Curis and is being developed by Roche and Genentech, as a treatment for advanced solid tumours. Hedgehog proteins control a signalling pathway that is highly reactivated during the formation and progression of various types of cancers. Genentech has filed for approval of vismodegib in the US for basal cell carcinoma, and is collaborating with the National Cancer Institute for development in other solid tumours.

Vismodegib was also being evaluated in colorectal and ovarian cancers; however, development in these indications have been discontinued.

【Company Agreements】

Chugai Pharmaceutical was to develop and commercialise vismodegib in Japan under an agreement with Roche. Chugai exercised right of first refusal to develop the compound in February 2010 and was to pay an upfront fee and milestone payments to Roche 1 2. Genentech previously granted a licence to Roche for the rights to vismodegib outside the US 3.

In June 2003, Curis licensed the sole rights to its small molecule and antibody inhibitors to Genentech. In January 2005, Curis elected to exercise a co-development option applying solely to the US marketplace in the field of basal cell carcinoma. However, Curis terminated this co-development agreement effective 31 August 2006 and Genentech became solely responsible for all future costs and development decisions regarding this compound. Curis remains a collaborator for other indications and remains eligible for milestone payments and royalties on sales should Genentech proceed with further development in basal cell carcinoma 4 5.

【Key Development Milestones】

Genentech and the US National Cancer Institute (NCI) established a CRADA allowing the NCI to develop vismodegib in a number of cancer indications 6.

Oral formulation

Basal cell carcinoma: in September 2011, Genentech submitted an NDA to the US FDA for vismodegib for the treatment of advanced basal cell carcinoma. The filing was based on the results of the ERIVANCE trial. If the filing is accepted, Curis is eligible to receive an $US8 million milestone payment from Genentech 7.

Genentech conducted a pivotal phase II clinical trial of vismodegib for the treatment of metastatic or locally advanced basal cell carcinoma (ERIVANCE; NCT00833417) 8. The study evaluated the efficacy and safety of the drug in 104 patients in the US, Australia and Europe, and met its primary endpoint of overall response rate with regard to tumour shrinkage. The trial met its primary endpoint of achieving a target overall response rate demonstrating that vismodegib shrank advanced basal cell carcinoma tumours in a pre-defined percentage of patients in this trial 9 10 11 12 13. Curis received $US6 million cash payment from Genentech with the initiation of this trial 14. The timing of an European submission is subject to planned discussions with the EMA 15 16.

In June 2011, Roche initiated a single arm, open-label phase II trial to assess the safety and efficacy of once-daily oral vismodegib 150mg in 150 patients with locally advanced or metastatic basal cell carcinoma (NCT01367665). Enrolment is underway in France and Sweden, and is yet to begin in Italy and Switzerland 17.

In July 2010, Genentech initiated a phase II trial of vismodegib in the US in patients with locally advanced or metastatic basal cell carcinoma (NCT01160250). This is an open-label, expanded access study for patients who do not have any satisfactory treatment options 18.

Genentech has initiated a phase II trial of vismodegib as monotherapy in patients with operable basal cell carcinoma (BCC) (NCT01201915) 19. The trial is expected to enrol approximately 50 patients with operable nodular BCC who will receive a daily 150mg oral dose of vismodegib for 12 weeks 20. NDA filing for this additional indication is projected after 2014.

In September 2009, positive results were reported from the phase I "Hedgehog" trial of vismodegib in the treatment of advanced and metastatic basal cell skin cancer. The trial was conducted in collaboration with researchers at Johns Hopkins University and Karmanos Cancer Institute 21 22.

Genentech has completed a phase I study to assess the effect of vismodegib on the QT/QTc interval in healthy female volunteers of non-childbearing potential (NCT01173536). The randomised, double-blind, placebo- and active-controlled trial enrolled 61 volunteers in France 23.

Basal cell nevus syndrome: an investigator-sponsored phase II study has been initiated to determine the efficacy and safety of vismodegib in paediatric patients with basal cell nevus syndrome (BCNS or Gorlin syndrome) (SHH-4685s; NCT00957229). Approximately 41 subjects were enrolled from the Children's Hospital and Research Centre in Oakland, California. Interim results have been reported. A Data Safety Monitoring Board has recommended ending the placebo arm of the trial due to statistically significant efficacy in the vismodegib group, in order for all of the patients to receive vismodegib 24 25.

Breast cancer: the National Cancer Institute, in collaboration with the Barbara Ann Karmanos Cancer Institute, was conducting a phase I clinical trial to evaluate the side effects and recommended dose of vismodegib in combination with RO 4929097 in the treatment of advanced breast cancer (NCT01071564) 26. The trial was suspended in June 2011 for potential risk of arrhythmia.

Gastric cancer: a phase II clinical trial is being conducted by the NCI and the New York Cancer Consortium, to assess combination chemotherapy with or without vismodegib in treating patients with advanced stomach cancer or gastro-oesophageal junction cancer (NCT00982592) 27. This trial will enrol approximately 116 subjects.

Glioblastoma: the NCI is conducting a phase II clinical trial to assess vismodegib in the treatment of recurrent glioblastoma multiforme that can be removed by surgery (NCT00980343). This trial enrolled 40 subjects.

Medulloblastoma: under a CRADA between the US NCI and Genentech, the NCI is investigating the efficacy of vismodegib in medulloblastoma and other cancer indications 6. The NCI, in collaboration with the Pediatric Brain Tumor Consortium (PBTC) and St. Jude Children's Research Hospital, is conducting a phase I trial of the agent in paediatric patients with medulloblastoma (PBTC-025; NCT00822458). Interim findings showed that the drug has early signs of efficacy in this population, with some children still on treatment after almost a year with no disease progression. Researchers have also found that patients whose tumours had the Hedgehog molecular pathway activated, appear to be some of the same patients who have responded to treatment 28 29. The phase I trial has enrolled 30 patients as of June 2011, ranging from 3-21 years of age. All received one of two doses of vismodegib for a minimum of 28 days; patients are continuing on treatment for as long as their disease remains stable.

A phase II study is underway to evaluate the efficacy and safety of vismodegib in patients under 22 years of age with recurrent or refractory medulloblastoma (NCT01239316). The open-label study is being conducted by the PBTC in collaboration with the US NCI, and expects to enrol approximately 50 children in the US 30.

The PBTC, in collaboration with the US NCI, is also conducting a phase II trial of the agent in young adults (aged 22 years and above) (NCT00939484). This open-label trial is evaluating the safety and efficacy of the agent in adults with refractory or recurrent medulloblastoma. Approximately 50 patients are being enrolled at sites in the US 31.

Vitespen
(G-100, G-200, HSPPC-96, NP-150, Oncophage®, Prophage Series, Prophage Series G-200 vaccine)
AntigenicsMarketedImmunostimulantsColorectal cancer(米P2), Gastric cancer, Glioma(米P2), Malignant melanoma(米欧P3), Non-small cell lung cancer(英P2), Pancreatic cancer(米P1/2), Renal cancer(露発売、米P2、欧申請中断) 
【メモ】
Vorinostat
(MK 0683, MK0683, SAHA, Suberanilohydroxamic acid, Suberoylanilide hydroxamic acid, Vorinostat, Zolinza®, Zolinza™)
Aton Pharma(Licensee USA)/Columbia University, Memorial Sloan-Kettering Cancer Center(Originator)MarketedHistone deacetylase inhibitors, T lymphocyte stimulantsAcute myeloid leukaemia(米P2), B cell lymphoma(米P2), Breast cancer(米P2), Colorectal cancer, Cutaneous T cell lymphoma(日米発売、欧P3), Glioblastoma(米P2), Gynaecological cancer, HIV-1 infections, Mesothelioma(日米欧P3), Multiple myeloma(米P3), Myelodysplastic syndromes(米欧P2), Non-small cell lung cancer, Peritoneal cancer, Renal cancer 
【メモ】Malignant glioma: the NCI in the US is conducting a phase II trial of vorinostat in patients with malignant gliomas (NCT00268385) and has completed a separate trial in patients with glioblastoma multiforme (NCT00238303).
■開発パイプライン(脳腫瘍~遺伝子治療) /2011.10.1 by R&D Insight
(19件) (INDICATIONCHILD = ‘Brain cancer’ OR INDICATIONCHILD = ‘Brain metastases’ OR INDICATIONCHILD = ‘Astrocytoma’ OR INDICATIONCHILD = ‘Anaplastic astrocytoma’ OR INDICATIONCHILD = ‘Glioblastoma’ OR INDICATIONCHILD = ‘Glioma’ OR INDICATIONCHILD = ‘Germ cell and embryonal neoplasms’ OR INDICATIONCHILD = ‘Ependymoma’ OR INDICATIONCHILD = ‘Medulloblastoma’ OR INDICATIONCHILD = ‘Neuroblastoma’ OR INDICATIONCHILD = ‘Meningioma’ OR INDICATIONCHILD = ‘Pituitary cancer’) AND (BIOLOGICALCLASSCHILD = ‘Gene-product-vaccines’ OR BIOLOGICALCLASSCHILD = ‘Gene-protein-vaccines’ OR BIOLOGICALCLASSCHILD = ‘Gene-therapies’ OR BIOLOGICALCLASSCHILD = ‘Gene-therapy’)
製品名開発会社開発段階作用適応症備考
Belagenpumatucel-L
(Belagenpumatucel-L, Glionix, Lucanix®)
NovaRx Corporation(Licensee World)/Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins(Originator)Phase-IIIImmunostimulantsGlioma(米P1), Non-small cell lung cancer(米欧P3)Antisense-DNA, Cancer-vaccines, Cell-Based Gene-therapies
【メモ】NovaRx Corporation is developing a vaccine called belagenpumatucel-L for the treatment of cancer. The vaccine is made from the patients own tumour cells, which are genetically modified to express an antisense DNA molecule that binds to the transforming growth factor beta (TGFβ)-producing gene and prevents its expression. TGFβ helps cancer cells evade the immune system. The vaccine is in phase III development for non-small cell lung cancer in the US, Canada, India and Europe.

Company Agreements

NovaRx and the Immune Response Corporation (now Orchestra Therapeutics) signed a licensing transfer agreement in September 2004 covering Immune Response Corporation's in-licensed development and marketing rights for the Sidney Kimmel Cancer Center's patent portfolio for cancer cell line vaccines. The technology is used in this vaccine and Immune Response Corporation previously granted NovaRx an exclusive, worldwide license to it in June 1997. NovaRx will pay $US1 050 000 by August 2007 for the rights to the patent portfolio, which Immune Response Corporation licensed from the Sidney Kimmel Cancer Center in 1994 1. In April 2007, The Immune Response Corporation was renamed as Orchestra Therapeutics, Inc. 2. Orchestra Therapeutics no longer appears to be operating.

Key Development Milestones

Glioma: a phase I trial in patients with advanced brain cancer has reported promising results and preparations are being made for a phase II/III clinical trial in glioma 9 3.

Brain cancer vaccine - Advanced Biotherapies
(Antisense TGF-beta-2 gene therapy, Brain cancer vaccine - Advanced Biotherapies )
Advanced BiotherapiesNo-development-reported-I
(中止1 June 2006)
Immunostimulants, Transforming growth factor beta 2 antagonistsGlioblastomaAntisense-DNA, Cancer-vaccines, Cell-based Gene-therapies
【メモ】Advanced Biotherapies was developing a vaccine for the treatment of brain cancer based on the observation that glioblastoma tumour cells produce transforming growth factor-β-2 (TGF-β2), a naturally occurring peptide that has immunosuppressant properties. Advanced Biotherapies vaccine contains autologous tumour cells, which have been genetically modifed to inhibit the production of TGF-β therefore making the cells more immunogenic.

Advanced Biotherapies reported the successful use of its antisense TGF-β2 gene therapy vaccine in the treatment of patients with recurrent glioblastoma multiforme or gliosarcoma. Gene modification resulted in a significant reduction in TGF-β2 levels. One action of TGF-β2 is to suppress T cell immunity. Multiple subcutaneous injections of TGF-β2 antisense gene to intracranial tumour bearing animals, generated anti-tumour immunity and eradicated previously implanted tumours.

Phase I trials were being carried out to investigate the efficacy of the anitsense TGF-β2 gene therapy vaccine in patients with recurrent glioblastoma multiforme or gliosarcoma. However, no recent development has been reported.

Cancer gene therapy - Advantagene
(Cancer gene therapy - Advantagene, Gene Mediated Cytotoxic Immunotherapy, GliAtak™, PancAtak™, ProstAtak™, TKR therapy - Advantagene)
AdvantagenePhase-IIIThymidine kinase stimulantsBrain cancer(米P1), Glioma(米P2), Pancreatic cancer(米P1), Prostate cancer(米P3)Gene-therapies
【メモ】Advantagene, a US based company, is developing a proprietary method of administering cancer-suicide gene-therapy for the treatment of primary and metastatic disease. The therapy, named Gene Mediated Cytotoxic Immunotherapy™ (GMCI™) involves the local delivery of an adenoviral vector with the Herpes thymidine kinase gene (AdV-tk) in combination with radiation therapy, and an oral anti-herpetic prodrug. The orally administered prodrug is self administered on an outpatient basis. The therapy is given different names: ProstAtak™ for prostate cancer, GliAtak™ for malignant glioma, and PancAtak™ for pancreatic cancer. ProstAtak™ is in a pivotal phase III study in the US. GliAtak™ is in phase II and PancAtak™ is in phase I development.

Preclinical studies evaluating the use of AdV-tk in conjunction with radiotherapy have led to the discovery of their synergistic effects with standard anti-cancer therapy. Among the discoveries were the increased local and systemic anti-tumour effects when HSV-tk gene therapy is combined with radiation therapy.

Company Agreements

Baylor College of Medicine and Advantagene entered into an exclusive agreement in April 2007 whereby the latter gained worldwide rights to intellectual property related to a cancer immunotherapy technology. The technology covers methods of treating cancer by transferring genes to the tumour cells to make them highly sensitive to approved anti-herpetic drugs which are then used to kill tumour cells. The financial terms of the agreement were not disclosed 1.

Key Development Milestones

Brain cancer: Advantagene is conducting a phase II trial of GliAtak™ in patients with malignant gliomas. Patient enrollment has been completed, and results are expected in late 2011.

Advantagene has completed a phase I study with GliAtak™, which established a safe dose range for the therapy in patients with malignant glioma.

Dana-Farber Cancer Institute, in collaboration with Advantagene and Children's Hospital Boston, is conducting a phase I study (NCT00634231) to evaluate the safety and effectiveness of GliAtak™ + valaciclovir in combination with radiation therapy in paediatric patients with malignant brain tumours. The trial will enroll approximately 12 patients in the US 2.

GliAtak™ has an orphan drug designation in the US for the treatment of malignant brain tumours.

Contusugene ladenovec - Gendux/Introgen
(Ad-p53, Ad5CMV-p53, Adenoviral p53, ADVEXIN®, Contusugene ladenovec - Gendux/Introgen, INGN 201, RPR/INGN 201 )
スエーデンGendux(Originator;倒産2009)/米国Introgen Therapeutics(Originator;倒産2009)Discontinued-preregistration
(中止5 November 2009)
Tumour suppressor protein p53 stimulantsHead and neck cancer(欧申請取下、米P3中止),Li-Fraumeni syndrome(欧申請取下),Glioblastoma(米P1中止)Gene-therapies
【メモ】Introgen and its wholly-owned European subsidiary Gendux AB were developing contusugene ladenovec (ADVEXIN®), an adenoviral p53 gene therapy, as a treatment for cancer. The FDA has refused to file an NDA for the product in head and neck cancer, and Gendux has withdrawn its MAA for Li-Fraumeni cancer. The development of contusugene ladenovec with Introgen is deemed to have been discontinued as the company filed for bankruptcy in December 2008 1.

Contusugene ladenovec had been in clinical development for head and neck cancer, Li-Fraumeni syndrome, breast, non-small cell lung, oesophageal, bladder, orofacial, ovarian, and prostate cancers, gliobalstoma, and bronchiolo alveolar adenocarcinoma. The therapy was available on a compassionate use basis to eligible Li-Fraumeni syndrome cancer patients under a protocol authorised by the US FDA.

The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently mutated genes in human tumours. The p53 protein is one of the most intricate elements in the apoptotic signalling cascade, and a mutation in the gene encoding it, is believed to result in a decreased ability of a cell to apoptose. Thus replacing this gene via adenovirally-mediated p53 gene therapy is hoped to result in increased apoptosis where it is administered.

Contusugene ladenovec was available for licensing although Introgen favours retaining partial or full rights to the therapy in the US.

Company Agreements

Introgen entered into a licence agreement with The University of Texas System and M. D. Anderson Cancer Centre in 1994. The technologies licenced include p53 and fus1 (INGN 401). The collaboration has yielded exclusive patent and licensing rights to numerous technologies 2.

Introgen entered into a collaboration with Rhone-Poulenc Rorer Pharmaceuticals (now sanofi-aventis) to develop therapeutics based on p53 inhibition in October 1994. However, in June 2001 this relationship was restructured and Introgen assumed responsibility for the worldwide development of all p53 products including contusugene ladenovec, and acquired all marketing and commercialisation rights with respect to those products.

Introgen has received European certification for its US manufacturing facilities from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), which is part of the EMEA. The company's facilities and production processes are compliant with European cGMP criteria for the commercial production of contusugene ladenovec. Introgen will supply the drug to Gendux and its European marketing partners 3.

Key Development Milestones

Introgen completed phase I trials of contusugene ladenovec in patients with ovarian, bladder, and bronchoalveolar cancers and also in patients with glioblastoma. These trials were conducted in conjunction with the US NCI. Intratumoral injection of RPR/contusugene ladenovec in patients with recurrent glioblastomas was safe and resulted in expression of the p53 protein. Direct administration of RPR/contusugene ladenovec to the lower airways of patients with bronchioalveolar cell lung carcinoma resulted in symptomatic improvement and improved lung function in some patients. However, development contusugene ladenovec of has been discontinued.

Cytosine deaminase gene therapy - Tocagen
(Cytosine deaminase gene therapy - Tocagen, Toca 511, Toca-511)
TocagenPhase-I/IIGene transferenceGlioblastomaGene-therapies
【メモ】Tocagen is developing a cytosine deaminase gene therapy, called Toca 511, for the treatment of brain cancer. Toca 511 is a modified live virus-based replication-competent retroviral vector engineered to deliver a modified cytosine deaminase (CD) prodrug activating gene to glioma cells. CD converts prodrug flucytosine to anticancer 5-fluorouracil intratumourally. A phase I/II trial of Toca 511 is in progress in the US.

Tocagen used its Controlled Active Gene Transfer Technology (CAGT™) platform to develop Toca 511. The CAGT virus selectively multiplies in cancer cells sparing the healthy ones.

Key Development Milestones

Tocagen initiated a phase I/II trial to assess the safety and tolerability of single, ascending doses of Toca 511 in patients with recurrent glioblastoma multiforme (GBM) who have undergone surgery, radiation therapy and chemotherapy with temozolomide (NCT01156584). The trial will enrol 30 patients in the US. The study comprises two parts: in the first part, subjects will receive a single, transcranial, intratumoural injection of Toca 511, followed by cyclic treatment with 5-flucytosine; in the second part, additional subjects will receive Toca 511 at the maximum tolerated dose determined in the first part, followed by cyclic treatment with 5-flucytosine. In June 2011, Tocagen reported that the trial would include patients with recurrent high grade glioma, such as those with glioblastoma multiforme grade IV 1.

Tocagen also plans to develop the gene therapy in primary GBM and inoperable brain tumours. Positive results from a preclinical study of Toca 511 were reported in June 2010 2.

DA 3607
(DA 3607, DA-3607)
韓国Dong-A PharmaceuticalPhase-ITNF related apoptosis inducing ligand stimulantsBrain cancerGene-therapies
【メモ】Dong-A Pharmaceutical Co. is developing DA 3607, a cancer gene therapy targeting the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), specifically for the treatment of brain tumours. Phase I development is underway in South Korea. The company expects to launch the product in 2013.

DA 3607 is available for licensing.

EGEN 001
(EGEN 001, EGEN-001, EGEN001, IL-12 gene therapy - Expression Genetics, Interleukin-12 gene therapy - Expression Genetics, phIL-12-005/PPC)
(EGEN)Expression GeneticsPhase-IIImmunostimulants, Interleukin 12 stimulantsColorectal cancer(米P1/2), Fallopian tube cancer(米P2), Glioblastoma(米前臨床), Ovarian cancer(米P2), Peritoneal cancer(米P2)Cytokine-genes, Gene-therapies
【メモ】EGEN is developing EGEN 001, an anticancer immunotherapy product composed of an interleukin-12 (IL-12) gene expression plasmid and a biocompatible delivery polymer, for the treatment of various tumour types. EGEN 001 is designed for intraperitoneal delivery into the local tumour environment. Ovarian cancer will be the indication of initial focus and development is at the phase II stage in the US. Preclinical evaluation is ongoing for other solid tumour indications.

EGEN 001 utilises the company's proprietary TheraPlas™ delivery technology and is designed to increase the local concentration of IL-12, a potent anticancer cytokine. The TheraPlas™ technology platform is a non-viral polymeric-based system for delivery of nucleic acids to cells. Preclinical studies have shown that this strategy is safe for repeated administration as a monotherapy and also in combination with standard chemotherapy.

Key Development Milestones

Glioblastoma: in September 2011, EGEN entered into a colaboration with the National Cancer Institute′s Nanotechnology Characterization Laboratory to characterise the behaviour of EGEN 001 in preclinical models of brain cancer. Following characterisation, EGEN plans to initiate phase I development in glioblastoma 2 3.

GlioStat gene therapy - Oxford BioMedica
(GlioStat, GlioStat gene therapy - Oxford BioMedica)
Oxford BioMedicaDiscontinued-Preclinical
(13 August 2003中止)
Undefined mechanismgliomaGene-therapies
【メモ】GlioStat™ is a gene therapy product that was under preclinical development by Oxford BioMedica. It may have potential in the treatment of glioma. However, as of August 2003, GlioStat™ no longer appears on Oxford BioMedica's pipeline and so it appears that GlioStat™ is no longer in active development.

The cancer programme of Oxford BioMedica utilizes 2 technologies. The first is called XiaGenTM which utilises a hypoxia response element (HRE) that selectively switches on genes within a hypoxic environment. The second technology is called MacroGenTM which uses the body's own macrophages to selectively infiltrate and deliver gene-based therapeutics to the hypoxic regions of solid tumours. Both technologies are based on the bystander effect where tumour cells that receive the gene-based product and neighbouring tumour cells are destroyed. The therapeutic gene does not need to get into every tumour cell. This is achieved using 2 broad classes of genes: those which activate chemotherapeutic prodrugs (as in XiaGenTM technology) and those that, once introduced into the tumour, make the cells visible to the immune system and therefore vulnerable to destruction (immune coercion). GlioStatTM is available for licensing worldwide.

HSV thymidine kinase gene therapy
(HSV thymidine kinase gene therapy, Retrovector™)
AVAX Technologies(Originator)/Edison Biotechnology Institute(Originator)/Novartis(Originator)/Scientific Institute San Raffaele(Originator)/ Universite Pierre et Marie Curie(Originator)Discontinued-II
(22 July 2010中止)
Thymidine kinase stimulantsGliomaGene-therapies
【メモ】Genopoïetic, a French company established as the exclusive licensee of gene therapy technologies patented by the Université Pierre et Marie Curie, Paris, has a herpes simplex virus (HSV) thymidine kinase gene therapy product in clinical trials for the treatment of malignant melanoma and glioblastoma. However, as it does not appear on the company pipeline, and no development was reported, it is presumed discontinued.

Transfer of the HSV thymidine kinase gene, followed by the administration of antitumour agents is one experimental approach currently being employed for the treatment of solid tumours. For example, ganciclovir is phosphorylated by HSV thymidine kinase to form an intermediate that inhibits DNA synthesis, thus killing dividing cells while quiescent cells remain unaffected.

Company Agreements

Aventis Gencell (formerly Rhône-Poulenc Rorer Gencell) has exclusive worldwide rights to all HSV thymidine kinase antitumour programmes developed by Genopoïetic. In August 2000, Genopoïetic was acquired by AVAX Technologies. AVAX was developing a gene therapy technology based on the thymidine kinase suicide gene for the treatment of graft vs host disease, cancer and other indications.

In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.

Chiron was acquired and merged into Novartis in April 2006 1.

Key Development Milestones

In the US, phase I trials using "suicide" HSV thymidine kinase gene therapy were conducted in patients with malignant glioma, malignant mesothelioma and ovarian cancer. These clinical trials were conducted in the US by the Department of Neurosurgery, Childrens Hospital, Los Angeles, CA; the Human Gene Therapy Research Institute, Des Moines, IA; University of Alabama, Birmingham, AL; and the Tulane University Medical Center in New Orleans, LA. HSV-TK gene-modified cells kill nearby unmodified cells as a result of a 'bystander effect' generated by a cytokine cascade.

In addition, preclinical studies using combinations of HSV thymidine kinase gene therapy and ganciclovir were underway in Japan for the potential treatment of liver and renal cancers. US based studies investigating a combination of the HSV thymidine kinase gene, interleukin-2 gene and ganciclovir were also carried out in models of ovarian cancer.

Novartis (formerly Chiron) was conducting preclinical development of HSV thymidine kinase gene therapy (as Retrovector™) as a treatment for brain tumours.

Genetic Therapy received approval from the US NIH Recombinant DNA Advisory Committee (RAC) to commence clinical trials of HSV thymidine kinase gene therapy in patients with multiple myeloma. The trial, in collaboration with the University of Arkansas, involved ex vivo transfer of the thymidine kinase gene into T cells of allogenic bone marrow, which was to be administered to patients who had relapsed following an allogenic bone marrow transplant. Genetic Therapy was also conducting phase I/II trials with HSV thymidine kinase gene therapy for the treatment of glioblastoma, in collaboration with Jefferson Medical College at Thomas Jefferson University (Philadelphia, PA, USA). The trial was to involve about 260 patients and thymidine kinase gene therapy was to be used in conjunction with surgery as first-line treatment. However, it appears that Genetic Therapy's involvement with HSV thymidine kinase gene therapy development has ended.

HSV gene therapy was also believed to have potential in the treatment of cancer metastases, head and neck, CNS, and oesophageal cancer. Researchers at Progenitor (a subsidiary of Interneuron Pharmaceuticals) in collaboration with researchers at the Edison Biotechnology Institute of Ohio University, Ohio, USA, have incorporated the HSV thymidine kinase gene in Progenitor's nonviral gene therapy system T7T7. Direct injections of the T7T7-TK construct into human solid tumour implants in mice receiving ganciclovir caused tumour shrinkage in 6 of 10 treated animals and permanent tumour regression in 3 of the 6 tumours 2. However, Progenitor has since closed down its operations and sold its assets, and on 3 April 2002, Interneuron Pharmaceuticals changed its name to Indevus Pharmaceuticals.

The San Raffaele Scientific Institute in Milan, Italy, has reported on the successful use of HSV-TK gene transfer to control graft vs host disease after allogeneic bone marrow transplantation. Transplanted patients are treated with donor lymphocytes transduced with the HSV-TK suicide gene. Graft vs host disease in transplanted patients was effectively controlled by ganciclovir-induced elimination of the transduced cells 3. In the US, the Human Gene Therapy Research Institute the MD Anderson Cancer Center and Novartis conducted clinical investigations on the control of graft vs host disease in bone marrow transplant recipients. However, no further development was reported suggesting the programme was discontinued.

HSV thymidine kinase gene therapy - Avigen
(HSV thymidine kinase gene therapy - Avigen)
Avigen, Inc(originator)(2009.12.18 MediciNova, Inc. [日本]が買収)Discontinued-Preclinical
(中止27 June 2005)
Thymidine kinase stimulantsGliomaGene-therapies
【メモ】Transfer of the HSV (herpes simplex virus) thymidine kinase gene, followed by the administration of antiviral agents is one experimental approach currently being employed for the treatment of solid tumours. For example, ganciclovir is phosphorylated by HSV thymidine kinase to form an intermediate which inhibits DNA synthesis, thus killing dividing cells while quiescent cells remain unaffected.

At the BIO 2005 Annual International Convention (BIO-2005), Avigen reported that it has shifted its focus from AAV-based gene therapy drugs to traditional pharmaceuticals, primarily small molecule therapeutics and biologics, effectively confirming the discontinuation of this programme.

Avigen in collaboration with scientists from the department of neurosurgery at Nagoya University in Japan was conducting preclinical investigations using thymidine kinase gene therapy with systemically administered ganciclovir for the treatment of gliomas. Avigen had hoped to begin phase I trials by the end of 1999.

INGN 251
(Ad-PTEN, Adenoviral-PTEN, INGN 251, PTEN gene therapy)
米Introgen Therapeutics(Market Licensee USA;倒産2009 )/英Cancer Research Technology(Originator)Discontinued-Preclinical
(中止7 February 2005)
 Brain cancer(英前臨床),Cardiovascular disorders (米前臨床),Colorectal cancer (米前臨床),Malignant melanoma (英前臨床),Urogenital cancer(英前臨床)Gene-therapies
【メモ】Introgen Therapeutic was developing adenoviral-PTEN [INGN 251, Ad-PTEN], a gene therapy treatment for various cancers including colorectal cancer and malignant melanoma. Preclinical studies suggested that Ad-PTEN may also have potential in the treatment of vascular proliferative disorders such as those which cause arterial blockage (restenosis) which frequently occurs following common treatments for cardiovascular disease and peripheral arterial disease, i.e., angioplasty, stenting and bypass grafting. However, in February 2005, Introgen discontinued development of Ad-PTEN.

Ad-PTEN is a modified adenoviral vector which carries the PTEN gene, a novel tumour suppressor gene coding for a lipid phosphatase that reduces phosphorylation and hence activity of the cell survival factor, Akt. PTEN gene expression is critical for normal cell growth and loss of function may lead to cancer. Indeed, PTEN gene modifications are said to be present in 60% of advanced prostate cancers and in more than 70% of glioblastomas. In contrast, overexpression of PTEN has been shown to suppress tumour cell growth with minimal effect on normal cells. PTEN may also be involved in processes critical for the growth and spread of cancer cells, i.e. cell migration, invasion and metastasis and angiogenesis.

Company Agreements

Imperial Cancer Research Technology (later Cancer Research Technology) granted Introgen an exclusive licence to the tumour suppressor gene, PTEN, for therapeutic applications such as cancer and hyperproliferative diseases. In exchange, Imperial Cancer Research Technology received an upfront payment, and will also receive undisclosed research funding, milestone payments and royalties on potential product sales.

In March 2001, Introgen Therapeutics and the Texas Heart Institute signed a research agreement to study the effects of gene therapy in cardiovascular disease, with PTEN as the candidate gene. The research was to be conducted at both the Texas Heart Institute and the University of Texas Health Science Center at Houston, Texas, USA. The studies conducted under the sponsored research agreement extended preclinical studies to more complex tissue culture and animal models of cardiovascular disease.

Interferon beta gene therapy - Biogen Idec/Targeted Genetics
(Ad-beta-Ifn, Beta-interferon gene therapy - Biogen Idec/Targeted Genetics, IDEC-201, Interferon beta gene therapy - Biogen Idec/Targeted Genetics)
Biogen Idec(Originator)/AmpliPhi Biosciences(旧Targeted Genetics)(Originator;2011.3.9社名変更)Discontinued-I
(中止31 December 2007)
Interferon beta stimulantsGlioblastomaCytokine-genes, Gene-therapies
【メモ】An interferon beta gene therapy delivered using an adenovirus vector for the treatment of cancer, called IDEC 201 or Ad-IFN-β, was the lead candidate identified from a collaboration originated between Biogen (later Biogen Idec) and Genovo (1995-2000) in which the former had an equity interest. In September 2000, Genovo was acquired by, and merged into, Targeted Genetics, and Biogen replaced the original agreement between Biogen and Genovo [see separate profile: Research programme: gene therapies - Biogen/Targeted Genetics]. The treatment would allow direct delivery of interferon-β to affected organs and was in phase I development for glioblastoma. However, development has been discontinued.

Company Agreements

Biogen Idec stated, in its Form 10-K for the year ended 31 December 2007, that its agreements with Targeted Genetics Corporation for gene therapy and research have expired and it has no ongoing commitments with respect to Targeted Genetics Corporation.

In January 2003, IDEC Pharmaceuticals (later Biogen Idec) entered into a collaborative agreement with Biogen to accelerate the development of the interferon-β gene therapy for patients with glioma. Under the terms of the agreement, IDEC in-licensed three products, including IDEC 201. Biogen retained future rights to participate in the development and commercialisation of IDEC 201 1. In November 2003, Biogen and IDEC merged to form Biogen Idec.

In September 2000, Targeted Genetics and Biogen established a 3-year research and development collaboration [see separate profile: Research programme: gene therapies - Biogen/Targeted Genetics] in gene therapy research including the interferon-β gene as a treatment for malignant glioma. Under the terms of the agreement, Biogen Idec was eligible to worldwide rights to product candidates resulting from this research and Targeted Genetics was to provide Biogen Idec with input on the manufacturing process of a potential product. In September 2003, the collaboration ended. However, Targeted Genetics continued to be entitled to royalties on any future sales resulting from this therapy 2.

Key Development Milestones

The interferon beta gene therapy product was not listed in the product pipelines of Biogen Idec or Targeted Genetics in March 2008. In addition, the two companies have no ongoing mutual commitments. Development of the product appears to have been discontinued.

In 2003, IDEC reported that it would complete an ongoing phase I/II trial which Biogen had started. Previously (in June 2001), Biogen began a phase I trial in the US to evaluate the safety of interferon-β gene therapy in the treatment of glioblastoma multiforme. In preclinical studies, the interferon-β gene therapy had shown direct and indirect anti-tumour activity and potential for the treatment of a range of tumours.

In addition to the glioblastoma indication, interferon-β gene therapy was also being evaluated by researchers in the US and Japan to determine its efficacy in the treatment of malignant mesothelioma and metastatic pleural effusions. Biogen Idec supplied the researchers with its interferon-β gene therapy for these studies 3.

Combination therapy: a combination of interferon-β gene therapy and immunotherapy using tumour lysate-pulsed dendritic cells was in preclinical investigation as a potential glioma treatment. In an experimental mouse intracranial glioma model, interferon-β therapy following tumour lysate-pulsed dendritic cell immunotherapy significantly prolonged survival time 4.

Modified vectors: Biogen Idec researchers were evaluating modifications to the first generation adenoviral vectors to reduce the likelihood of RCA (replication-competent adenovirus) formation from contaminating large-scale production of vectors for gene therapy trials; the US FDA recommended limit is fewer than 3 RCA in 1011 vector particles. Ad-hIFN-β-R9 is a modified vector that has shown improvements over its parental Ad-IFN-β vector. During serial passaging, the frequency of RCA emergence from homologous recombination was significantly lower by at least 4 logs in the Ad-hIFN-β-R9 vectors versus Ad-IFN-β vectors. Furthermore, Ad-hIFN-b-R9 vector particle thermostability and transgene function were not markedly altered. Additional modifications that could improve the production efficiency and further reduce the possibility of homologous recombination during large-scale production were being considered 5.

Interferon-gamma gene therapyChiron Corporation(Chiron Viagene, Inc.)Discontinued-II
(中止19 July 2003)
ImmunostimulantsNeuroblastoma(米前臨床中止;神経芽細胞腫、神経芽腫),Malignant melanoma(米P2中止)Cytokine-genes, Gene-therapies
【メモ】One strategy used for neuroblastoma treatment involves presentation of tumour antigens to elicit an antitumour response. The transfer of cytokines can enhance a local antitumour response and groups at Chiron Technologies (formerly Viagene), the Los Angeles Children's Hospital and the Sloan-Kettering Cancer Center in New York were investigating this preclinically using retroviral transfer of interferon-γ. Chiron was also evaluating interferon-γ gene therapy in phase II US clinical trials in combination with interleukin-2 for the treatment of malignant melanoma. However, development of this gene therapy appears to have been discontinued.
Research programme: central nervous system therapeutics - ArmaGen
(AGT 110, AGT 115, AGT 120, AGT 160, AGT 185, AGT 190, AGT-110, AGT-115, AGT-120, AGT-160, AGT-185, AGT-190, Research programme: central nervous system therapeutics - ArmaGen)
ArmaGen TechnologiesPreclinicalAcetylcholinesterase inhibitors, Amyloid beta-protein inhibitors, Tumour necrosis factor alpha inhibitorsAlzheimer's disease(米前臨床), Brain cancer(米前臨床), Brain disorders(米前臨床), Major depressive disorder(米前臨床), Neurodegenerative disorders(米前臨床), Neuroprotection(米前臨床), Poisoning(米前臨床), Spinal cord injuries(米前臨床)Gene-therapies
【メモ】ArmaGen is developing therapies for the treatment of central nervous system (CNS) disorders utilising their trojan horse delivery system. This delivery system involves binding a substrate capable of crossing the blood brain barrier (BBB) to a therapeutic agent. Seven lead candidates have emerged from this programme; AGT 110 for the treatment of acute disorders including stroke, brain trauma and spinal injury and chronic disorders including neurodegeneration and depression, AGT 115 for neuroprotection after stroke, brain or spinal cord trauma and chronic neurodegeneration, AGT 120 for neuroprotection against stroke, AGT 160 for the treatment of Alzheimer's disease, AGT 185 as an antidote for nerve gas poisoning, AGT 190 for neuroprotection against stroke or Parkinson's disease and AGT 2000 for the treatment of brain cancer. Preclinical development is ongoing in the US.

AGT 110 is an IgG-decoy receptor fusion protein comprised of the extracellular domain of the human tumor necrosis factor-alpha receptor (TNFR) type II as the decoy receptor, and a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the fusion protein acts as a molecular trojan horse to ferry the TNFR decoy receptor across the blood brain barrier (BBB) for neutralisation of TNF-alpha action in the central nervous system 1.

AGT 115 is a re-engineered brain-penetrating erythropoietin (EPO) developed for use as a neuroprotectant agent in acute brain disorders such as stroke, traumatic brain or spinal cord injury and chronic neurodegeneration. The agent is a genetically engineered fusion protein comprised of a BBB molecular Trojan horse (MTH) protein fused to human EPO. AGT 115 binds to two receptors. Firstly, to the human insulin receptor (HIR) on the BBB to initiate receptor-mediated transcytosis (RMT) across the BBB; this enables the agent to enter the brain from blood after IV administration. The agent then binds the EPO receptor (EPOR) in the brain to trigger neuroprotection 2.

AGT 120 is an engineered fusion protein containing a BBB molecular trojan horse protein fused to a neurotrophin variant. AGT 120 first binds to a receptor on the BBB to initiate receptor-mediated transport across the BBB, then binds to a specific neurotrophin receptor in the brain enabling neuroprotection.

AGT 160 is a fusion protein containing a molecular trojan horse moving the specific therapeutic agent across the BBB via receptor mediated transport. The compound then inhibits the formation of β-amyloid responsible for dementia in Alzheimer's disease.

AGT 185 is a recombinant fusion protein comprised of a human serum organophosphatase, believed to be paraoxonase 1 (PON1), and a genetically engineered monoclonal antibody to the human insulin receptor. The modified antibody is able to cross the BBB acting as a trojan horse where it can deliver PON1 which in turn hydrolyses chemical nerve gas agents 3 4.

AGT 190 is a recombinant fusion protein containing human neurotrophin being developed to offer neuroprotection acutely for stroke and chronically for Parkinson's disease. This therapy also uses a trojan horse method of transport, utilising an IgG molecule which undergoes receptor mediated transport across the BBB. ArmaGen believe this therapy may allow long term treatment of Parkinson's disease.

AGT 2000 is a non-viral gene therapy for primary or metastatic brain cancer that is delivered using trojan horse technology. The delivery system utilised not only allows transport across the BBB but also across the cancer cell membrane allowing delivery of plasmid DNA directly to the cancers nucleus. According to ArmaGen, AGT 2000 is being developed to knock out an oncogene, for the epidermal growth factor receptor, present in approximately 70% of human brain cancers 5.

Company Agreements

In September 2006, ArmaGen expanded their license of drug delivery technologies from the University of California to include technologies that cross the blood brain barrier (BBB). The expanded license also grants ArmaGen exclusive use of avidin-biotin technology for drug delivery. Armagen had previously licensed a series of patents from the University of California including molecular trojan horse technology 6 7.

ArmaGen was known as Neurogene Technologies until March 2004 8.

Research programme: nerve-targeted gene therapy - Diamyd Medical
(NC 3, NC3, NE 2, NE2 Endomorphin, NG 2, NG2, NG2 GAD, Research programme: nerve-targeted gene therapy - Diamyd Medical )
Diamyd MedicalPreclinicalGABA modulators, Glutamate decarboxylase stimulants, Nerve growth factor stimulants, Opioid receptor agonists, Opioid receptor modulatorsErectile dysfunction(米前臨床), Glioma(米前臨床), Neuropathic pain(米前臨床)Gene-therapies
【メモ】Diamyd Medical's US subsidiary Diamyd Inc is developing therapeutics for the treatment of CNS disorders, including pain, neuropathy and nerve protection, using a nerve-targeting drug delivery system (NTDDS). The company is also developing NTDDS for the treatment of glioma. In addition, the technology has potential for the treatment of erectile dysfunction caused by nerve damage. Preclinical development is underway in the US.

The system comprises a viral backbone that is unable to replicate in the patient and a gene of the desired biologic. The vector has a natural affinity for nerve cells which results in a highly targeted delivery vehicle. After administration via injection, the gene therapy produces the biologic in the first order neuron and it is then released into the nerve synapses for a period of up to several weeks. Diamyd believes that this gene therapy system has a reduced risk of adverse events as the targeted nature of this gene therapy reduces the chance of systemic adverse events and it does not integrate into the patient's DNA.

A previous lead candidate, NP 2 (NTDDS expressing enkephalin), has entered clinical development for the treatment of chronic pain, including cancer pain, in the US [see separate profile].

Development of the next advanced candidate, NG 2, is at the preclinical stage in the US. NG 2 is being developed for the treatment of diabetic neuropathies, neuropathic pain, and chronic pain following spinal cord injury. The NG2 NTDDS product is designed to deliver the GAD (glutamate decarboxylase) gene to release GAD into nerve synapses, where it converts glutamate into the inhibitory neurotransmitter GABA (gamma aminobutyric acid). Release of GABA from the first order neuron into the synapse will bind the GABA receptor on the second order spinal neuron, stimulating intracellular signalling that will dampen the transmission of pain signals.

NC 3 is being developed for the treatment of glioma. NC 3 delivers a gene which is designed to express compounds capable of killing cells over for up to one week. The product will be delivered in conjunction with prodrugs able to be activated by the introduced vector and radiosurgery. Preclinical toxicology studies have been funded by the US National Institutes of Health. It is anticipated that NC 3 may have potential in the treatment of other types of solid tumours as well. Diamyd plans to develop this cancer platform in a separate company with collaboration with partners.

NE 2 is in the preclinical stage of testing for the treatment of neuropathic pain. NE 2 allows the administration of endomorphin to the pain area focally via NTDDS. Diamyd anticipates this new treatment will overcome the issues associated with the use of the modern clinical pain relief agent, morphine.

A further candidate is being developed to deliver neurotrophic factors to nerve cells and this product will act as a neuroprotectant. In addition, Diamyd has stated that a single prophylactic dose of nerve growth factors delivered via NTDDS would be the entire treatment required for erectile dysfunction resulting from nerve damage related to prostate surgery. Nerve growth factors have been effective in preclinical studies for improvement of erectile dysfunction caused by nerve damage 1.

Worldwide licensing opportunities are available for the development of these NTDDS-based drug candidates.

Company Agreements

In March 2009, Diamyd acquired an exclusive licence for technology to deliver endomorphin peptides using NTDDS. The technology has potential in the treatment of pain including diabetic neuropathic pain. With addition of endomorphin technology to the company's exclusive licenses for GAD and enkephalin gene delivery platforms, Diamyd completed its pain NDDS portfolio having products targeting all three major pain receptors, providing an opportunity to develop products for multiple pain types, including neuropathic pain 2.

Diamyd Medical has an exclusive licence to a portfolio of patents for the nerve-targeted gene delivery system. This was obtained when Diamyd acquired Nurel Therapeutics in December 2005. Nurel Therapeutics, based in Pennsylvania, had licensed the gene delivery platform from the University of Pittsburgh. Nurel Therapeutics is now a US-based subsidiary of Diamyd known as Diamyd Inc 3.

In December 2006, Diamyd entered into an exclusive licensing agreement with the Centre National de la Recherche Scientifique (CNRS) in Paris for the rights to a patent portfolio covering the use of GAD via viral vectors in the treatment of neurodegenerative diseases 4.

Key Development Milestones

Glioma: preclinical studies of NC 3 have been conducted in the US, funded by the US National Institutes of Health.

Research programme: SeV-based gene therapies - DNAVEC
(Research programme: SeV-based gene therapies - DNAVEC, SeV 10102, SeV 10401, SeV 10501, SeV 20201, SeV 20202, SeV 20301, SeV 20302, SeV1 0102, SeV1 0401, SeV1 0501, SeV2 0201, SeV2 0202, SeV2 0301, SeV2 0302, SeV2 0401)
日本DNAVEC CorporationPreclinicalUndefined mechanismBrain cancer(日前臨床), Cystic fibrosis(日前臨床), Ischaemic heart disorders(日前臨床), Malignant melanoma(日前臨床), Rheumatoid arthritis(日前臨床)Gene-therapies
【メモ】DNAVEC Corporation in Japan is conducting preclinical studies on a series of Sendai Virus (SeV) vector-based gene therapies for the potential treatment of ischaemic heart disease [SeV 10102, SeV1 0102], brain tumours [SeV 20201, SeV2 0201], melanoma [SeV 20202, SeV2 0202], cystic fibrosis [SeV 10401, SeV1 0401] and chronic rheumatoid arthritis [SeV 10501, SeV1 0501].

Preclinical development of SeV vector-based gene therapies was initiated for other indications including HIV infection [SeV 20301, SeV2 0301], Severe Acute Respiratory Syndrome (SARS) [SeV 20302, SeV2 0302] and Alzheimer's disease [SeV 0401]; however, these indications are no longer listed on the company's SeV pipeline.

The advantages of using the SeV vector is that it is a non-replicating cytoplasmic ribonucleic acid vector, it does not enter the cellular nucleus but rather expresses its gene in the cytoplasm. There is therefore negligible risk of chromosomal damage, hence the SeV vector has an improved safety profile for genetic toxicity, compared with existing vectors. In addition, the efficiency of the gene transfer is 10-10 000 times greater than that of existing vectors suggesting applications with reduced dosing frequencies. A disadvantage, as seen with other vectors, is the antigenicity associated with the vector 1.

At the BIO-2005 Annual International Convention (BIO-2005), DNAVEC Corporation indicated that it is seeking partnering opportunities in the US and Europe for the development of products in this programme.

Key Development Milestones

At BioSquare-2005, DNAVEC Corporation reported that lead candidates for each indcation are in the preclinical phase of development 2.

Cancer: a matrix metalloproteinase (MMP)-targeted oncolytic SeV vector armed with a yeast suicide gene, yeast cytosine deaminase (yCD) has been developed which showed cancer killing properties in vitro and in vivo 3.

SDZ GLI 328
(GLI 328, HS thymidine kinase gene therapy - Genetic Therapy, SDZ GLI 328)
Novartis(Genetic Therapy(Originator)を1995.12.31買収)Discontinued-III
(中止29 August 2007)
Gene transferenceGliomaGene-therapies
【メモ】SDZ GLI 328 is Genetic Therapy/Novartis' novel herpes simplex thymidine kinase gene therapy that was being developed for the treatment of patients with glioblastoma. SDZ GLI 328 was undergoing phase III clinical trials in Canada, Europe and the US in patients with glioblastoma multiforme. Another US clinical trial was evaluating the efficacy of surgery, radiation and SDZ GLI 328 vs surgery and radiation in the treatment of patients with newly diagnosed, previously untreated glioblastoma. However, development appears to have been discontinued.
Sitimagene ceradenovec
(Cerepro®, EG009, Sitimagene ceradenovec)
Ark TherapeuticsDiscontinued-III
(中止9 September 2010)
Gene transference, Thymidine kinase stimulantsGliomaGene-therapies
【メモ】Sitimagene ceradenovec consists of the herpes simplex virus (HSV) thymidine kinase gene enveloped in an Ad5 adenovirus vector. It was being developed by Ark Therapeutics as a treatment for operable high-grade glioma. Following surgical removal of the glioma, sitimagene ceradenovec is administered by injection into the walls of the cavity, where it transfects normal brain cells with the thymidine kinase gene. Five days after surgery, ganciclovir is given intravenously. By this time the tissue surrounding the resection site is expressing thymidine kinase which converts ganciclovir to ganciclovir triphosphate, a compound that kills dividing cells via inhibition of DNA synthesis. Since cell division is a key characteristic of cancer and the normal brain cells are non-dividing, any remaining glioma cells that try to divide to form a new tumour are destroyed. Ark filed for marketing authorisation in the EU for the treatment of operable malignant glioma; however, the EMA requested an additional trial to support the filing, and consequently, Ark withdrew its filing. Following a strategic review, Ark has refocussed its programmes, excluding sitimagene ceradenovec. It is assumed that development has been discontinued, pending an out-licensing arrangement.

Ark planned to market sitimagene ceradenovec either alone or through a commercial partnership in the US and European territories. Throughout the rest of the world, including Japan, Ark Therapeutics intended to out-license sitimagene ceradenovec 1.

Key Development Milestones

In June 2010, the US FDA announced that an additional trial will be required before sitimagene ceradenovec is able to be accepted for review. Ark is seeking a partner to further finance this trial 2 3. However, in September 2010, Ark refocussed its programmes, excluding sitimagene ceradenovec. It is assumed that development has been discontinued, pending a partnership arrangement 4.

In March 2010, Ark Therapeutics withdrew its MAA application for sitimagene ceradenovec in operable malignant glioma following a presentation to the EMA's Sicentific Advisory Group on Oncology (as part of an MAA re-examination procedure). The advisory committee recommended initiation of an additional pivotal trial as the phase III trial data included in the MAA did not provide reliable evidence of a clinical benefit. Ark is seeking a partner to conduct the trial, expected to take approximately 4 years to complete. The company initiated a full review of its asset portfolio, and was in an Offer Period for the purposes of the Takeover Code 3. However, Ark ceased discussions regarding a potential potential sale of the company, and was no longer in an offer period as of the second half of 2010 5.

The European Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion for Ark's Marketing Authorisation Application (MAA) for sitimagene ceradenovec, filed in November 2008. It was accepted for review under the centralised procedure in January 2009, and included data from the phase III 904 study. The Committee's negative opinion was based on possible differences between groups in treatment delays, which could have affected the primary endpoint of survival duration (defined as time to re-intervention or death). However, all issues relating to the other elements of the regulatory package (key Chemistry and Manufacturing Controls, and Preclinical and Environmental Dossiers) were deemed 'approvable'. Via the standard appeal procedure, Ark filed a formal request with the EMEA for re-examination of its MAA for sitimagene ceradenovec and the EMA acknowledged receipt of the filing 6 7 8 9 10.

In February 2009, the first Named Patient Supply (NPS) for sitimagene ceradenovec was approved by the French Medicines Control Agency, making the drug available to patients under exceptional circumstances in France. The second NPS was approved in Finland in May 2009. Ark previously submitted the MAA for early approval in October 2005 under "exceptional circumstances" - provisions which allowed the use of safety and efficacy data from completed phase II trials. The authority concluded that there was not a sufficient weight of clinical evidence from the limited number of patients included in the phase II data to conclude that the risk benefit for patients has been proven beyond doubt 11 12 13 14 15 16 17.

In April 2007, Ark completed recruitment in its phase III study (Study 904) of sitimagene ceradenovec as a treatment for operable high-grade glioma. This trial was initiated in October 2005 and is being conducted at centres in the EU and Israel. The independent data and safety monitoring board (DSMB) review, conducted in July 2007, concluded that there were no safety issues with the study and that the trial should continue as planned. In a preliminary analysis of results in July 2008, the primary endpoint of survival was met and sitimagene ceradenovec treatment resulted in significant improvements in median survival on the primary endpoint compared with various controls. Updated results were presented in April 2009, with results consistent with those previously reported 12 14 18 19 17 20.

Sitimagene ceradenovec was granted orphan drug status in the EU and US for the treatment of glioma.

Ark received a positive opinion from the EMEA regarding the company's investigation plan for the use of sitimagene ceradenovec in the treatment of paediatric patients with high grade glioma. This allowed Ark to investigate sitimagene ceradenovec in paediatric patients. However, the company did not plan to initiate development until an MAA had been granted for adult patients 21.

VB 111
(GT-111, VB 111, VB-111 )
イスラエルVBL Therapeutics (Vascular Biogenics)Phase-IIAngiogenesis inhibitors, Vascular disrupting agentsGlioblastoma(米P1/2), Lung cancer(イスラエル前臨床), Solid tumours(米P1/2), Thyroid cancer(米P2)Gene-therapies
【メモ】VBL Therapeutics (formerly Vascular Biogenics) is developing VB 111, an intravenously administered dual-action, anti-angiogenic and vascular disrupting agent (VDA) for the treatment of solid tumours. VB 111 is in a phase I/II clinical trial in glioblastoma multiforme and a phase II trial in thyroid cancer.

VB 111 was identified using VBL's proprietary Vascular Targeting System (VTS™) technology platform.

Key Development Milestones

In December 2010, VBL Therapeutics initiated an open-label, single dose phase I/II trial (NCT01260506) of VB 111 in patients with relapsed glioblastoma multiforme, in the US. The trial will measure efficacy by 6-month progression-free survival, as well as bio-distribution, safety and tolerability 1 2.

In December 2010, VBL Therapeutics initiated a phase IIa trial (NCT01229865) of VB 111 in patients with advanced, differentiated thyroid cancer. All participants will have been previously treated with radioiodine and will be divided into two cohorts, one including those with no former anti-angiogenic treatment and the other including those who have received at least one conventional anti-angiogenic therapy. The trial will assess efficacy, safety and tolerability in 82 patients in the US 1 3.

Results from a phase I clinical trial of VB 111 in patients with advanced solid tumours showed that the drug was well-tolerated with no dose-limiting toxicities and promising evidence of efficacy. The trial enrolled 27 patients from the Cleveland Clinic and the University of Texas Health Science Centre, and evaluated the safety, pharmacokinetics, immune and tumour responses of a single intravenous dose of VB 111809 4 5.

Preclinical in vitro and in vivo studies demonstrated that VB 111 is safe and specific; furthermore, it was shown to have a dual action, with anti-angiogenic and vascular disrupting properties 6. It showed potent anti-angiogenic activity in glioblastoma xenografts in rats 7.

医療用医薬品添付文書 /2011.10.10
製品組成適応症用法用量備考
テモダールカプセル20mg,100mg [製造販売元/MSD株式会社]
発売2006年9月
1カプセル中テモゾロミド20mg,100mg悪性神経膠腫[1. 初発の場合] 放射線照射との併用にて、通常、成人ではテモゾロミドとして1回75mg/m2(体表面積)を1日1回連日42日間投与し、4週間休薬する。その後、本剤単独にて、テモゾロミドとして1回150mg/m2を1日1回連日5日間投与し、23日間休薬する。この28日を1クールとし、次クールでは1回200mg/m2に増量することができる。
[2. 再発の場合] 通常、成人ではテモゾロミドとして1回150mg/m2(体表面積)を1日1回連日5日間投与し、23日間休薬する。この28日を1クールとし、次クールで1回200mg/m2に増量することができる。
 
テモダール点滴静注用100mg [製造販売元/MSD株式会社]
発売
1バイアル中テモゾロミド104.5mg
ニドラン注射用25mg,50mg [製造販売元/第一三共株式会社 ]
発売1980年2月
1バイアル中ニムスチン塩酸塩 25mg,50mg 下記疾患の自覚的ならびに他覚的症状の寛解:脳腫瘍、消化器癌(胃癌、肝臓癌、結腸・直腸癌)、肺癌、悪性リンパ腫、慢性白血病   
注射用サイメリン50mg,100mg[製造販売元/田辺三菱製薬株式会社]
発売1987年7月
1瓶中ラニムスチン 50mg,100mg 膠芽腫,骨髄腫,悪性リンパ腫,慢性骨髄性白血病,真性多血症,本態性血小板増多症 通常,下記用量を生理食塩液又は5%ブドウ糖注射液100~250mLに溶解し,30~90分で点滴静注するか,又は10~20mLに溶解し,ゆっくり(30~60秒)静脈内に投与する.ラニムスチンとして1回投与量は50~90mg/m2とし,次回の投与は血液所見の推移にしたがって6~8週後に行う. 
オンコビン注射用1mg [製造販売元/日本化薬株式会社]
発売2004年4月
1バイアル中ビンクリスチン硫酸塩 1mg 1. 白血病(急性白血病、慢性白血病の急性転化時を含む)
2. 悪性リンパ腫(細網肉腫、リンパ肉腫、ホジキン病)
3. 小児腫瘍(神経芽腫、ウィルムス腫瘍、横紋筋肉腫、睾丸胎児性癌、血管肉腫等)
4. 以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法 :多発性骨髄腫、悪性星細胞腫、乏突起膠腫成分を有する神経膠腫
[3. 悪性星細胞腫、乏突起膠腫成分を有する神経膠腫に対する他の抗悪性腫瘍剤との併用療法の場合]ビンクリスチン硫酸塩として1.4mg/m2(体表面積)を、2回静脈注射する。1回目の投与の3週間後に2回目の投与を行い、6~8週を1クールとし、投与を繰り返す。ただし、副作用を避けるため、1回量2mgを超えないものとする。  
塩酸プロカルバジンカプセル50mg「中外」 [製造販売元/中外製薬株式会社]
発売1978年4月
1カプセル中日局プロカルバジン塩酸塩 58.3mg(プロカルバジンとして50mg)1)悪性リンパ腫(ホジキン病、細網肉腫、リンパ肉腫)
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法:悪性星細胞腫、乏突起膠腫成分を有する神経膠腫
[2. 悪性星細胞腫、乏突起膠腫成分を有する神経膠腫に対する他の抗悪性腫瘍剤との併用療法の場合]プロカルバジンとして1日量60~75mg/m2を14日間経口投与し、これを6~8週毎に繰り返す。体表面積より算出されたプロカルバジンの1日量が75mg未満の場合は、50mg(1カプセル)、75mg以上125mg未満となった場合は100mg(2カプセル)、125mg以上175mg未満となった場合は150mg(3カプセル)を1日1~3回に分割して投与する。 先発品ナツラン中止
ベプシド注100mg[製造販売元/ブリストル・マイヤーズ株式会社]
発売1987年5月
1バイアル5mL中エトポシド 100mg 1)肺小細胞癌,悪性リンパ腫,急性白血病,睾丸腫瘍,膀胱癌,絨毛性疾患,胚細胞腫瘍(精巣腫瘍,卵巣腫瘍,性腺外腫瘍)
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法:小児悪性固形腫瘍(ユーイング肉腫ファミリー腫瘍,横紋筋肉腫,神経芽腫,網膜芽腫,肝芽腫その他肝原発悪性腫瘍,腎芽腫その他腎原発悪性腫瘍等)
[併用療法の場合]他の抗悪性腫瘍剤との併用において,エトポシドの投与量及び投与方法は,1日量100~150mg/m2(体表面積)を3~5日間連続点滴静注し,3週間休薬する。これを1クールとし,投与を繰り返す。 
ブレオ注射用5mg,10mg,30mg[製造販売元/日本化薬株式会社]
発売1969年2月
1バイアル中ブレオマイシン塩酸塩 5mg,10mg,30mg皮膚癌、頭頸部癌(上顎癌、舌癌、口唇癌、咽頭癌、喉頭癌、口腔癌等)、肺癌(特に原発性及び転移性扁平上皮癌)、食道癌、悪性リンパ腫、子宮頸癌、神経膠腫、甲状腺癌、胚細胞腫瘍(精巣腫瘍、卵巣腫瘍、性腺外腫瘍) [1. 静脈内注射] 通常成人には、ブレオマイシン塩酸塩として15mg~30mg(力価)を生理食塩液又は、ブドウ糖液等の適当な静脈用注射液約5~20mLに溶解し、緩徐に静注する。
[2. 筋肉内注射、皮下注射] 通常成人には、ブレオマイシン塩酸塩として15mg~30mg(力価)を生理食塩液等の適当な溶解液約5mLに溶解し、筋注又は皮下注する。患部の周辺に皮下注射する場合はブレオマイシン塩酸塩として1mg(力価)/1mL以下の濃度とする。
[3. 動脈注射] 通常成人には、ブレオマイシン塩酸塩として5mg~15mg(力価)を生理食塩液又はブドウ糖液等の適当な注射液に溶解し、シングルショット又は連続的に注射する。
[4. 注射の頻度] 1週2回を原則とし、症状に応じて1日1回(連日)ないし1週間1回に適宜増減する。
 
注射用エンドキサン100mg,500mg[ドイツバクスター社提携 製造販売元/塩野義製薬株式会社]
発売1962年8月
1瓶中シクロホスファミド水和物106.9mg,534.5mg(無水物として100mg,500mgに相当)1. 下記疾患の自覚的並びに他覚的症状の緩解: 多発性骨髄腫,悪性リンパ腫(ホジキン病,リンパ肉腫,細網肉腫),肺癌,乳癌、急性白血病,真性多血症,子宮頸癌,子宮体癌,卵巣癌,神経腫瘍(神経芽腫,網膜芽腫),骨腫瘍 ただし,下記の疾患については,他の抗悪性腫瘍剤と併用することが必要である。:慢性リンパ性白血病,慢性骨髄性白血病,咽頭癌,胃癌,膵癌,肝癌,結腸癌,睾丸腫瘍,絨毛性疾患(絨毛癌,破壊胞状奇胎,胞状奇胎),横紋筋肉腫,悪性黒色腫
2. 以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法 :乳癌(手術可能例における術前,あるいは術後化学療法)
3. 下記疾患における造血幹細胞移植の前治療:急性白血病,慢性骨髄性白血病,骨髄異形成症候群,重症再生不良性貧血,悪性リンパ腫,遺伝性疾患(免疫不全,先天性代謝障害及び先天性血液疾患:Fanconi貧血,Wiskott-Aldrich症候群,Hunter病等)
4. 治療抵抗性の下記リウマチ性疾患:全身性エリテマトーデス,全身性血管炎(顕微鏡的多発血管炎,ヴェゲナ肉芽腫症,結節性多発動脈炎,Churg-Strauss症候群,大動脈炎症候群等),多発性筋炎/皮膚筋炎,強皮症,混合性結合組織病,及び血管炎を伴う難治性リウマチ性疾患
  
注射用イホマイド1g[ドイツバクスター社提携 製造販売元/塩野義製薬株式会社]
発売1985年7月
1瓶中イホスファミド1g1)下記疾患の自覚的並びに他覚的症状の寛解:肺小細胞癌,前立腺癌,子宮頸癌,骨肉腫,再発又は難治性の胚細胞腫瘍(精巣腫瘍,卵巣腫瘍,性腺外腫瘍)
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法:悪性骨・軟部腫瘍,小児悪性固形腫瘍(ユーイング肉腫ファミリー腫瘍,横紋筋肉腫,神経芽腫,網膜芽腫,肝芽腫,腎芽腫等)
[4. 小児悪性固形腫瘍(ユーイング肉腫ファミリー腫瘍,横紋筋肉腫,神経芽腫,網膜芽腫,肝芽腫,腎芽腫等)に対する他の抗悪性腫瘍剤との併用療法の場合](1) 他の抗悪性腫瘍剤との併用において,通常,イホスファミドとして1日1.5~3g/m2(体表面積)を3~5日間連日点滴静注する。これを1コースとし,末梢白血球の回復を待って3~4週間ごとに反復投与する。 (2) 総投与量はイホスファミドとして1コース10g/m2以下,全治療コース80g/m2以下とする。 
ランダ注10mg/100ml;25mg/50ml;50mg100ml[製造販売元/日本化薬株式会社]
発売1984年3月
1バイアル中シスプラチン10mg,25mg,50mg1)睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、卵巣癌、頭頸部癌、非小細胞肺癌、食道癌、子宮頸癌、神経芽細胞腫、胃癌、小細胞肺癌、骨肉腫、胚細胞腫瘍(精巣腫瘍、卵巣腫瘍、性腺外腫瘍)、悪性胸膜中皮腫
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法:  悪性骨腫瘍、子宮体癌 (術後化学療法、転移・再発時化学療法)、再発・難治性悪性リンパ腫、小児悪性固形腫瘍 (横紋筋肉腫、神経芽腫、肝芽腫その他肝原発悪性腫瘍、髄芽腫等)
  
パラプラチン注射液50mg,150mg,450mg[製造販売元/ブリストル・マイヤーズ株式会社]
発売1990年5月
1バイアル中カルボプラチン 50mg,150mg,450mg 1)頭頸部癌,肺小細胞癌,睾丸腫瘍,卵巣癌,子宮頸癌,悪性リンパ腫,非小細胞肺癌
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法:小児悪性固形腫瘍(神経芽腫・網膜芽腫・肝芽腫・中枢神経系胚細胞腫瘍,再発又は難治性のユーイング肉腫ファミリー腫瘍・腎芽腫)
  
フエロン注射用100万,300万,600万[製造販売元/東レ株式会社 販売元/東レ・メディカル株式会社 販売元/第一三共株式会社]
発売2009年10月
1バイアル中インターフェロン ベータ 600万国際単位(備考:ヒトの線維芽細胞由来)○膠芽腫,髄芽腫,星細胞腫 ○皮膚悪性黒色腫 ○HBe抗原陽性でかつDNAポリメラーゼ陽性のB型慢性活動性肝炎のウイルス血症の改善 ○C型慢性肝炎におけるウイルス血症の改善 ○リバビリンとの併用による以下のいずれかのC型慢性肝炎におけるウイルス血症の改善(1)血中HCV-RNA量が高値の患者 (2) インターフェロン製剤単独療法で無効の患者又はインターフェロン製剤単独療法後再燃した患者 ○C型代償性肝硬変におけるウイルス血症の改善(HCVセログループ1の血中HCV-RNA量が高い場合を除く) >[膠芽腫、髄芽腫、星細胞腫]添付溶解液の適量に溶解し、通常成人は1日100万~600万国際単位を髄腔内(腫瘍内を含む)に投与する。または生理食塩液又は5%ブドウ糖注射液等に溶解し、通常成人は1日100万~600万国際単位を点滴静注する。 
IFNβモチダ注射用100,300,600万単位[製造販売元/持田製薬株式会社 ]
発売[100,300]1988年12月[600]1996年2月
1バイアル中インターフェロン ベータ 100,300,600万国際単位 ヒト線維芽細胞由来 皮膚悪性黒色腫 膠芽腫、髄芽腫、星細胞腫 HBe抗原陽性でかつDNAポリメラーゼ陽性のB型慢性活動性肝炎のウイルス血症の改善 C型慢性肝炎におけるウイルス血症の改善 亜急性硬化性全脳炎患者におけるイノシン プラノベクスとの併用による臨床症状の進展抑制 
アドリアシン注用10,50[製造販売元/協和発酵キリン株式会社 提携/ファイザー株式会社]
発売1975年3月
1瓶中日局ドキソルビシン塩酸塩 10mg,50mg(力価) 1)下記諸症の自覚的及び他覚的症状の緩解: 悪性リンパ腫(細網肉腫、リンパ肉腫、ホジキン病)、肺癌、消化器癌(胃癌、胆のう・胆管癌、膵臓癌、肝癌、結腸癌、直腸癌等)、乳癌、膀胱腫瘍、骨肉腫
2)以下の悪性腫瘍に対する他の抗悪性腫瘍剤との併用療法: 乳癌(手術可能例における術前、あるいは術後化学療法)、子宮体癌(術後化学療法、転移・再発時化学療法)、悪性骨・軟部腫瘍、悪性骨腫瘍、多発性骨髄腫、小児悪性固形腫瘍(ユーイング肉腫ファミリー腫瘍、横紋筋肉腫、神経芽腫、網膜芽腫、肝芽腫、腎芽腫等)
  




【解説資料】
 日本で脳腫瘍の適応を持つものは、塩酸ニムスチン(ACNU)/ラニムスチン(MCNU)/シクロホスファミド/エトポシド/シスプラチン(CDDP)/カルボプラチン(CBDA)/硫酸ビンクリスチン(VCR)/硫酸ビンブラスチン(VLB)/ブレオマイシン(BLM)。
「脳腫瘍 Brain Tumor」 嘉山孝正(山形大学教授・脳神経外科) 今日の治療指針1998年版(IGAKU-SHOIN)によると、「c.化学療法: 水溶性nitrosourea薬剤であるACNU(ニドラン)が星細胞腫に使用されている。シスプラチン,エトポシド,ビンクリスチンの併用によって胚芽腫の治療結果の向上が認められ,髄芽腫の補助療法としても筆者らは良好な結果を得ている。」「2.脳腫瘍の予後: 全国脳腫瘍統計(1993)での手術後の5年生存率は全脳腫瘍では68%。悪性脳腫瘍では星細胞腫63%,膠芽腫8%。」
 Online版各種がんの解説[国立がんセンター]の●神経膠腫(しんけいこうしゅ) 「神経膠腫 glioma(グリオーマ)とは、脳に発生する悪性腫瘍で、原発性脳腫瘍の約3/1。腫瘍を構成する細胞の形態から、星細胞腫Astrocytoma(せいさいぼうしゅ:最も悪性である膠芽腫を含めると原発性脳腫瘍の25%程度)、乏突起膠腫oligodendroglioma(原発性脳腫瘍の約2.5%)、上衣腫Ependymoma(じょういしゅ:約2.5%)、脈絡乳頭腫(約0.5%)、髄芽腫Medulloblastoma(約2.8%)などに分類。一般に、この腫瘍は周囲の脳にしみ込むように拡がっていき(浸潤)、正常脳との境界が不鮮明で、手術で全部摘出することは困難です。そのため、通常は再発を予防する目的で手術後の放射線療法や化学療法などが必要となります。」
 「国内における脳腫瘍(転移性脳腫瘍を除く)の発生頻度は、人口10万人に対し10人程度とされ、欧米とほぼ同じであるといわれています。神経膠腫はそのうちのおおよそ30%を占め、最も多い腫瘍です。神経膠腫の中で最も多いのは星細胞腫で、その悪性度によって大きく4段階(グレード1~4)に分けられます。最も悪性度の低いグレード1は、小児の小脳に発生する星細胞腫で、この腫瘍だけはあまり周囲の脳に浸潤しないので、手術のみで治癒することが期待できます。グレード2以上は手術だけでは再発することが多く、手術後に放射線療法や抗がん剤による化学療法が行われます。特にグレード4は、脳腫瘍の中でも最も悪性度の高い腫瘍のひとつで、膠芽腫(こうがしゅ)と呼ばれています。膠芽腫は、現在なお治療が困難な疾患であり、手術だけでは大半が数ヶ月以内に再発するため、術後の放射線療法や化学療法は必須です。」



メルクマニュアル第18版日本語版
頭蓋内腫瘍
神経膠腫[メルクマニュアル家庭版]脳腫瘍各種がんの解説(部位・臓器別もくじ)[がん対策情報センター]
脳腫瘍(小児)
脳腫瘍(成人)
神経膠腫脳腫瘍 - Wikipedia[がんサポート情報センター]脳腫瘍[標準医療情報センター]脳腫瘍[総論][標準医療情報センター]脳腫瘍[各論]東京大学医学部脳神経外科:脳腫瘍[NCI]Brain Tumor 



【疫学資料】
●患者調査
疾病分類名  (単位:千人)1999年度2002年度2005年度2008年度
C71  脳の悪性新生物(2)(3)(4)(4)
 C719  脳,部位不明2344
 C793  脳および脳髄膜の続発性悪性新生物2246

 「患者調査」から日本のC71脳腫瘍患者数は(2008年)4000人、(2005年)4000人、(2002年)3000人、(1999)2000人;C793脳の続発性腫瘍は(2008年)6000人、(2005年)4000人、ほかは各2000人。 日本で脳腫瘍患者死亡数は年間1,730人(2009; 悪性腫瘍全体の0.50%; )。
 米国では脳腫瘍患者死亡数は年間12,760人(2005年推定)、脳腫瘍の新患は18,500人、うちグリオーマが50%。。 脳腫瘍疫学データは●!American Brain Tumor Association - Facts and Statistics About the Incidence of Brain tumors


【臨床ガイドライン】NCCN Tumor Practice Guidelines - Central Nervous System Cancers   the National Comprehensive Cancer Network (NCCN)
 ●[PDQ®日本語版]脳腫瘍の治療
 - 
 - National Guideline Clearinghouse - 米国

EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force
. 2006 Jul. NGC:005485
European Federation of Neurological Societies

Radiotherapy for newly diagnosed malignant glioma in adults: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2000 Sep 19 (revised 2005 Nov 2). 32 pages. NGC:004954

Carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.
National Institute for Health and Clinical Excellence - National Government Agency [Non-U.S.]. 2007 Jun. 45 pages. NGC:005735

Gliadel wafers in the treatment of malignant glioma: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2006 Aug 15. 19 pages. NGC:005649

Adjuvant systemic chemotherapy, following surgery and external beam radiotherapy, for adults with newly diagnosed malignant glioma: a clinical practice guideline.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]. 2004 Mar 10 (revised 2006 May 8). 23 pages. NGC:005092

 - NICE - Clinical Guidelines
 --- http://www.nice.org.uk/ ; NICE = National Institute of Clinical Experiences
 英国NHS [National Health Service]の1部門。1999年4月設立。
 - 英国における診療ガイドライン開発[IMIC; pdf,30p; あいみっく24(3)Jul 2003]
 ★Glioma
Glioma (recurrent) - carmustine implants (terminated appraisal)[2008.6]
  - 非推奨
Glioma (newly diagnosed and high grade) - carmustine implants and temozolomide[2007.6]
 - Carmustine implants は推奨。

★文献
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
 Stupp R.:the European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group 
 N Engl J Med 2005; 352:987-996, Mar 10, 2005. Original Articles
 関連ニュース
 - House of Commons Hansard Debates for 1 Mar 2006 (pt 23)
 - NICE Poised to Deny Brain Tumour Patients Access to Latest Breakthrough Treatments[2006.2.22]
 - Scottish Medicines Consortium[SMC] - NHS Scotlandの一部門
 - 2002年1月以降、新薬についてNHS Boards and their Area Drug and Therapeutics Committees (ADTCs)に勧告を行っている。
 - Medicines
 - Carmustine 7.7mg implant (GliadelR) (215/05)- Link Pharmaceuticals Ltd 12 December 2005 [pdf,7p]|[Press Statement]
   一般ニュース - Breakthrough Cancer Treatment Approved in Scotland but Still not Available to all on NHS[2005.12.12]



【総説記事・文献】特集 脳腫瘍研究の最前線―遺伝子解析から治療まで
BRAIN and NERVE 61巻7号(2009.07)
●[New therapeutic options in therapy of glioblastoma multiforme].
Lakomý R, Burkon P, Burkonová D, Jancálek R.
Klin Onkol. 2010;23(6):381-7. Review. Czech. 
●Educational paper. The development of new therapies for pediatric oncology.
Horton TM, Berg SL.
Eur J Pediatr. 2011 May;170(5):555-9. Epub 2010 Dec 30. Review.
●Towards drug discovery for brain tumours: interaction of kinins and tumours at the blood brain barrier interface.
Harford-Wright E, Lewis KM, Vink R.
Recent Pat CNS Drug Discov. 2011 Jan;6(1):31-40. Review.
●Adenoviral gene therapy in high-grade malignant glioma.
Pedersini R, Vattemi E, Claudio PP.
Drug News Perspect. 2010 Jul-Aug;23(6):368-79. Review.
●Cellular and vaccine therapeutic approaches for gliomas.
Hickey MJ, Malone CC, Erickson KL, Jadus MR, Prins RM, Liau LM, Kruse CA.
J Transl Med. 2010 Oct 14;8:100. Review.[Free PMC Article]
●Oncolytic adenoviruses for the treatment of brain tumors.
Gomez-Manzano C, Fueyo J.
Curr Opin Mol Ther. 2010 Oct;12(5):530-7. Review.




【ニュース・トピックス】





【リンク&リソース】MEDLINEplus: Brain CancerBT JAPAN: B級脳腫瘍日本語版

【主要サイト】日本脳腫瘍学会 - Jap Soc Neuro-Oncology
 - Neuro-Oncology日本脳腫瘍の外科学会 -Jap Congress for Brain Tumor Surgery
●日本脳腫瘍病理学会 - Jap Soc Brain Tumor Pathology
●NPO法人脳腫瘍ネットワーク(Japan Brain Tumor Allience 略JBTA)小児脳腫瘍の会
FDA - Cancer Liaison ProgramThe Brain Tumor Societythe National Brain Tumor FoundationAmerican Brain Tumor Association[脳腫瘍に関する一般向け・専門家向け各種データが充実。]




 







●解説


■脳腫瘍/Brain Tumor
●概要

脳腫瘍(Brain tumor)とは、脳の疾病のひとつで、頭蓋内組織に発生する新生物(腫瘍)のことを意味する。すなわち、脳腫瘍は脳細胞だけでなく、硬膜、クモ膜、頭蓋内の血管や末梢神経、その他の頭蓋内に存在するあらゆる組織から発生する。発生頻度は毎年約100,000人に12人の割合であるとされている。具体的な発生要因は明らかではない。
頭蓋内腫瘍は脳またはそれ以外の構造(例,脳神経,髄膜)を侵す。脳腫瘍は剖検全体の約2%に発見される。腫瘍は通常,成人期初期または中年期に発生するが,どの年齢層にも発生する;高齢者における頻度が増加している。良性腫瘍の場合もあるが,頭蓋内は増大する余地がないため,これらの腫瘍も重篤になる可能性がある。

●分類

脳腫瘍は、前述のように多種多様な組織から発生するため、分類には発生母地を基準にした、世界保健機構 (WHO) による脳腫瘍組織分類 (histological typing of tumours of the central nervous system) が世界的に用いられており、2006年度版では
・神経上皮組織性腫瘍(星細胞腫、乏突起細胞腫などの神経膠腫、上衣腫、脈絡叢腫瘍、その他の神経上皮性腫瘍、神経細胞性腫瘍、松果体部腫瘍、胎児性腫瘍など)
・ 神経鞘性腫瘍(神経鞘腫、神経線維腫など)
・ 髄膜性腫瘍(髄膜腫、その他の間葉性腫瘍、悪性黒色腫など)
・ リンパ腫および造血細胞性新生物(悪性リンパ腫、形質細胞腫など)
・ 胚細胞性腫瘍(胚細胞腫、卵黄嚢腫瘍、絨毛癌、奇形腫など)
・ トルコ鞍部腫瘍(頭蓋咽頭腫、下垂体細胞腫など)
・ 転移性腫瘍

に大別された、約130種類の脳腫瘍の組織型が定義されている。

原発性頭蓋内腫瘍には,脳実質に由来するもの(例,神経膠腫,髄芽腫,脳室上衣腫)および神経外構造に由来するもの(例,髄膜腫,聴神経鞘腫,その他のシュワン細胞腫)がある。頭蓋外腫瘍は頭蓋内構造または頭蓋骨に転移することがある。脳においては,転移性腫瘍が原発性腫瘍の約10倍多くみられる。

腫瘍の型は部位(頭蓋内および脊髄の腫瘍: 脳腫瘍による一般的な局在症状)および年齢によって若干異なる。小児においてよくみられる原発性腫瘍は,小脳の星状細胞腫,髄芽腫,脳室上衣腫,脳幹および視神経の神経膠腫,胚細胞腫,先天性腫瘍である。先天性腫瘍には,頭蓋咽頭腫,脊索腫,胚細胞腫,奇形腫,類皮嚢腫,血管腫,血管芽腫がある。最もよくみられる小児の転移性腫瘍は,神経芽腫(通常硬膜外)と白血病(髄膜性)である。

成人においてよくみられる原発性腫瘍は,髄膜腫,シュワン細胞腫,原発性リンパ腫,および大脳半球の神経膠腫(特に,悪性の多型性膠芽腫と未分化星状細胞腫,および,より良性の星状細胞腫とオリゴデンドログリオーマ)である。成人において最もよくみられる転移原発巣は,気管支原性癌,乳房の腺癌,悪性メラノーマ,肺転移する全ての癌であるが,全ての転移性癌が脳に転移する可能性がある。

■原発性脳腫瘍 
  ■神経膠腫 glioma 
    ■星状細胞腫 astrocytoma 
      ■毛様細胞性星状細胞腫 pilocytic astrocytoma 
      ■びまん性星状細胞腫 diffuse astrocytoma 
      ■退形成星状細胞腫(未分化星細胞腫) anaplastic astrocytoma 
      ■膠芽腫 glioblastoma 
    ■乏突起膠腫 oligodendroglioma 
    ■上衣腫 ependymoma 
    ■脈絡叢乳頭腫 choroid plexus papilloma 
  ■髄芽腫 medulloblastoma 
  ■神経鞘腫 neurinoma ,neurilemmoma
  ■髄膜腫 meningioma 
  ■血管芽腫 hemangioblastoma 
  ■胚細胞腫瘍 germ cell tumor 
    ■胚腫 germinoma 
  ■下垂体腺腫 pituitary adenoma 
  ■頭蓋咽頭腫 craniopharyngioma 
  ■悪性リンパ腫 

■転移性脳腫瘍 


YN.J.188

部位種類小児成人
頭蓋骨頭蓋骨腫瘍
大脳半球神経膠腫 
髄膜腫 
松果体胚細胞腫 
小脳半球星細胞腫 
血管芽腫 
小脳虫部髄芽腫 
第四脳室上衣腫 
鞍上部・
視交叉部・
下垂体部
頭蓋咽頭腫 
視神経膠腫 
胚細胞腫 
下垂体腺腫 
髄膜腫 
小脳橋角部聴神経鞘腫 
脳幹部神経膠腫
悪性度

一般に、脳腫瘍における病理組織学的な悪性度も、組織型の分類と同じくWHOによる分類法が利用されており、悪性度が最も低いGrade Iから悪性度が最も高いGrade IVまでの4段階に分類して個々の腫瘍と対比している。この悪性度と発生部位には関連性があり、一般に脳外 (Extra-axial) の場合は比較的良性の場合が多く、逆に脳内 (Intra-axial) の場合は悪性である可能性が高い傾向にある。WHOのGrade Iとは限局性で良性、Grade IIとは浸潤性であるが低悪性(細胞異型のみ)、Grade IIIとは退形成性(細胞異型と核分裂像)、Grade IVは悪性(細胞異型、核分裂像に加え、微小血管増生、壊死)である。このGradeは予後に相関すると考えられており、治療法の選択に影響する。

ただし、脳腫瘍はその発生場所が、脳という生命維持に重要な器官であり、かつ丈夫な頭蓋骨に囲まれた狭い場所であるという特殊条件ゆえに、前述の病理学的なものだけで判断するのは好ましくなく、臨床的な立場で悪性度を考える必要がある(例えば、病理学的にはGrade I=良性腫瘍であっても、頭蓋内圧亢進から脳ヘルニアを起こして致命的となりうる)。すなわち、腫瘍の発生部位、大きさ、浸潤性(後述)であるかどうか、放射線もしくは薬剤に対する反応性などを考慮する必要性がある。なお、脳腫瘍には基本的には病期 (Stage) という概念は存在しない。

浸潤性
浸潤性(しんじゅんせい)とは腫瘍の成長の仕方のひとつで、周囲の正常組織に分け入って、あたかも正常細胞を腫瘍細胞に置き換えていくように成長することをいう(対義語が「膨脹性」或いは「圧排性」で、周りの組織を機械的に押しのけながら成長するのみであることをいう)。すなわち、腫瘍と非腫瘍の境界が不明瞭であるため、この特性を持った腫瘍を全摘出しようとすると、同時に正常な細胞組織をも摘出しなければならないことになる。言い換えれば、腫瘍の全摘出が極めて困難であることを意味する。
退形成
退形成(たいけいせい)とは腫瘍細胞の分化度がより未分化であることを示している。未分化であるほど増殖速度が早く、また特異的マーカーに乏しく治療しにくいと考えられている。

発症年齢による分類
小児に多い脳腫瘍
(小脳)髄芽腫、上衣腫、脈絡叢乳頭腫、胚細胞腫瘍、頭蓋咽頭腫
成人に多い脳腫瘍
髄膜腫、下垂体腺腫、神経膠腫、神経鞘腫
つまり、子供が両耳側半盲を訴えたら、頭蓋咽頭腫や胚細胞腫を疑い、成人が同じように両耳側半盲を訴えたら、下垂体腺腫を疑うのが通常である。頭蓋咽頭腫、胚細胞腫、下垂体腺腫はいずれもトルコ鞍部に好発するため、両耳側半盲で気づくことが多い。これはこの部位の腫瘍は重篤な脳ヘルニアを起こしにくく、慢性進行性の頭痛などを主訴にしにくいからである。

 
発症部位による分類
 テント上腫瘍
  神経膠腫、髄膜腫、第3脳室の上衣腫など。基本的に成人に多い。
 テント下腫瘍
  髄芽腫、上衣腫、星細胞腫、神経鞘腫など。基本的に子供に多い。 
こういった部位は脳ヘルニアの起こし方などにも関わってくる。

放射線感受性による分類 放射線感受性が高い腫瘍 胚細胞腫、髄芽腫、脳室上衣腫 放射線感受性が低い腫瘍 神経膠腫、髄膜腫、血管芽腫、頭蓋咽頭腫など

脳内や脳の近くに由来する腫瘍

腫瘍の種類

発生場所

悪性度

原発性脳腫瘍に占める割合*

罹患する人

腺腫(アデノーマ)下垂体の細胞大部分が非癌性10%成人
脊索腫脊柱の胎児細胞非癌性だが、侵襲性1%未満成人(出生時から存在する)
頭蓋咽頭腫下垂体の胎児細胞大部分が非癌性1%未満成人(出生時から存在する)
類皮嚢胞と類表皮腫皮膚の胎児細胞非癌性1%未満小児と成人(類皮嚢胞は出生時にすでに存在)
上衣細胞腫脳室の内面を覆う組織の細胞大部分が非癌性約1%(小児期脳腫瘍の約9%)小児
生殖細胞腫瘍(胚細胞腫を含む)松果体の近くの胎児細胞癌性または非癌性1%小児(胚細胞腫は出生時に存在)
神経膠腫  65% 
星状細胞腫
神経細胞を支える組織の細胞(グリア細胞)癌性または非癌性(初期には非癌性の星状細胞腫の一部が、3〜5年後に癌性の未分化星状細胞腫になる) 小児と成人
希突起グリオーマ
脳神経線維を取り巻く髄鞘をつくる細胞(希突起グリオーマ細胞)通常は非癌性だが、癌性の未分化希突起グリオーマになることがある 小児と成人
多形グリア細胞腫
低分化のグリア細胞と希突起膠細胞癌性 成人
血管芽腫血管のもとになる胎児細胞非癌性1〜2%小児と成人
髄芽腫小脳の胎児細胞癌性(小児期脳腫瘍の25%)小児(通常は思春期前)と、まれに成人
髄膜腫脳を覆う髄膜の細胞非癌性だが、再発の可能性あり20%成人
骨腫頭蓋骨非癌性2%小児と成人
骨肉腫頭蓋骨癌性1%未満小児と成人
松果体腫松果体の細胞非癌性1%未満小児
下垂体腺腫下垂体の細胞非癌性2%小児と成人
肉腫結合組織癌性1%小児と成人

*他に特別な事情のない場合。

脳腫瘍“WHO 分類”の改訂の要点

●疫学

脳腫瘍は、頭蓋内の組織から発生する原発性脳腫瘍と他臓器がんからの転移性脳腫瘍に分けられ原発性脳腫瘍は10万人に年間11~12人発生するといわれており、国内全体では年間13,000~14,000人程度となる(脳腫瘍全国統計委員会、日本病理学会編。脳腫瘍取扱い規約。2002年7月第2版)。
中でも、悪性の膠芽腫は、現在の治療法では最も治療が困難な腫瘍として恐れられています。

瘍別発生頻度

腫瘍別発生頻度小児成人
神経膠腫33%星状細胞腫髄膜腫
髄膜腫22%髄芽腫膠芽腫
下垂体腺腫15%頭蓋咽頭腫下垂体腺腫
神経鞘腫9%胚細胞腫神経鞘腫
頭蓋咽頭腫5%上衣腫転移性脳腫瘍
発生率:10万人対10-15人。罹患率:10万人対46人

原発性脳腫瘍の種類割合
1.神経膠腫28%(悪性)
 1-1 星細胞腫(せいさいぼうしゅ)(28% )比較的良性
 1-2 悪性星細胞腫(18%)悪性
 1-3 膠芽腫(こうがしゅ)(32%)悪性
 1-4 髄芽腫(ずいがしゅ)(4%)悪性
 1-5 その他(18%)
2.髄膜腫26%(良性)(一部悪性)
3.下垂体腺腫17%(良性)
4.神経鞘腫(しんけいしょうしゅ)11%(良性)
5.先天性腫瘍(頭蓋咽頭腫など) 5%(比較的良性)
6.その他13% 
 

●症状

脳腫瘍は通常何らかの症状が出現したときには、すでに腫瘍はある程度の大きさに成長しているため、脳浮腫を引き起こしている場合がほとんどであり、頭蓋内圧亢進症状すなわち、頭痛、吐き気、嘔吐等を起こすとともに、発生部位によっては局所症状として視野欠損や難聴、運動麻痺、言語障害などを伴うことがある。また皮質に病巣がある場合はけいれん発作を起こす場合が少なくない。なお、頭痛は朝起きてすぐが最も痛みが強く、morning headache と呼ばれる。

女性の場合は(時には男性も)初期徴候として、妊娠していないにもかかわらず、母乳が出る(乳汁漏出)というものがある。これは乳汁分泌ホルモン(プロラクチン)の過剰産生によるもので視床下部、脳下垂体の機能障害によるものとされ、トルコ鞍近傍の腫瘍に特徴的にみられる。

1)局所症状

脳は神経の中枢ですが、運動や感覚などのいろいろな機能は脳の中で分散して行われている。例えば、左の前頭葉の運動野という手足などを動かす部位に腫瘍ができると右半身の麻痺がおこるというというぐあいである(右側に腫瘍ができた時は、麻痺は左半身におこる)。  脳の前方にある前頭葉の左側に腫瘍ができた右利きの人の場合には、無気力、痴呆様行動などの性格変化や尿失禁、右半身の麻痺、言語障害などが出現する。 後頭葉に腫瘍ができた時は、視野狭窄、視野欠損などがみられる。 右利きの人の左前頭葉(左利きの多くの人では右前頭葉)に腫瘍ができると言語障害がおこる。

脳の中心にある下垂体や松果体、視床下部付近に腫瘍ができると眼を動かす動眼神経の障害で複視(物が二重に見える)などの異常をおこしたり、ホルモンの分泌異常のために無月経や成長障害などの内分泌障害などがおこることがる。 小脳や脳幹と呼ばれる部位に腫瘍ができた場合には、手足などがふらつき、調整が効かない失調になったり、聴力障害、顔面麻痺、めまいなどがおこってくる。

2)頭蓋内圧亢進症状

限られた頭蓋内で腫瘍が大きくなると、正常な脳を圧迫し頭蓋内圧が上昇する。これにより持続的な頭痛、吐き気、うっ血乳頭(眼底検査で視神経乳頭がはれていること)などがみられるようになる。

慢性頭痛はその中でも最も注意しなければならないもの。頭痛は脳腫瘍以外の病気でもおこるが、脳腫瘍の場合には慢性的に持続し、朝起床時に強く、その後は次第に症状が弱くなっていく傾向がある。初期の脳腫瘍の約20%にみられる、進行するにつれ70%以上みられるようになる。頭痛の増悪とともに吐き気、痙攣、失神などもみられるようになる。これらの症状がみられた時は、すぐに医師の診察を受ける必要がある。

●原因



●画像診断

頭蓋咽頭腫は高頻度に石灰化がみられる。髄膜腫もしばしば石灰化を伴い、造影剤使用CTまたはMRI(Gd造影T1強調画像)で、均一な増強効果を認める("dural tail sign" - 硬膜と腫瘍の付着 - が特徴)。神経膠腫は脳実質との境界が不鮮明で、造影すると不均一な濃染像、またはリングエンハンスメントが認められる(膠芽腫)。他にリングエンハンスメントがある疾患には脳膿瘍や転移性脳腫瘍があげられる。悪性度の低い神経膠腫(星状細胞腫など)は、一般的に造影効果が低い。

脳腫瘍の場合、脳ドックを除いて他のがんで行われているような検診制度はない。今まで述べたような脳腫瘍を疑わせる自覚症状がある場合、早期に診察を受け、症状の経過を詳しく説明して、神経学的な異常があるかどうかを調べてもらうことが大切。また、脳に転移しやすいがんで他のがんの治療を受けている場合、前に述べた自覚症状があらわれた時には、CT、MRIなどの精密検査を受ける必要がある。

1)CT(コンピュータ断層撮影)、MRI(核磁気共鳴像)

現在の画像診断の中心をなす撮影法。腫瘍の位置や大きさ、画像上の特徴がわかり、重要な検査である。現在では5mmほどの大きさの腫瘍までわかるようになっている。大きさの変化や形状の時間的変化、周囲の脳との位置関係などを見る上で重要。

2)脳血管造影

脳の血管を造影することにより、腫瘍への栄養血管や腫瘍自体の血管の性状などの詳細な情報を取得でき、診断や手術検討に用いる重要な検査。

3)その他

超音波検査は現在手術中に行われ、術中の腫瘍の位置を正確に知る上で重要な役割を担っている。その他にも、いろいろな検査機器が開発されている。

●診断

初期の脳腫瘍はしばしば誤診される。脳腫瘍を考慮すべき患者は,進行性の局所的または脳全体の脳神経障害,新たに発生した発作,最近始まり説明のつかない持続性頭痛で特に睡眠により悪化するもの,頭蓋内圧亢進の証拠(例,乳頭浮腫,説明のつかない嘔吐)を示した患者である。類似の所見は,頭蓋内のその他の病変(例,膿瘍,動脈瘤,動静脈奇形,脳内出血,硬膜下血腫,肉芽腫,神経有鉤嚢虫症などの寄生虫性嚢胞)または虚血性脳卒中から生じる可能性もある。下垂体または視床下部の内分泌障害の原因としても腫瘍を考慮すべきである。

完全な神経学的診察,神経画像診断,胸部X線(転移の原発巣のため)検査を行うべきである。選択肢にはガドリニウムによるT1強調MRIがある。他の方法として造影剤を用いたCTがある。MRIは低悪性度の星状細胞腫およびオリゴデンドログリオーマを通常CTより早期の段階で検出し,また骨付近の脳構造(例,後頭蓋窩)をより鮮明に示す。全脳画像が標的部位(例,トルコ鞍,小脳橋角,視神経)の細部を十分に示せない場合には,その部位に限局した画像またはその他の特殊画像を得る。神経画像では正常だが頭蓋内圧亢進が疑われる場合には特発性頭蓋内高血圧(頭痛: 特発性頭蓋内圧亢進症 )を考慮し腰椎穿刺を行うべきである。

X線画像における腫瘍の型に関する手掛かりは主にMRI上の部位(頭蓋内および脊髄の腫瘍: 脳腫瘍による一般的な局在症状)と増強パターンであるが,これらは決定的なものではなく脳生検が必要である。特殊検査(例,血液およびCSFの分子腫瘍マーカーおよび遺伝子腫瘍マーカー)が有用となりうる症例もある:後天性免疫不全症候群の患者においては,CSFのEBウイルス力価の増加が,中枢神経系リンパ腫の発症時に典型的にみられる。

病期診断

成人脳腫瘍が画像診断で見つかった場合には、次に治療方法を決定するために脳腫瘍がどのような種類で悪性なのか良性なのか、悪性の場合にはどの程度悪性なのかを決める必要がある。

このためには、開頭手術を行って腫瘍をできるだけとってその組織を顕微鏡で調べ、脳腫瘍の種類と悪性の場合には悪性度を診断する病理診断が行われる。また、画像診断所見によっては、手術で腫瘍の一部を採取して同様に病理診断を行う方法がある。どちらを選ぶかの基準の多くは、画像診断と全身状態による。

●検査

腫瘍の遺伝子解析と分子・病理診断

 腫瘍の病理診断は、脳腫瘍に関して経験豊富な病理診断医によってなされる。さらに、この従来からの病理診断に加えて、最新の科学技術を用いた遺伝子解析や分子病理診断を追加して腫瘍の性質を見極め、適切な術後治療(放射線治療、化学療法など)の選択を行うことを目指している。

その一例として、乏突起細胞系腫瘍の患者に対しては、腫瘍における染色体1番短腕、19番長腕の欠失を全例において調べ(図6、診断と治療選択の参考にしている。現在では一般に広く行われるようになった検査であるが、東京大学においては有効性の最初の報告があった平成10年頃より継続してこの検査を行っており、長年にわたり多くの経験を重ねている。

 

図 染色体欠失の検査の一例。上段のそれぞれ2つずつあるピーク(2本の染色体に対応)が、下段の腫瘍では1つずつであり、該当部位の染色体が欠失していることが分かる。

●治療

脳腫瘍の治療において使用される治療法は基本的に外科手術であるが、他に放射線療法や化学療法といったものがあり、それぞれの特徴や現状などについて簡単に述べる。

外科手術

脳腫瘍治療の原則は手術による可及的な摘出である。良性腫瘍であれば腫瘍と正常脳組織との境界が明瞭であることが多く、全摘出できれば完治が期待できる。一方悪性脳腫瘍は周囲の正常脳組織に浸潤性に発育するため、全摘出は困難か不可能なことがほとんどである。摘出の際に隣接した正常組織まで摘出してしまうと、摘出部位によっては術後に片麻痺や言語障害などの重篤な後遺症を残してしまうことになる。したがって手術中に、motor evoked potential (MEP) やsensory evoked potential (SEP) などの電気生理学的モニタリング、あるいは現在の手術操作位置をリアルタイムに知ることができるニューロナビゲータ、術中CTやMRI等を駆使して、腫瘍をできるだけ多く摘出することが試みられる。また、言語野に存在する神経膠腫などに対しては、覚醒下手術も行われている。

術中MRIの導入により、悪性脳腫瘍および周辺の構造、特に錐体路(運動神経束)などの機能情報を含む神経線維の位置関係を明確に可視化し、ナビゲーションすることにより、悪性脳腫瘍の摘出の際に永年脳外科医を悩ませてきた脳の移動(ブレインシフト)問題も解決され、機能領域を温存することによる合併症の低減と摘出率の最大化が可能となった。悪性脳腫瘍の切除率を平均93%まで向上させ、全摘出率を46%(全日本脳腫瘍統計では8%)まで高めた。しかし、残存腫瘍を低侵襲で正確に摘出する精密治療の実現には、コンピュータを使った迅速な医療情報処理と可視化技術にもとづいて手術戦略を構築する低侵襲手術治療を推進し、外科医の技能の限界を超える微細操作・狭隘空間操作のための手術器具が不可欠である。画像誘導下手術は、機能領野を把握しながらの集学的手術で、悪性脳腫瘍の体積摘出率を95%程度に高めることに成功している。悪性脳腫瘍の5年生存率は95%除去時に22%程度である一方、100%除去時には40%超と倍増することから、残り5%の除去が重要である。ところが、残存腫瘍は切除部断面に薄く散在する形でごく少量の組織が残るのみである。浸潤性の悪性脳腫瘍の場合、術中に通常利用可能な観察手段、計測手段で腫瘍と正常組織を弁別することは困難であり、その位置の把握が難しい。術中MRIが利用可能であっても、検出の可否は腫瘍の体積に依存するため困難である。さらに位置が把握できた場合も、機能領野の損傷を防ぎつつ用手的にこれを除去するのは、安定した治療成績を挙げることが難しい作業である。
これらの問題を解決するために、残存腫瘍をレーザスキャンにより蒸散させるシステム「脳腫瘍焼灼レーザスキャンシステム」(2008,経済産業省)を開発した。

放射線療法

放射線治療は放射線を使って腫瘍細胞を破壊するもので50~60Gy(グレイ)を十数回に分けて照射するのが一般的である。放射線感受性の高い(効果の現れやすい)腫瘍には胚細胞腫、リンパ腫、髄芽腫などがあり、これらの中で胚芽腫は特に感受性が高く放射線照射のみで治癒する場合もある。また、一部の腫瘍ではガンマナイフ (γ-knife) やサイバーナイフ (Cyber Knife) と呼ばれる患部に集中的に放射線を浴びせる機械を使用した治療が行われる。 このガンマナイフは悪性脳腫瘍に対して有効とされている。線源は違うが、SMARTという集光照射の方法もある。

化学療法

化学療法は薬剤を使用して腫瘍の縮小させる方法であるが、脳には血液脳関門 (BBB; blood-brain barrier) と呼ばれる異物の進入を阻害する機構があるため、薬剤が目標箇所に到達しにくいという問題を抱えている。最近では神経膠腫に対してはテモゾロミドを用いるのが一般的である。また、頭蓋内悪性リンパ腫に対しては、high-dose MTX療法が行われる。

抗浮腫療法

転移性脳腫瘍に対しては抗浮腫療法としてグリセオール200mlを1日2回やデキサメサゾン6.6mgまたはプレドニン20mg一日二回の抗浮腫療法にて一過性の症状改善が得られることがある。30Gyの全脳照射など放射線療法が併用されることがある。

その他

その他の治療法としては、生体の免疫作用を高めて、腫瘍の成長を阻害する免疫療法(BRM; biological response modifiers 生体応答調節剤)や遺伝子療法、さらには重粒子線、陽子線を用いるものや温熱療法などが考案されているが、現段階ではこれらはあまり期待できるものではない。

昏睡または気道反射障害の患者には気管内挿管が必要である。腫瘍による脳ヘルニアは,マンニトール25〜100g点滴静注,コルチコステロイド(例,デキサメタゾン16mg静注,その後4mgを経口または静注にて6時間毎)および気管内挿管により治療する。塊状病変はできるだけ速やかに外科的に減圧すべきである。

腫瘍による頭蓋内圧亢進がヘルニアを伴わない場合はコルチコステロイド投与(例,デキサメタゾンを上述の方法による,またはプレドニゾン30〜40mgを,経口にて1日2回)により治療する。

脳腫瘍の治療は病理および部位によって決まる(聴神経腫瘍は内耳障害: 聴神経腫瘍を参照 )。診断および症状緩和のため外科的切除を用いるべきである。良性腫瘍であれば治癒することもある。脳実質へ浸潤している腫瘍では治療は多方式である。放射線療法が必要であり,また,化学療法が有効な患者もあるようである。

転移性腫瘍の治療には放射線療法があり,定位放射線手術が行われる場合もある。孤立性転移の患者では,放射線療法の前に外科的切除を行うことにより,よりよい結果が得られる。

1)成人星細胞腫
1.外科手術(腫瘍摘出術)が主に行われる。
2.病理学的診断でやや悪性の所見が疑われる場合には、外科手術後放射線療法が行われることがある。
3.外科療法後の放射線療法や化学療法の有効性については、臨床試験による検討が行われている。

2)成人悪性星細胞腫と成人膠芽腫
1.通常は外科療法によって腫瘍をできるだけ摘出し、その後放射線療法により残存した腫瘍をたたく治療法が行われる。
2.悪性度の高いものでは、外科療法後放射線療法に加え化学療法が行われる。
3.放射線療法には現在いろいろな方法があり、通常の外照射と呼ばれる照射法の他に、腫瘍内部へ針を刺して照射する方法、摘出された腔に照射する方法、手術中に照射する方法、放射線増感剤を利用した照射方法がある。これらについては臨床試験が行われ、既存の治療法と比較して有効かどうかの検討が行われている。
4.放射線療法後の化学療法や免疫療法などの治療法は、臨床試験で有効性の検討が行われている。

3)成人脳室上衣腫
1.外科療法による摘出療法が中心。
2.病理学的診断でやや悪性の所見が疑われる場合には、外科手術後放射線療法が行われることがある。

4)成人悪性脳室上衣腫
1.外科手術による摘出術後に放射線療法が施行される。
2.摘出後、化学療法併用の放射線療法は、臨床試験により有効性の検討が行われている。

5)成人悪性乏突起細胞腫
1.外科手術による摘出術後に放射線療法が施行される。
2.悪性度の高いものや化学療法がよく効く種類に対しては、手術摘出後に放射線療法と化学療法が行われる。
3.放射線療法後の維持化学療法や免疫療法などの治療法は、臨床試験で有効性の検討が行われている。

6)成人髄芽腫
1.外科手術後、放射線療法が行われる。
2.外科手術後に放射線療法を施行し、さらに化学療法を施行する治療法の有効性については臨床試験中。

7)成人髄膜腫
外科手術で完治する場合がほとんどですが、外科手術後腫瘍が残った場合には放射線療法が行われる場合もある。

8)成人悪性髄膜腫
1.外科療法後、放射線療法を施行する。
2.放射線療法後の化学療法や免疫療法については、臨床試験で有効性についての検討が行われている。

●薬物治療

化学療法

悪性神経膠腫に対しては、多くの場合で放射線照射に加えて主にテモゾロミド(テモダール)という内服の抗がん剤を用いて治療する。テモゾロミドは日本では2006年7月より保険適応となった薬剤で、現在悪性神経膠腫に対する世界的な標準治療薬である。副作用の程度を確認しながら、外来にても一定の期間、継続投与を行っていく。

新しい治療法

分子標的治療

 分子標的治療は、体内の特定の分子を狙い撃ちしてその機能を抑えることにより病気を治療する治療法である。癌細胞と正常細胞の違いをゲノムレベル・分子レベルで解明し、癌の増殖や転移に必要な分子を特異的に抑えることで治療する。欧米では新生血管を抑えるなどの効能を持つアバスチン(ベバシズマブ)という分子標的薬が使用されており、再発膠芽腫の治療成績を向上させた報告がなされている。

免疫療法~樹状細胞(Dendritic Cell, DC)療法:

腫瘍を樹状細胞という細胞に認識させることで免疫反応を高め、抗腫瘍免疫により効果を期待する治療法である。 東大でGrade3および4の星細胞系腫瘍の再発患者を対象として実施。治療に先立ち、手術で腫瘍組織を採取することが必要になる。一般的なホルマリン固定の腫瘍検体では治療に用いることができない。

免疫療法~ヒト臍帯静脈内皮細胞(HUVEC)ワクチン療法:

脳腫瘍は他の腫瘍や癌と同様、腫瘍を栄養する血管(腫瘍新生血管)ができることによって腫瘍が増大する。東京大学脳神経外科では輸血部と共同で、再発脳腫瘍を対象に、ヒト臍帯静脈内皮細胞(HUVEC)をワクチンとして用いる抗血管新生療法を臨床研究として行っている。

免疫療法~テーラーメード型がんペプチドワクチン

伊東恭悟教授(久留米大学免疫学・先端癌治療研究センター)は2010年4月に国内初の「がんワクチン外来」を開設し、来院初日からあまりにも応募が殺到し、約2時間で締め切るという騒ぎになった。同教授は2003年5月にベンチャー企業「株式会社グリーンペプタイド」を久留米市に設立した。 2005年10月 膠芽種に対する世界初のテーラーメイド型ペプチドワクチン第I相試験を開始。 初期治療(術後放射線化学療法または放射線治療)に抵抗性の膠芽腫を有するHLA-A24陽性患者を対象として、治験薬の単独投与を行い、その安全性の評価と有効性の評価を現在行っている。(数十種類のヒト自己蛋白由来ペプチドから選択)

硼素(ほうそ)中性子捕捉療法(BNCT): 

放射線治療法の選択肢の1つとして、硼素中性子捕捉療法を臨床研究として実施している。この治療法は、硼素化合物を点滴で投与した上で、腫瘍のある部位に熱外中性子という特殊な放射線を照射すると、硼素化合物を取り込んだ細胞のみが反応して死滅することを利用する。

ウイルス療法:

ウイルス療法とは、腫瘍細胞に限定して増えることができる遺伝子組換えウイルスを用いて腫瘍細胞を破壊する治療法。悪性脳腫瘍に対しては、単純ヘルペスウイルスを用いた臨床試験が欧米ですでに行われている。東京大学でもウイルス療法に関する基礎研究と臨床試験にむけた準備が行われているが、2009年1月の段階では臨床試験はまだ行っていない。 br>

●予後

脳腫瘍全体の5年生存率は75%を超えるようになった。良性の脳腫瘍である髄膜種では93%、下垂体腺腫は96%、神経鞘腫は97%。一方、神経膠腫全体では38%、最も悪性度の高い神経膠芽腫は6%、その次に悪性度の高い悪性星細胞腫は23%、星細胞腫が66%程度。転移性脳腫瘍は13%にすぎない。このように悪性脳腫瘍の治療が今後の課題となっている。

●参考資料

メルクマニュアル第18版日本語版
頭蓋内腫瘍
神経膠腫[メルクマニュアル家庭版]脳腫瘍各種がんの解説(部位・臓器別もくじ)[がん対策情報センター]
脳腫瘍(小児)
脳腫瘍(成人)
神経膠腫脳腫瘍 - Wikipedia[がんサポート情報センター]脳腫瘍[標準医療情報センター]脳腫瘍[総論][標準医療情報センター]脳腫瘍[各論]東京大学医学部脳神経外科:脳腫瘍[NCI]Brain Tumor 




■神経膠腫/Glioma
●概要

神経膠腫は脳実質に由来する原発性腫瘍である。症状および診断は他の脳腫瘍と類似している。治療には外科的切除,放射線療法があり,化学療法による場合もある。切除による治癒はまれである。 グリア細胞由来の腫瘍であり、神経上皮性腫瘍の大部分を占める。ほとんどが悪性腫瘍である。現在、星状膠細胞、乏突起膠細胞、上衣細胞に由来する腫瘍が知られている。グリア細胞としては他にミクログリアが存在するが、それを由来とする腫瘍は知られていない。 gliomaという名称は、19世紀にドイツの病理学者のルドルフ・ルートヴィヒ・カール・ウィルヒョーが初めて使用し、それ以来研究が続けられている。

●分類

神経膠腫(グリオーマ/Glioma)とは、脳に発生する悪性腫瘍で、原発性脳腫瘍の約30%を占める。 腫瘍を構成する細胞の形態から、星細胞腫(最も悪性である膠芽腫を含めると原発性脳腫瘍の22%程度を占める)、乏突起膠腫(原発性脳腫瘍の約1.3%)、上衣腫(約1.1%)、脈絡乳頭腫(約0.4%)、髄芽腫(約1.2%)などに分類される。

多くの神経膠腫はびまん性および不規則性に脳組織に浸潤するため、正常脳との境界が不鮮明で、手術で全部摘出することは困難である。そのため、通常は再発を予防する目的で手術後の放射線療法や化学療法などが必要となる。

星状細胞腫(Astrocytoma)は最もよくみられる神経膠腫である。昇順の悪性度では,グレード1または2(低悪性度星状細胞腫),グレード3(未分化星細胞腫),グレード4(膠芽腫,最も悪性度の高い多型性神経膠芽腫を含む)に分類される。低悪性度星状細胞腫または未分化星状細胞腫は,より若年の患者に発症する傾向があり膠芽腫に進行する可能性もある(二次性膠芽腫)。膠芽腫は染色体的に異種細胞を含有する。通常中年または高齢者において,新たな腫瘍(原発性膠芽腫)として発症しうる腫瘍である。原発性膠芽腫と二次性膠芽腫には明瞭な遺伝的特徴があり,これは腫瘍の進行に従って変化しうる。

乏突起膠腫(oligodendroglioma/オリゴデンドログリオーマ)は最も良性の神経膠腫の1つである。主に大脳皮質,特に前頭葉を侵す。

髄芽腫(Medulloblastoma)は主に小児および青年において通常第4脳室付近に発症する。脳室上衣腫はあまりみられない腫瘍である。主に小児において通常第4脳室付近に発症する。髄芽腫および脳室上衣腫は閉塞性水頭症の素因になる。

神経膠腫の分類は、1926年にベイリーとクッシングが発表したものが基礎となっている。その後、カーノハンが1949年に悪性度をgrade I~IVの4段階に分ける分類法を発表し、現在ではWHO gradeとして広く用いられている。

■星細胞系腫瘍 毛様細胞性星細胞腫
   びまん性星細胞腫
   退形成性星細胞腫
   膠芽腫
 星細胞系腫瘍は悪性度によって上記の4種に分けられる。
 毛様細胞性星細胞腫はgrade I,びまん性星状細胞腫はgrade II、退形成性星細胞腫は
 grade III、膠芽腫はgrade IVの悪性度とされる。 
■乏突起膠細胞系腫瘍
  乏突起膠腫(oligodendroglioma)
■上衣系腫瘍
  上衣腫(Ependymoma)
■脈絡叢腫瘍
  脈絡叢乳頭腫


●疫学

神経膠腫は脳腫瘍のうち約20%を占め、髄膜腫についで発生頻度が高い。小児では約40%で最も多いが、これは小児に好発する腫瘍が存在するためである。

また、脊髄腫瘍の約20%を占め、神経鞘腫についで発生頻度が高い。髄内腫瘍では約80%が神経膠腫である。

●症状

1)星細胞腫(Astrocytoma)

一般に脳腫瘍の症状は、徐々に増強する頭痛と片麻痺などの神経症状を特徴とする。悪性度の高い星細胞腫では、症状の発現から重篤な意識障害をきたすまでの期間が短く、数週間~数ヶ月ですが、悪性度の低いものでは数年におよぶこともある。また、突然の痙攣(けいれん)発作で発症する場合もある。一般に悪性度の低い星細胞腫は、CTでは黒くはれた画像として映る。造影剤を静脈注射してもほとんど変化が認められないため、脳梗塞と区別のつきにくいものもあるが、多くは症状の出現のしかたで脳血管障害と区別される。悪性度が高い星細胞腫は、造影剤により辺縁がリング状に白く造影され、内部は壊死をおこしているため黒く抜けたままである。また、周辺には広範な脳浮腫が認められる。MRIにより、腫瘍の拡がりや周囲の正常脳との関係はよりいっそう明瞭になる。治療法については後述するが、正常な脳との境界が不明瞭なため、手術のみでは腫瘍全部を摘出できないために、術後に放射線治療や化学療法が行われる。予後はグレードによって異なる。比較的おとなしいタイプのグレード2の星細胞腫であれば5年生存率は60~70%ですが、最も悪性のグレード4では10%以下。

2)乏突起膠腫(oligodendroglioma)

星細胞腫に比べ、経過が長いことが多く、数年来の痙攣発作を主症状とすることも珍しくない。前頭葉に多くみられ、石灰化を伴うことが多く、ときに硬膜への浸潤や腫瘍内出血もみられる。まれには再発を繰り返し、頭蓋外への転移も報告されている。予後は星細胞腫よりもよく、5年生存率は70~80%で、悪性の乏突起膠腫でも比較的よく化学療法に反応する。

3)上衣腫(Ependymoma)

大脳の深部には脳室と呼ばれる脳脊髄液を貯留する部屋があり、その壁を形成しているのが上衣細胞と呼ばれる細胞です。その上衣細胞より発生するのが上衣腫であり、普通は脳室壁に接する形で存在する。悪性度はあまり高くないが、大脳深部に発生することが多いため、手術で全部摘出することが難しく、術後に放射線療法や化学療法が追加される。上衣腫の中には治療後すぐに再発し、急速に病状が進行する場合もある。5年生存率は60~70%程度である。

4)脳幹グリオーマ(Brain Stem Glioma)

脳幹部、特に橋と呼ばれる大脳と脊髄の中間部分に発生する星細胞腫は、特別に脳幹グリオーマとして扱われ、小児に好発する。眼の動きをつかさどる動眼神経や顔の筋肉を動かす顔面神経などの脳神経の障害側と手足の麻痺が反対側になるのが特徴です。また、両手両足の四肢が麻痺することもある。手術が困難な部位であるため、手術が行われたとしても組織を確認するだけのことが多く、放射線照射主体の治療が行われているが、予後はよくない。

5)髄芽腫(Medulloblastoma)

小脳の中央部(虫部)より発生する小児の悪性腫瘍です。脳脊髄液の通過障害により、水頭症をきたしやすい疾患です。頭痛、嘔気、嘔吐などの頭蓋内圧亢進症状があらわれる他、歩行失調をきたしたり、姿勢保持が困難になったりする。元来、極めて悪性度が高く予後不良の腫瘍ですが、放射線の治療効果が高く、手術で摘出後、全脳、全脊髄に放射線照射を行うことにより、長期生存が期待できるようになってきました。また、抗がん剤が有効で、放射線と同時に用いられる他、放射線照射前に化学療法を行って照射量を減少させる試みがなされている。

●原因



●診断

診断は他の脳腫瘍と同じである

CT、MRIによってほとんどの脳腫瘍の診断は可能である。専門医が診れば、腫瘍の部位だけでなく、多くはその腫瘍の種類まで診断可能になる。CTはX線を用い、MRIは磁気を利用して断層写真をつくるものだが、情報量はMRIのほうが多く、人体に対する影響も少ないとされている。しかし、強力な磁気を用いるため、ペースメーカーを使用している場合や、過去の手術で体内に金属を埋め込んである場合などは検査ができないこともある。

手術を行う際には、腫瘍と脳の血管との関係をみたり、腫瘍にどの程度血管が入っているかなどを調べる目的で脳血管撮影が行われる。足のつけ根の動脈から細い管を挿入し、頸動脈や椎骨動脈まで進めて造影剤を注入してレントゲン撮影を行います。より簡便な方法として、頸動脈に直接針を刺して造影剤を注入することもある。また、最近ではMRIやCTを用いて脳血管を映し出す方法もとられている。

●検査



●治療

悪性神経膠腫に対しては手術、放射線療法、化学療法などを組み合わせた治療が行われる。この腫瘍は、正常脳に浸潤する形で発育するため、手術で全部摘出することは不可能であるが、最も悪性度の高い膠芽腫でも可能な限り広範に切除できた場合ほど生存期間が延びている。しかし、腫瘍を全部摘出すると正常な脳の機能を損なう可能性もある。

放射線療法は、原則としてすべての悪性神経膠腫に対して行われる。かつては全脳に照射されていたが、最近では放射線治療後の障害を少なくするため、腫瘍になるべく限局して照射するようになってきた。

抗がん剤は、単独では脳腫瘍に対する治療効果は大きくないが、放射線との併用により、その治療効果が高まる。わが国においては、ニトロソウレア系の薬剤であるACNU(ニドラン)が多く用いられる。一般には放射線療法開始時と6週目の2回静脈内注射されるが、さらに他の抗がん剤やインターフェロンなども組み合わせて投与されることがある。その後も約2ヶ月ごとに繰り返し、維持療法としてこれらの薬剤が投与される。

また、最近では,経口の抗癌剤であるテモダールが新規の治療薬として認可され、悪性神経膠腫の治療に使われ始めている。

未分化星状細胞腫および膠芽腫(anaplastic astrocytoma & glioblastoma )は,手術,放射線治療,化学療法で治療し腫瘍体積を小さくする。可能な限り大きく腫瘍を切除することは安全で,生存期間を延ばし,神経機能を改善する。外科手術の後,患者は腫瘍全体に線量(60Gy)の放射線を受けるが,その照射方法は理想的には原体照射法,つまり腫瘍を標的にし正常細胞には影響を与えない方法を用いる。化学療法にはニトロソウレア(例,カルムスチン,ロムスチン)の単剤または併用投与がある。併用化学療法の代わりに,テモゾロマイド150mg/m2,経口にて1日1回,最初の月に5日/月投与,その後の月には200mg/m2を投与することもある。化学療法を受けている患者では様々な間隔による全血球計算を行う必要があるが,各化学療法の少なくとも24~48時間前に行う。研究段階の治療法(例,chemotherapy wafers,定位放射線手術,新規化学療法剤,遺伝子または免疫療法)も考慮すべきである。従来の多方式による治療後,未分化星状細胞腫または膠芽腫の患者の生存率は1年後50%,2年後25%,5年後10~15%である。よりよい予後は,45歳以下,組織学的に未分化星状細胞腫(多形膠芽腫より),初回切除時に神経機能の改善がみられ残余腫瘍がごくわずかかまたはない場合に得られる。

低悪性度星状細胞腫(astrocytoma, low-grade)は可能であれば切除し,その後放射線治療を行う。放射線治療の開始時期については議論のあるところである:早期の治療は有効性を最大にするが脳への損傷を早める可能性がある。治療した場合の5年生存率はおよそ40〜50%である。

オリゴデンドログリオーマ(Oligodendroglioma;乏突起膠腫)は,低悪性度星状細胞腫と同様に切除および放射線療法により治療する。化学療法もときに用いられる。治療した場合の5年生存率はおよそ50~60%である。

髄芽腫(medulloblastoma )は約35Gyの全脳放射線照射,15Gyの後頭蓋窩照射,約35Gyの脊髄照射により治療する。化学療法は補助療法として,また再発例に対して用いられることがある。数種類の薬物―ニトロソウレア系,プロカルバジン,ビンクリスチンの単独使用または併用,随腔内へのメトトレキサート,多剤併用化学療法(例,メクロレタミン,ビンクリスチン[オンコビン],プロカルバジン,プレドニゾン[MOPP]),シスプラチン,カルボプラチンなど―が,ある患者では有効であるが,一貫して効果のある方法はまだない。治療した場合の生存率は5年で50%以上,10年でおよそ40%である。

脳室上衣腫(ependymoma)は,通常手術により腫瘍を切除しCSF灌流を確保し,その後,放射線療法により治療する。放射線療法は組織学的に良性の脳室上衣腫の場合には腫瘍を標的にして行うが,より悪性で外科手術後の残余腫瘍がある場合には,全脳照射療法を用いる。播種の証拠のある腫瘍の場合には全脳および脊髄に対して照射する。腫瘍をどの程度切除できるかにより生存率が最もよく予測される。治療した場合の5年生存率は全体では約50%であるが,残余腫瘍のなかった患者では70%以上である。

●薬物治療



●予後

神経膠腫は脳実質や脳幹に浸潤する特徴があるため、境界がわかりにくく、腫瘍を完全に摘出するのは非常に困難である。したがって、術後に放射線療法や化学療法を追加することが多いが、5年生存率は38.6%と原発性脳腫瘍全体の5年生存率(75.7%)の約半分となっている。

●参考資料

神経膠腫 - Wikipedia











●データ








●臨床ガイドラインなど





●総説記事・文献








●ニュース・トピックス








●リンク&リソース

MEDLINEplus: Brain Cancer

Contents of this page:
From the NIH
General/Overviews
Anatomy/Physiology
Clinical Trials
Diagnosis/Symptoms
Prevention/Screening
Research
Specific Conditions/Aspects
Treatment
Directories
Journals/Newsletters
Organizations
Children

The primary NIH organization for research on Brain Cancer is the
 National Cancer Institute
Search MEDLINE for recent research articles on
Brain Cancer:
・ In AdultsIn Children
You may also be interested in these MEDLINEplus related pages:
・ Brain and Nervous SystemCancersFrom the National Institutes of Health
Brain and Spinal Cord Tumors -- Hope Through Research (National Institute of Neurological Disorders and Stroke)
What You Need to Know About Brain Tumors (National Cancer Institute)

●General/Overviews
Brain Cancer (Patient Education Institute) - requires Flash plug-in
Also available in:  SpanishAnatomy/Physiology
Anatomy of the Brain (American Association of Neurological Surgeons, Congress of Neurological Surgeons)

●Clinical Trials
ClinicalTrials.gov: Brain Neoplasms (National Institutes of Health)

●Diagnosis/Symptoms
Brain Imaging (Society of Nuclear Medicine)
Computed Tomography (CT)-Head (American College of Radiology, Radiological Society of North America)
Functional MR Imaging (fMRI) - Brain (American College of Radiology, Radiological Society of North America)
Lumbar Puncture (Spinal Tap) (Harvard Medical School)
MR Imaging (MRI)-Head (American College of Radiology, Radiological Society of North America)

●Prevention/Screening
What Are the Risk Factors for Brain and Spinal Cord Tumors? (American Cancer Society)

●Research
Cellular Telephone Use and Cancer (National Cancer Institute)
Genetic Analysis of Childhood Brain Tumors Improves Diagnosis and Predicts Survival (National Institute of Neurological Disorders and Stroke)
Vaccine Increases Survival Rate for Patients With Deadly Brain Cancer (American Cancer Society)
Women with Rare Lung Disease Found to Also Have High Prevalence of Meningiomas (National Heart, Lung, and Blood Institute)

●Specific Conditions/Aspects
Craniopharyngioma (Pituitary Network Association)

●Treatment
Adult Brain Tumor (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Astrocytomas (International Radiosurgery Support Association)
Craniotomy (Animation Education Group)
Gamma-Knife Radiosurgery: Neurosurgery Without a Scalpel (Mayo Foundation for Medical Education and Research)
Glioblastomas (International Radiosurgery Support Association)
Metastatic Brain Tumors (International Radiosurgery Support Association)
Other Malignant Tumors (International Radiosurgery Support Association)
Radiation Injury to the Brain (International Radiosurgery Support Association)
Treatment of Specific Types of Brain and Spinal Cord Tumors (American Cancer Society)

●Directories
Find a Neurosurgeon (American Association of Neurological Surgeons, Congress of Neurological Surgeons)

●Journals/Newsletters
Childhood Brain Tumor Foundation Newsletter (Childhood Brain Tumor Foundation)

●Organizations
American Cancer Society
Brain Tumor Society
National Brain Tumor Foundation
National Cancer Institute
Neurosurgery://ON-CALL (American Association of Neurological Surgeons, Congress of Neurological Surgeons)

●Children
Brain Tumors (Nemours Foundation)
Childhood Brain Stem Glioma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Brain Tumors (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Cerebellar Astrocytoma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Cerebral Astrocytoma / Malignant Glioma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Ependymoma Childhood Ependymoma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Medulloblastoma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Supratentorial Primitive Neuroectodermal Tumors (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Childhood Visual Pathway and Hypothalamic Glioma (PDQ): Treatment (National Cancer Institute)
Also available in:  Spanish
Young People with Cancer: A Handbook for Parents (National Cancer Institute)
Page last updated: 13 November 2002
Topic last reviewed: 07 October 2002



BT JAPAN: B級脳腫瘍日本語版

脳腫瘍に悩むあらゆるひとのために情報を提供します。
準備がまにあいませんのでしばらくおまちください。
とりあえず下記のリンクからたどってください。

仮想脳神経病院(狭北病院)
東京大学藤巻高光先生の脳腫瘍ページ
Give hope
National Brain Tumor Foundation
American Brain Tumor Association
The Brain Tumor Society
Pediatric Brain Tumr Foundation

週刊医学界雑誌が脳腫瘍の特集をやっています。
直接読めますので参照してください。(98/11/7)
【脳腫瘍-発生要因から遺伝子治療まで】

(第1回)なぜ、いま脳腫瘍なのか-脳腫瘍の現在 発生原因から遺伝子治療まで(1) 野村和弘(国立がんセンター中央病院病棟部長)
〔第2回〕脳腫瘍のリスク因子(国立がんセンター研究所がん情報疫学部長 山口直人)
〔第3回〕脳腫瘍の性格を規定する因子,悪性化を促す遺伝子変化(佐賀医大教授 田渕 和雄)
〔第4回〕最新の診断・診療機器の現状と展望(1)-CT, MRIなどの機器の改良と臨床応用に ついて(東女医大教授 小林直紀)
〔第5回〕最新の診断・診療機器の現状と展望(2)-三次元画像,バーチャルリアリティの 臨床応用について(国立がんセンター中央病院 小山博史)
〔第6回〕脳の機能分野の確定とその手術への応用(東北大 中里信和)
〔第7回〕新しい放射線治療の臨床応用(東女医大教授 高倉公朋)
〔第8回〕抗がん化学療法の現状と問題点(熊本大教授 生塩之敬)
〔第9回〕遺伝子治療の現状と将来性(名大教授 吉田純)
〔第10回〕増加傾向にある転移性脳腫瘍の治療(国立がんセンター中央病院 渋井壮一郎)







●主要サイト

FDA Drug Information

Cancer Clinical Trials Listing (4/6/1999)
 This is an alphabetical listing of cancer organizations with extensive information about cancer treatments and clinical trials.
Drug Approvals for Cancer Indications
FDA Response to Letters Requesting Approval of Temozolomide for the Treatment of Adult Patients with Malignant Glioma at First Relapse, April 14, 1999. (Posted 4/23/1999)

FDA/Center for Drug Evaluation and Research
Last Updated: December 02, 1999
=======================================================

■■■FDA - Cancer Liaison Program

Patient Support, drugs and Clinical Trials, OSHI
[U.S. Food and Drug Administration]
Cancer Liaison Program
The Food and Drug Administration's Cancer Liaison Program in the Office of Special Health Issues answers questions directed to FDA by patients, their friends and family members and patient advocates about therapies for life-threatening diseases.

The Cancer Liaison Program staff is versed in the issues confronting patients dealing with a life-threatening illness and conversant with cancer information resources within FDA and other federal agencies, including the National Cancer Institute (NCI) and the private sector. The staff works closely with cancer patients and cancer patient advocacy programs, listening to their concerns and educating them about the FDA drug approval process, cancer clinical trials and access to investigational therapies.
Highlights:

developed a process for recommending, recruiting, and training patient representatives to serve on FDA advisory committees

established a program for cancer survivors to become temporary FDA employees and spend time with FDA medical staff reviewing drug company applications for the approval of new cancer therapies

collaborative with the NCI on a project to encourage pharmaceutical manufacturers to list clinical trials on the NCI's public access data base known as the Physicians Data Query Database (PDQ)

conducted educational programs for cancer survivors, cancer patient advocates, and cancer organizations to broaden their understanding of FDA's regulatory responsibilities in cancer drug developmen

presented education programs to pharmaceutical companies sponsoring cancer clinical trials about patient recruitment to cancer clinical trials
What's New
New Items placed on the Cancer Liaison Program web site.
Cancer Patient Representative Program
As part of the "FDA Initiative on Reinventing the Regulation of Cancer Drugs,'' the Cancer Liaison Program was charged with developing a process for recruitment, assessment, and selection of patient representatives to serve as members of cancer-related advisory committees in the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH). This initiative is intended to provide representation for cancer patients and to ensure that the selection process will provide for broad representation in the nominee pool, and to develop criteria for the selection of the patient representatives.
The criteria for both the nomination and selection process will help ensure that the patient representative will provide the perspective of the patients with the disease for which a therapeutic product is being considered by the advisory committee.

●FDA Approved Products 承認品目
FDA Approved Cancer Drugs listed by Cancer Type, January 5,2000
FDA Approved Cancer Drugs listed by Approval Date, January 5,2000
FDA Approved Cancer Drugs listed Alphabetically, January 5, 2000
FDA Approved Diagnostic Aids for Cancer, October 19, 1999

Cancer Clinical Trials Directory 臨床試験
This booklet is prepared by the Cancer Liaison Program for cancer patients and their
families which are frequently in search of information about the latest drugs being
researched to treat the patient's cancer. It contains links to clinical trial
information and sites conducting the trials. (last Updated November 29, 1999)

●News Releases プレスリリース
Press Releases, Department of Human Services press releases relating to FDA cancer activities.
Talk Papers, FDA press releases relating to cancer activities.
Cancer Related Articles
Cancer related articles written by the Cancer Liaison Staff, the FDA Consumer and other publications.

●Cancer Meetings ★制ガン剤諮問委員会
Cancer Meetings Archives, information about previously held cancer meetings with links to meeting transcripts.

Cancer Initiatives

●Other Cancer Web Sites and Information Sources リンク

Comments
For Additional Information, Please Contact: Cancer Liaison Program
Office of Special Health Issues
Food and Drug Administration
5600 Fishers Lane HF-12 Room 9-49 , Rockville, MD 20857
301.827.4460 888-INFOFDA (toll free) 301.443.4555 (FAX)
E-mail OSHI@oc.fda.gov
Office of Special Health Issues Home Page
Cancer Liaison Program
Office of Special Health Issues
Office of International and Constituent Relations
Last revised January 5, 2000
=======================================================

■■Cancer, approvals, oncology, treatments, approvedOSHI, FDA★承認品目・癌分類別

[U.S. Food and Drug Administration]
Drug Approvals by Cancer Indications
December 1999 through June 1996
Cancer Type
Bladder | Brain | Breast
| Colon/Rectal | Head and Neck |
Kaposi's sacrcoma
| Leukemia | Lung | Lymphoma
| Melonoma |
Miscellaneous
| Ovarian | Pancreatic | Prostate

Brain
Gliadel (carmustine wafer) for Implantation, sponsored by
Guilford Pharmaceuticals Incorporated, was approved on September 23, 1996, for use in addition to surgery to prolong survival in patients with recurrent glioblastoma multiforme who qualify for surgery.
[略]
Miscellaneous
[略]
Temodar (temozolomide),
from Schering-Plough Corporation received accelerated approval on August 11, 1999 for the treatment of adult patients with refractory anaplastic astrocytoma, (i.e. patients at first relapse who have experienced disease progression on a drug regimen containing a nitgrosourea and procarbazine).
[略]
=======================================================

Cancer Related meetings, archive★制ガン剤諮問委員会

[U.S. Food and Drug Administration]
Cancer Liaison Program
Cancer Meeting Archives
Last Revised November 8, 1999
For additional transcript and meeting materials, please visit the
Oncologic Drugs advisory committee meeting page at http://www.fda.gov/ohrms/dockets/ac/cder99t.htm
Description of Meetings
[略]
Oncologic Drugs Advisory Committee Meeting, on March 23, 1999 to discuss NDA 21-051, Temodal (temozolomide) Capsules,
Schering Corporation, indicated for the treatment of patients with advanced metastatic malignant melanoma. Transcript in Text Format (172 kb)

Oncologic Drugs Advisory Committee Meeting, on January 12,
1999 to discuss (1) NDA 21-029, Temodal (temozolomide) Capsules, Schering
Corporation, indicated for the treatment of adult patients with malignant glioma
(glioblastoma multiforme and anaplastic astrocytoma) at first relapse; and (2) NDA 50-766 Progal (tacrolimus) capsules 1 mg and 5 mg, and Prograf (tacrolimus)
injection 5 mg (for IV infusion only), Fujisawa Healthcare, Inc. indicated for the
prophylaxis of graft-versus-host disease in patients receiving allogenic
bone marrow transplants.(Transcript of meeting PDF
Format, RTF Format)
[略]
=======================================================

■■●Cancer Clinical Trials Directory

[U.S. Food and Drug Administration]
Cancer Clinical Trials Directory
November 29, 1999
Disclaimer of Endorsement: Reference in this document to any specific commercial products, process, manufacturer, or company does not constitute endorsement or recommendation by the U.S. Government. The Food and Drug Administration (FDA) or the Office of Special Health Issues (OSHI) is not responsible for the contents of any of the referenced internet web pages or telephone hot lines.
Table of Contents
Clinical Trials by Tumor Type
Brain Cancer | Breast Cancer | Colon Cancer | Kidney Cancer |
Leukemia |
Lung Cancer | Lymphoma
| Melanoma | Myeloma
| Prostate Cancer
Clinical Trials by General Categories
NCI Designated Cancer Centers
Pediatrics and
U.S. Government
NCI Designated Cancer Center Definition
[略]
Clinical Trials by Tumor Type
Brain Cancer
Organization
 Name/Address
Telephone
Web Address
Type of Clinical Trial Information Available
American Brain Tumor Association
2720 River Road
 Des Plaines, IL 60018
1-800-886-2282
www.abta.org
Links to NCI/PDQ and CenterWatch.
Children's Brain Tumor Foundation
274 Madison Avenue #1301
 New York, NY 10016
212-448-9494
www.childrensneuronet.org
Provides NCI's Cancer Information Service's phone number.
Clinical Trials & Noteworthy Treatments for Brain Tumors
1100 Peninsula Boulevard
 Hewlett, NY 11557
516-295-4740
virtualtrials.com
Lists some clinical trials on brain tumors. Links to NCI/PDQ.
National Brain Tumor Foundation
785 Market Street #1600
 San Francisco, CA 94103
1-800-934-2873
www.braintumor.org
Links to NCI/CancerNet, Oncolink and Virtual Trials.
The Brain Tumor Society
84 Seattle Stree
 Boston, MA 02134
1-800-770-8287
www.tbts.org
Links to Virtual Trials.
[略]
=======================================================
■■●Cancer Talk Papers, OSHI, FDA
[U.S. Food and Drug Administration]
Cancer Talk Papers
January 6, 2000
[略]
FDA Approves New Drug for Brain Cancer (Date Released August 11, 1999)★temozolomide
[略]
=======================================================
■■●Cancer Related Articles from FDA
[U.S. Food and Drug Administration]
Cancer Liaison Program
 Office of Special Health Issues
Cancer Related Articles
[略]
FDA Response to letters requesting approval of temozolomide for the treatment of adult patients with malignant glioma at first relapse, April 14, 1999
[略]



The Brain Tumor Society Home Page

Basic Information About Brain Tumors
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AWARDS

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Call For Research Grant Applications: 2000
Cancereducation.com videotaped many of the sessions at Frontiers of Hope in Providence.


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by mberling@ma.ultranet.com
Last updated on 01/09/2000

Recent topics
Dinner remarks by Rachel Henderson, a ten-year anaplastic astrocytoma survivor
 Ten Scientists Receive 1999 Grants for Basic Brain Tumor Research
Phase IA Trial with ONYX-015 Adenovirus for Recurrent Malignant Gliomas
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the National Brain Tumor Foundation

Home | Welcome!
| About NBTF | What's New | Survivor's Story | Physician Interview
Resources | Frequently Asked Questions
| Treatments & Rehabilitation | Clinical Trials
Tumor Types | Keep Me Posted | Volunteering & Contributing | Acknowledgements

Copyright ゥ 1996 National Brain Tumor Foundation.
 All rights reserved.
1-800-934-CURE
National Brain Tumor Foundation
414 Thirteenth Street, Suite 700 Oakland, CA 94612-2603
Tel: (510) 839-9777 - Fax: (510) 839-9779
nbtf@braintumor.org 
=======================================================
■Resources

The National Brain Tumor Foundation is pleased to
present a comprehensive and growing list of resources to help
you find out more about brain tumor diagnosis, treatments and
other organizations providing related information. This lis
is quite extensive, and we would like to keep it growing to make
sure you have accurate and helpful resources to research your
options. Please let us know if you have any suggestions to make
this more useful.
Click on the follwoing to find out more information:
NBTF RESOURCES
INTERNET RESOURCES
BRAIN TUMOR ORGANIZATIONS
CANCER ORGANIZATIONS
CAREGIVER RESOURCES
=======================================================

Resources: National Brain Tumor Foundation (NBTF) Resources


Brain Tumors, A Guide - This comprehensive 56-page guidebook helps patients and their families understand and cope with brain tumors.
SEARCH - A quarterly newsletter that covers topics of current interest to brain tumor survivors and their families. For a free subscription, please sign our guest book.

★Fact Sheets:
Questions about Brain Tumors (in Spanish)
Issues to Consider when Choosing a Brain Tumor Treatment Center
Clinical Trials for Brain Tumors
New Chemotherapy Drugs for Brain Tumor Patients
Gene Therapy
Brochure: Understanding Brain Tumors: Glioblastoma Multiforme
National Brain Tumor Conference Audiotapes At NBTF's biennial National Brain
Tumor Conference, leading researchers, physicians and health professional address a range of issues affecting brain tumor survivors such as new approaches to radiation and surgery, research, and coping skills for families. Audiotapes of keynote addresses and conference workshops are available from the 1994, 1996 and 1998 conferences by calling 800-360-1145 or online at http://www.caltapes.com/nbtf.
Clinical Trials and Questions about Brain Tumors - Fact Sheets (in Spanish)
Returning to Work: Strategies for Brain Tumor Patients - This brochure reviews brain tumor survivors' rights with respect to returning to work and suggest several strategies to make transition into the workplace.
A Guide for Parents, Understanding and Coping with Your Child's Brain Tumor - This guide provides information about diagnosis, tumor types, treatment methods, social and emotional support and more. It also contains a glossary and listings of organizations and resources.
A Brain Tumor Resource Directory for health care providers. The directory contains the names and phone numbers of various organizations who offer services and products of particular interest to brain tumor patients and their families.

★Other Publications
Gathering a Life: A Journal of Recovery ュ A wife's experience of dealing with her husband's brain tumor. By Jeanne Lohman. Available from NBTF for $8.75
Navigating Through a Strange Land: A Book for Brain Tumor Patients and Their Families. - This 220-page book by a former brain tumor patient presents honest accounts of personal and family experience with the disease. By Patricia Ann Roloff. To order by phone call 1ュ888ュ294ュ8127 (A portion of the proceeds of the sale of this book are donated to NBTF).
Clinical Trial Information - Lists of clinical trial by state, tumor type and/or treatment type.
Brain Tumor Information Line -Toll-free phone number to quickly access brain tumor information and resources.
Resource Library - Printed information and articles on treatments, clinical trials, tumor types and brain tumor related topics.
Support Groups - A national listing of brain tumor support groups and assistance in starting support groups
Support Line Network - Phone contact with other brain tumor patients and family members.
National and Regional Conferences - NBTF sponsored educational conferences for patients, families and friends and health professionals.



American Brain Tumor Association

脳腫瘍に関する一般向け・専門家向け各種データが充実。
Brain tumor information

The American Brain Tumor Association provides information
and funds brain tumor research
through events such as these. Click here to learn more about other such events. Site last updated 1/6/00.
who we are

resources
guestbook
professionals
sitemap

Raising funds for brain tumor research, the Wallin brothers set off on
an amazing 13,000-mile canoe trip from Montana to Brazil. Track their
progress here!

The American Brain Tumor Association (ABTA) was founded in 1973 by two families who lost children to brain tumors. They vowed to find answers through research. Today, ABTA is a global organization making major strides by funding brain tumor research and providing the information patients need to make educated decisions about their healthcare.
American Brain Tumor Association
2720 River Road
Des Plaines, IL 60018
Phone: (847) 827-9910
Fax: (847) 827-9918
Patient Line: (800) 886-2282

E-mail: info@abta.org
http://www.abta.org
Copyright ©1997, 1998, 1999, 2000 American Brain Tumor Association
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!American Brain Tumor Association - Site Index

Site Index
Click on the subjects below for a quick link.
About ABTA
Advisory Council
Advocacy
Awareness Pin
Awareness Week '99
"Benign" vs. "Malignant" tumors
Brain tumors by type
Caregiver Support
Causes
Childhood tumors
Clinical trial explanation
Clinical trial listings
Definitions
Diagnosis/testing
Dictionary
Donations
Events
Glossary
Grading tumors
How the brain works
Incidence
Internet Basics
Links
Medical Student Fellowships
Medline
Meetings
Memorials
Memory Retraining
Mission
Net-Working Resources
New treatments
Newsletters
Nursing Research Grants
Parts of the brain
Patient and family meetings
Pathology Reports
PDQ searches
President's Message
Primer of Brain Tumors
"Primary" vs. "Metastatic" tumors
Publications available
Quality Care Principles
Rehabilitative Medicine
Research awards, 1999
Scans
Sign Our Guestbook
Specific tumor types/treatments
Statistics★統計ファクトデータ[別掲] 
Survivor/Family Stories
Symposia
Symptoms of tumors
"Thinking of You" cards
Town Hall meetings
Treatment explanations
Types of brain tumors
Volunteering for ABTA
Who we are
Your donations at work

Brain Tumor Information 
Comfort and Resources 
For Professionals
To Make A Donation
ABTA Publications & Services
Who We Are
=======================================================

!American Brain Tumor Association - For Professionals

For Professionals Research Funding Available Historical List of ABTA Research Awards Currently-Funded ABTA Research To Request Research Funding Information International Meeting Calendar Message Line Newsletter Patient Education Tools Finding Clinical Trials =======================================================

!American Brain Tumor Association - Information About Brain Tumors and Their Tr

Brain Tumor Information A Primer of Brain Tumors Extensive text and diagrams about the diagnosis, treatment, and effects of the many types of brain tumors Dictionary Definitions as well as pronunciations Finding Clinical Trials Search clinical trial databases to learn about the newest research treatments Questions to Ask Your Doctor --> Treating Adult Brain Tumors Online audio/video presentations Happiness is...Calendar Encourage your family, friends, and employer to help fight brain tumors in this special way... Audiotapes of the 1999 Sharing Hope Symposium Were you unable to attend? Use this form to obtain the tapes. International Meeting Calendar Opportunities for patients, family members, and healthcare professionals Calendar of Upcoming ABTA Events Continually updated list of special events across the US ABTA Publications and Services Online request form for additional materials and services Message Line Newsletter The latest in brain tumor news, research, and events Brain Tumor Information Comfort and Resources For Professionals =======================================================

!American Brain Tumor Association - State-of-the-Art Treatment

●Basic Research
Much brain tumor research is now focused on genes. Genes are the material inside our cells which makes each of us unique. Genes contain strings of chromosomes - tiny information bundles which tell the body how to do its work. Several types of brain tumor tissue including glioblastoma, anaplastic astrocytoma, medulloblastoma, and meningioma tissue appear to contain abnormal or missing chromosomes. Some of those chromosomes normally serve as tumor suppressors, controlling the number of cells made by the body to avoid overproduction. The overproduction of cells, especially abnormal cells, results in the growth of a tumor. Other chromosomes are thought to control the production of growth factors - natural hormones which nourish developing cells. Researchers are looking for causes of these abnormalities and possible ways of manipulating the chromosomes into appearing normal again.

The past year also brought a wealth of knowledge about angiogenesis - the growth of the blood supply which brings nutrients to a tumor. Several studies moved from the laboratory to early clinical work, and are discussed in the section on biologic therapies below. The knowledge gained in these studies paves the way for the development of additional products that interfere with the growth of tumor cells.

In your search for information about brain tumors, it is important to remember that the word "genetic" does not mean "hereditary." Scientists currently believe that brain tumors, and the defects found on the genes inside those tumor cells, are the result of several insults to normal cells. It is also known that only about 5% of brain tumors appear to be hereditary - passed from generation to generation. Those tumors tend to be part of genetic syndromes which cause the formation of multiple tumors in other parts of the body as well as the brain. For example, neurofibromatosis and tuberous sclerosis are hereditary diseases which cause brain tumors along with tumors in other organs of the body.

● Surgery
Current trends in neurosurgery focus around imaged-guided surgery - ways of combining three-dimensional computer-assisted technology and surgical tools. Collectively, these tools allow neurosurgeons the ability to plan and execute a surgical procedure in dimensional space.

Many tools take advantage of this technology. Holography helps the neurosurgeon plan and practice a surgical approach prior to the actual procedure by giving three-dimensional depth to scans. "Real-time MRI" units allow the neurosurgeon to use MRI guidance during surgery to verify the amount of tumor removal. Stereotactic navigational systems make use of a hand-held wand (the ISG Viewing Wand). When touched to the brain, the wand transmits three-dimensional coordinates to a computer screen, showing the location of the tumor in relation to the wand. Brain-mapping techniques enable the surgeon to locate the vital areas controlling language and motor functions, helping the surgeon avoid that area during tumor removal. Photodynamic therapy (PDT) helps the neurosurgeon visualize the border of a tumor by use of a special dye injected prior to surgery. The dye accumulates in tumor cells, causing them to fluoresce when a laser is aimed at them. A laser is then used to vaporize the tumor cells. Microsurgical tools, the smallest of surgical instruments, combined with exquisitely high-powered microscopes are used to remove tumors in the base of the skull and/or around cranial nerves.

● Radiation
Radiosurgery combines computer technology with radiation therapy to deliver focused, pin-point beams of high-dose radiation to the tumor. The goal of this approach is to limit the exposure of normal brain to the effects of radiation. Although there are three basic pieces of equipment used to deliver radiosurgery - the Gamma Knife, adapted linear accelerators, and cyclotrons which produce proton beams - the "brand names" of the equipment may vary with the manufacturer. For example, the Cyberknife and the X-Knife are both linear accelerator-based radiosurgery systems. Conformal radiation, also called intensity modulated radiation therapy (IMRT), shapes the pattern of radiation beams to the shape of the tumor. Radioprotectors are drugs, such as DFMO, which protect brain cells during radiation therapy. Radiosensitizers appear to make tumor cells more sensitive to radiation. Both of these techniques may allow the use of higher, more effective doses of radiation with fewer radiation side-effects. Radioenhancers, such as RSR13 or Gd-texaphyrin, are designed to increase the efficiency of radiation therapy without increasing the dosage of radiation. Boron neutron capture therapy uses a boron compound activated by neutron radiation beams. Monoclonal antibodies are radioactive molecules used to deliver radiation or immunotherapy substances to a tumor.

● Chemotherapy
A number of new drugs are being tested for effectiveness against malignant brain tumors. Temozolomide, a lower toxicity oral drug originally developed in England, has shown enough promise in initial testing that it is now offered in larger clinical trials for patients with both primary and recurrent malignant astrocytomas. CPT-11, a drug found effective in colon cancer, is being tested in gliomas. Biodegradable wafers containing the drug BCNU (Gliadel wafers) were approved by the FDA for patients with recurrent glioblastoma multiforme when surgery is otherwise indicated. A variant of these wafers, containing differing amounts of BCNU, are being tested in clinical trials for those with malignant gliomas. In other drug delivery research, scientists are working on tiny microspheres (called liposomes) capable of carrying chemotherapy drugs through the blood stream to the tumor. Receptor-mediated permeabilizers (RMP-7) are under investigation as a way of opening the blood brain barrier to allow increased amounts of chemotherapy drugs to reach the brain. PCV (a combination of the standard drugs procarbazine, lomustine, and vincristine) is being used against oligodendroglioma and malignant astrocytomas.

Differentiating drugs such as phenylbuterate and phenylacetate seem to return tumor cells to more normal behavior. O-BG is a drug used to help overcome tumor resistance to chemotherapy. Each of these are available in clinical trials.

● Biologic Therapies
Scientists are very cautiously exploring thalidomide - a drug linked to many birth defects in the 1950's - for its ability to control the growth of new blood vessels. An obviously undesirable effect in a developing embryo, this side-effect may be harnessed to control the growth of new blood vessels around a tumor. It is being tested in patients with recurrent glioblastoma.
Other angiogenesis inhibitors are in development; Angiostatin and Endostatin are expected to soon receive approval for testing. Suramin appears to prolong the lives of patients with metastatic prostate cancer and is now being tested in brain tumor patients. Squalamine is also in testing as an angiogenesis inhibitor - it is a substance discovered in the liver of the dogfish shark.

Gene therapy trials are now available at many institutions for both adults and children. In one clinical trial offered to patients with glioblastoma multiforme, a gene sensitive to ganciclovir, an anti-viral drug, is transferred into the tumor. Ganciclovir is then given to the patient intravenously in an attempt to kill the sensitized tumor cells. Other gene therapy trials are being designed to boost the body's immune response. Some trials are working toward the genetic manipulation of growth factors - natural nutrients which both feed tumor cells and control their reproduction. Other trials will soon attempt to replace damaged p53 genes, thought to control the natural death of cells. Researchers continue to explore the possibilities of using different viruses as delivery methods, therapies that will protect new blood cells from the effects of chemotherapy, and treatments which may ultimately allow for the replacement of damaged genetic material.

● To Find These Clinical Trials
PDQ is a database, sponsored by the Cancer Information Service of the National Cancer Institute, which provides information about state-of-the-art treatments and new, investigative treatments. Over 200 brain tumor clinical trials are referenced in PDQ. A basic search of this database can be performed online at http://cancernet.nci.nih.gov. Or, an information specialist at the Cancer Information Service can assist you in searching the database by tumor type, treatment type, geographic area, or sponsors. The Cancer Information Service can be reached at (800) 422-6237.

● Rehabilitation
As brain tumor patients live longer, they are discovering the benefits of rehabilitative medicine. Cognitive re-training specialists teach one area of the brain to take over for an injured part of the brain. Occupational therapists help patients learn new ways of successfully living with a disability. Physical therapists can help re-train and strengthen muscles. Neuro-psychologists are studying the long-term effects of brain tumor treatment, and quality of life is an important consideration in the evaluation of clinical trials. Social workers can help link patients to these rehabilitative resources as well as other community-based services which help to improve the lives of brain tumor patients and their families.

Brain tumor treatment and research is a growing, dynamic field in which things are always changing. This article offers a broad overview and does not address every treatment option available. Many of the treatments mentioned here are investigative, and it is still too soon to know their long term effects. But it is important for brain tumor patients to be aware of the neuro-oncology community's dedication to finding more effective, less toxic treatments for brain tumors. And this is, ultimately, what ABTA is all about ... Sharing Hope.

For a listing of physicians offering investigative treatments for brain tumor patients, please click here.
This article was updated April, 1998.
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!American Brain Tumor Association Newsletter

Fall 1999 Summer 1999 If you prefer to receive your newsletter via e-mail, please click here. =======================================================

!American Brain Tumor Association Newsletter - Fall '99

New Options North American Brain Tumor Coalition "Becoming Well Again" Through...Financial Aid Resources Managing a Glioblastoma Multiforme Hope for the New Millennium Rock Star Conquers Brain Tumor Mailbox =======================================================

!American Brain Tumor Association Newsletter - Fall '99 :New Options

Within the past few months, several new treatments became available to brain tumor patients. Here is a sampling:

● Thalidomide, the drug linked to fetal abnormalities in the 1950s, is now offered in carefully controlled research studies as an angiosuppressive treatment for gliomas. The drug's ability to stop the growth of blood vessels is now being harnessed as a potential means of controlling tumor growth. Thalidomide, used in combination with radiation therapy as a treatment for glioblastoma, is offered in clinical trials through the Radiation Therapy Oncology Group. Information is available from the Cancer Information Service at (800) 422-6237.

● Proxima Therapeutics, Inc. recently opened a clinical trial testing the delivery of liquid radiation directly into tumors. Offered through the New Approaches to Brain Tumor Therapy (NABTT) consortium, the GliaSite Radiation Therapy System is currently available to those experiencing regrowth of a malignant tumor. The liquid radiation is contained in a special balloon catheter positioned within the tumor during surgery. Detailed patient information about this study is available at Proxima's web site - www.proxima.org - or through our office at (800) 886-2282.

● Two new methods of delivering focused radiation were recently in the news. The first, called Novalis Shaped Beam Surgery, delivers high-energy focused photon beam radiation.
The radiation beams are shaped to conform with the shape of the tumor in an attempt to avoid radiating normal brain tissue. Markers placed on the jaw eliminate the need for the head-frame used in traditional radiosurgery. The first US hospital to offer the Novalis system is UCLA Medical Center. A video produced by the manufacturer, BrainLAB, is available from our office.

Another new radiosurgery device, which recently received FDA approval, is the CyberKnife. This equipment combines a miniature linear accelerator, a robotic arm and missile technology to deliver focused beams of radiation to the tumor. Skeletal landmarks are used to eliminate the need for a stereotactic head-frame. Originally developed at Stanford Medical Center, the CyberKnife is now available at 5 hospitals in the United States. Information about the unit, including locations, is available at the manufacturer's web site - www.accuray.com.

● FDA approval was recently received for the new chemotherapy drug, Temodar (temozolomide). First developed in England at the Charing-Cross Cancer Center as a lower-toxicity, oral drug for treating several types of cancer, temozolomide underwent clinical trial testing as a potential treatment for gliomas. Based on those results, Temodar was granted FDA approval as a treatment for refractory anaplastic astrocytoma. Specifically, the drug was approved for use in patients with anaplastic astrocytoma who have been treated with a nitrosourea and procarbazine combination of drugs who then experience tumor regrowth. Information about Temodar is available from our office.

Temozolomide continues to be offered in clinical trials to patients with other forms of brain tumors. For more information about those clinical trials, please call the Cancer Information Service at (800) 422-6237 and request a PDQ search for "temozolomide clinical trials."

● Penicillamine (a derivative of the antibiotic drug, penicillin) in conjunction with a copper-depletion diet is being studied as an angiosuppressive therapy for the treatment of glioblastoma. Offered by the New Approaches to Brain Tumor Therapy (NABTT) consortium, details of this study can be found a their web site: www.nabtt.org.
There are many other new methods of treating brain tumors; these are just a few. For additional information, we suggest:

Audio-tapes of the Sharing Hope Symposium presentations
Treating Adult Brain Tumors and
Treating Pediatric Brain Tumors
As We Approach the Millennium
Order forms are available from the ABTA office a
(800) 886-2282
*******
Cancer Information Service at (800) 422-6237
*******
www.cancertrials.nci.nih.gov
(Clinical trial web site of the National Cancer Institute)
*******
www.virtualtrials.org (Virtual Trials web site maintained by Al Musella)

Questions about your treatment options should be addressed to your healthcare team. Inclusion in the article above does not constitute endorsement of any of these products, treatments, or resources. The web sites and resources cited are responsible for their own content and availability.
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[1035]●製品 Gliadel Wafer (polifeprosan 20 with carmustine implant) [MGI Pharma]


 日本語版註)Gliadel Wafer (polifeprosan 20 with carmustine implant) [MGI Pharma]
 【別名】 【開発元】Guilford Pharmaceuticals Inc.→現MGI Pharma,Inc  [DBR_ID]
 【化学名】BCNUを含浸させた生分解性ポリマ-“薄シート”;carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. The copolymer, polifeprosan 20, consists of poly[bis(pcarboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine.
 【承認~多形性神経膠芽腫】FDA申請=、FDA承認=1996.9.23 ; 【承認~神経膠腫】FDA申請=2001.4.6、FDA承認=2003.2.25 ; 【製剤】GLIADEL Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine 【適応】1)[神経膠腫]GLIADEL Wafer is indicated in newly-diagnosed high grade malignant glioma patients as an adjunct to surgery and radiation. 2)[多形性神経膠芽腫]GLIADEL Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery. 【用法用量】10セント硬貨サイズの多無水物薄シートを、切除後に残った手術腔に植え込む。 【作用】腫瘍部位に直接アルキル化剤を放出するため、血液-脳関門を回避することができる。薄シートは、加水分解により分解され、約2-3 週間にわたって薬物を放出する。 【特徴】 【製品情報】http://www.gliadel.com/ 【添付文書】http://www.gliadel.com/pdf/211_029_Gliadel_PI.pdf 【EU】世界25か国で販売;英国Gliadel[Link Pharmaceuticals]2004.12発売 【日本】日本未開発 【その他】Drug Topics Red Book 1998年8 月改訂版の卸売価格(AWP) に基づく、薄シート8 枚のコストは12,480ドル





●承認データ:FDA

●2004.5.1 以降 Drugs@FDA

Drug Name(s) =Gliadel Rx FDA Application No. =NDA # 020637 Active Ingredient(s)=CARMUSTINE Company =MGI PHARMA INC Dosage Form/Route =IMPLANT; INTRACRANIAL:7.7MG Strength = - Approval Date=09/23/1996[000] :Label[添付文書]| - Approval Date=02/25/2003[016] :Label[添付文書]|Letter[承認書]|Review [New or Modified Indication]
Electronic Orange Book

Application Number: 020637 Rx Active Ingredient : CARMUSTINE Proprietary Name : Gliadel [MGI PHARMA INC] IMPLANT; INTRACRANIAL:7.7MG Approval Date : Sep 23, 1996 Exclusivity Data : ODE FEB 25,2010 I-382 FEB 25,2006 Patent Data : 4757128 AUG 01,2006 4789724 AUG 01,2006
●FDA Advisory Committees

参考●ML_ADD資料:FDA諮問委員会~議題 FDA Advisory Committees FDAAdvisorycommittee.com CDER■Oncologic Drugs - http://www.fda.gov/ohrms/dockets/ac/cder06.html#OncologicDrugs Oncologic Drugs 2005 | 2004 | 2003 | 2002 | 2001 | 2000 FDAAdvisorycommittee.com: Oncologic Drugs
ML開催日議題備考
 2001.12.6Pharmacia Camptosar Postmarketing Safety Issues; Guilford Gliadel 
Brief Information Gliadel Briefing Documents[pdf,98p] Clinical Review[pdf,108p] FOI Service GliadelのSBA資料が販売されている
金額頁数タイトル
$p5210869A: Oncologic Drugs Advisory Committee: 12/06/2001 Transcript Regarding Camptosar
$p5210869B: Oncologic Drugs Advisory Committee: 12/06/2001 Briefing Information Regarding Camptosar
$pAERS336A [N20637] Search of FDAs Adverse Event Reporting System Database for Gliadel (carmustine). Search results presented in an Access 2000 database file and delivered on CD. Be sure to select paper delivery in your order.

$585.95298p一括●149858A [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Approval Letter; Medical Officers Review; Pharmacology/Toxicology; Clinical Pharmacology & Biopharmaceutics; Statistical Review; Chemistry; Microbiology; Environmental Assessment; Corresponden
$134.9538p5228515F [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Chemistry
$241.95101p5228515B [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Medical Officers Review
137.95$40p5228515C [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Pharmacology/Toxicology
118.95$29p5228515H [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Environmental Assessment; Finding of No Significant Impact
$54.957p5228515D [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Clinical Pharmacology & Biopharmaceutics
$82.9522p5228515I [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Correspondence
$173.9561p5228515E [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Statistical Review
$9.956p5228515A [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Approval Letter
$44.954p5228515G [N20637] Gliadel Wafer (Guilford) 09/23/1996 Approval: Microbiology
$218.95172p諮問委記録●5204498A: Oncologic Drugs Advisory Committee Meeting: 6/14/1996 Transcript Regarding the Gliadel Wafer

$p5216788F: Guilford Pharmaceuticals, Baltimore, Maryland: 481, EIR, 483, Correspondence 02/01-12/1999
$p5227836B [N20637] Phillipe Bret, Lyon Cedex, France: EIR, 483, Company Response, Correspondence 09/03-04/2001
$p5210869C: Oncologic Drugs Advisory Committee: 12/06/2001 Slides Regarding Camptosar
$p5216788E: Guilford Pharmaceuticals, Baltimore, Maryland: EIR 10/26/1999
$p5227846B: Phillipe Cornu, Paris, France: EIR, 483, Correspondence 09/06-07/2001
●EU承認

EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ■[Enterprise and Industry DG] Directorate F - Consumer Goods -http://pharmacos.eudra.org/ ★The Community Register[承認製品リスト] - 医薬品は1995.10以降。 各製品データシートにリンク。 [医薬品]Community Register of medicinal products for human use - [年月別] - 取下げ・中断 - 却下 [総合索引~成分別]General index on active ingredient [総合索引~銘柄別]General index on brand nameCarmustine (solution for intratumoral injection) EU/3/02/085 Human Orphan designation - 2002.3.5 オーファン指定。 by Icon Clinical Research, UK; [適応] Glioma




MGI Pharma,Inc

PRODUCTS Aloxi(R) (palonosetron hydrochloride) injection ... 制吐剤 GLIADEL(R) Wafer (polifeprosan 20 with carmustine implant) ...脳腫瘍薬 Hexalen(R) (altretamine) Capsules ...膀胱癌 Salagen(R) (pilocarpine hydrochloride) Tablets ...シェーグレン症候群 ●PIPELINEINVESTORSAnnual ReportsSEC Filings 10-K Annual Filings[2006.3.16] - [PDF] 10-K Annual Filings[2005.3.11] - [pdf] News & MEDIA MGI PHARMA Reports Fourth Quarter and Full Year 2005 Financial Resul[2006.2.8] MGI PHARMA Reports Fiscal 2003 Results and Provides 2004[2004.2.11] MGI PHARMA Announces Expiration of Tender Offer for Guilford Pharmaceuticals Notes Due 2008[2005.11.29] MGI PHARMA Completes Acquisition of Guilford Pharmaceuticals[2005.10.3] -------------------------------------




 - http://www.mgipharma.com/; [本社]米国ミネソタ州;抗癌剤ベンチャー; NASDAQ:MOGN
 米国、カナダ
1990  Didronel静注をProcter & Gamble Pharmaceuticals, Inc.から買収
1993  MGIは、acylfulvene agents, including irofulvenに関してUnivCaliforniaから全世界ライセンスを受けた。
 Irofulvenは、単独または各種制癌剤との併用で臨床試験中
1994  MGI社開発のSalagen Tablets(R)がFDA認可。 適応は, 頭頚部癌患者の放射線によるドライマウス
1998  Salagen Tabletsの[適応拡大]Sjogren's syndromeによる口渇がFDA承認
2000  MGIはMG98およびa complementary small molecule DNA methyltransferase
 inhibitor programをMethylGene, Inc.から北米地域に関してライセンスを受けた。
Also, MGI purchased the worldwide rights to Hexalen capsules from MedImmune, Inc.
2001  MGIは、palonosetronの米国・カナダの販売権をHelsinn Healthcare SAからライセンス
2002  MGIとHelsinn Healthcare SAはAloxiをFDA申請
2003  AloxiがFDA承認[2003.7.25]
2005.10  Guilford社を買収



10-K Annual Filings[2006.3.16] - [PDF]から

Gliadel Wafer for Malignant Glioma as an Adjunct to Surgery and Radiation and for Recurrent Glioblastoma Multiforme

Gliadel (polifeprosan 20 with carmustine implant) Wafer (“Gliadel”) is a proprietary, targeted, site-specific cancer chemotherapy product approved in the United States for the treatment of malignant glioma, a form of primary brain cancer, and for the treatment of recurrent glioblastoma multiforme (“GBM”), a rapidly fatal form of malignant brain cancer. Gliadel, a biodegradable polymer wafer, is implanted into the cavity in the brain after a brain tumor is removed and gradually dissolves, delivering high concentrations of BCNU (or carmustine, the active chemotherapeutic ingredient) directly to the tumor site for an extended period of time. This product minimizes exposure to BCNU throughout the body and reduces or alleviates many of the side effects associated with intravenous chemotherapy. We estimate that there are approximately 11,000 cases of malignant glioma in the United States each year.
We acquired rights to Gliadel when we acquired Guilford in October 2005. Product sales of Gliadel for 2005 were $33.7 million (representing $25.2 million from January through September 2005, and $8.5 from October through December 2005). Product sales of Gliadel for 2004 and 2003 were $27.7 million and $19.2 million, respectively.
In addition to the U.S., we have regulatory approval to market Gliadel for use in patients with recurrent GBM in over 21 countries. During September 2004, Gliadel was granted expanded marketing authorization for use in newly-diagnosed patients with high-grade malignant glioma as an adjunct to surgery and radiation in France, Germany, Greece, Ireland, Italy, Netherlands, Portugal, Spain and the United Kingdom. We market, sell and distribute Gliadel in these countries either directly, on a named patient basis under applicable law, or through distribution agreements with various European companies.
We have a right to the underlying technology for Gliadel pursuant to a license agreement with the Massachusetts Institute of Technology (“MIT”) that requires us to pay annual royalties based on our net revenue from Gliadel, as defined per the license agreement. From January through September 2005, Guilford recognized approximately $1.0 million in royalty expense pursuant to that agreement, and from October through December 2005, we recognized $0.3 million in royalty expense pursuant to that agreement. Our domestic patent protection for Gliadel ends in August 2006; however, during September 2004, the FDA notified Guilford that Gliadel is entitled to market exclusivity for the treatment of patients with malignant glioma undergoing primary surgical resection until February 2010 under applicable orphan drug laws.

提携関連 Gliadel Wafer

In March 1994, Guilford entered into an agreement, the Gliadel Agreement, with Scios Inc. (“Scios”) pursuant to which Guilford licensed from Scios exclusive worldwide rights to numerous U.S. patents and patent applications and corresponding international patents and patent applications for polyanhydride biodegradable polymer technology for use in the field of tumors of the central nervous system and cerebral edema. Gliadel is covered under this license by two U.S. patents and certain related international patents and patent applications. The patent rights in the U.S. will expire in 2006. In April 1994, Scios assigned all of its rights and obligations under the Gliadel Agreement to MIT. We have exclusive worldwide rights to the technology for brain cancer therapeutics, subject to certain conditions, including a requirement to perform appropriate pre-clinical tests and file an Investigational New Drug Application (“IND”) with the FDA within 24 months of the identification of a drug-polymer product having greater efficacy than Gliadel.
Under the Gliadel Agreement, we are obligated to pay a royalty of 4% on all net product revenue incorporating the technology covered by the agreement, as well as 25% of all proceeds from sublicensees and 4% of proceeds from corporate partners. For a particular country, our obligation to pay a royalty on net revenue expires upon the later to occur of (i) the expiration of the relevant patent rights in such country or (ii) 15 years after the first sale of a commercial product derived from the licensed technology in such country. For the year ended December 31, 2005, we incurred a total of approximately $0.3 million in royalty expense to MIT under this license agreement. This amount represents royalty expense on account of Gliadel wafer product sales from October 2005 through December 2005 (following our acquisition of Guilford). Prior to our acquisition of Guilford, they incurred $1.0 million of royalty expense from January 2005 through September 2005.
Each party may terminate the agreement if the other party materially breaches the agreement, subject to prior notice to and an opportunity to cure by the offending party. Additionally, we may terminate the agreement at any time with six months prior written notice to MIT. Upon termination of the agreement (other than because of a material breach by MIT) all license rights revert to MIT, subject to our limited right to use the licensed technology for a 90-day transition period following termination of the agreement. Although we believe that we can comply with our obligations, our failure to perform these obligations could result in losing our rights to new polymer-based products.

●関連データ

EU Court Holds that an Ingredient that Controls the Release of an Active Ingredient Doesn't Make a Combination[2006.5.9] - Gliadelの2007年の特許失効を5年間延長するというMITの誓願は却下された。 ■Robert Langer MIT教授 MIT's Langer wins two prestigious prizes[2003.12.2] Scios Inc ~最近のパイプラインは乏しい。 ■日本特許 carmustine AND implant
公報番号国際分類識別記号出願番号発明の名称出願人全頁
特表平09-504042C08J 3/14他CFJ他平07-505393生分解性粒子米国マサチューセッツ インスティテュート オブ テクノロジー39
特表平09-504308C08G 81/00他NUS他平07-505337非直鎖状の親水性-疎水性マルチブロックコポリマーのナノ粒子およびマイクロ粒子米国マサチューセッツ インスティテュート オブ テクノロジー49
■Biodegradable polymers /生分解性ポリマー ドラッグデリバリーシステムの米国市場[The Freedonia Group -2008/03] ドラッグデリバリー技術:主要企業、製品および2015年までの展望[Espicom Business Intelligence -2007/11] ナノドラッグデリバリー技術:主要企業、製品および2015年までの展望[Espicom Business Intelligence -2007/11] 市場調査報告書:生分解性ポリマー市場[BCC Research - 2007/12] 市場調査報告書:生分解性ポリマー市場[Frost & Sullivan -2004/03] ■最近の注目すべき文献 /2008.6.26 A retrospective study of the safety of BCNU wafers with concurrent temozolomide
and radiotherapy and adjuvant temozolomide for newly diagnosed glioblastoma patients
Edward Pan et al.; Journal of Neuro-Oncology 88(3)353-357,Jul 2008 Monitoring the effects of BCNU chemotherapy Wafers (Gliadel(R))
in glioblastoma multiforme with proton magnetic resonance spectroscopic
imaging at 3.0 Tesla
Jonathan P. Dyke et al.; Journal of Neuro-Oncology 82(1)103-110,Mar 2007 2:Lin SH, Kleinberg LR. Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther. 2008 Mar;8(3):343-59. PMID: 18366283 [PubMed - in process]







■BCNU


 日本語版註)
 【別名】 【開発元】Bristol-Myers Squibb  [DBR_ID]
 【化学名】1,3-bis (2-chloroethyl)-1-nitrosourea
 【承認】FDA申請=、FDA承認= ; [Emcure Pharmaceuticals Ltd]
【製剤】Each package includes a vial containing 100 mg carmustine and an ampule containing 3 mL sterile diluent.
 【適応】BiCNU is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following:
1. Brain tumors - glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors.
2. Multiple myeloma - in combination with prednisone.
3. Hodgkin’s Disease - as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
4. Non-Hodgkin’s lymphomas - as secondary therapy in combination with other approved drugs for patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
 【用法用量】The recommended dose of BiCNU as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 75 to 100 mg/m2 on 2 successive days. When BiCNU is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.
 【作用】 【特徴】 
 【添付文書】BiCNU(R) -PI
 【提携】インドEmcure Pharmaceuticals Ltd.が2012年12月BMSからBiCNUの全世界の権利獲得 -[2] 【EU】 
【日本】未開発  【その他】




●承認データ:FDA

●2004.5.1 以降 Drugs@FDA

★Drug Name(s) =BICNU (CARMUSTINE) FDA Application No. =(NDA) 017422 Active Ingredient(s)=CARMUSTINE Company =BRISTOL Dosage Form/Route =100MG/VIAL INJECTABLE; INJECTION Strength = - Approval Date=03/07/1977[000][Approval]:   申請  適応 Original Approval or Tentative Approval Date March 7, 1977 Chemical Type 1 New molecular entity (NME) Review Classification S Standard review drug - Approval Date=08/17/2007[037][Manufacturing Change or Addition]:Label[添付文書]|Letter[承認書]|Review   申請  適応
Electronic Orange Book

Application Number: 017422 Active Ingredient : CARMUSTINE Proprietary Name : BICNU [BRISTOL ->EMCURE PHARMS LTD] INJECTABLE; INJECTION 100MG/VIAL Approval Date : March 7, 1977 Exclusivity Data : - Patent Data : -
●関連ニュース
FDA advises health care professionals that counterfeit BiCNU has been discovered in some foreign countries[05/12/2016] The authentic product is approved to treat different types of brain cancer, multiple myeloma , and lymphoma (Hodgkin’s and non-Hodgkin’s). BiCNU is manufactured by Emcure Pharmaceuticals Ltd. and distributed in the United States by Heritage Pharmaceuticals Inc. *Heritage Pharmaceuticals Inc. FOI Services, Inc. - FDAの情報公開法[FOI]に基づき公開される資料を販売する。 3400A [N17422] BiCNU(Bristol), NDA#17-422-Summary Basis of Approval, Package Insert & Bibliography [02/14/1977] 13p $183.95
BMS

InvestorsSEC Filings 10-K Annual Filings[2009.2.20] - [pdf] - [doc] - [xls] 10-K Annual Filings[2008.2.22] - [pdf,205p] Financial Reports & InformationAnnual Reports Annual Report 2008[2009.3.23] - [pdf] Annual Report 2007[2008.3.26] - [pdf] Earning Releases Bristol-Myers Squibb Company Reports Financial Results For The Fourth Quarter And Twelve Months Of 2006 And Announces EPS Guidance For 2007 [2007.1.25] Press release[html] - Press release[pdf] - ★重要★Quarterly Package of Financial Information [xls]Presentations & EventsNews Releases Bristol-Myers Squibb Company Reports Financial Results for the Fourth Quarter and Twelve Months of 2007[2008.1.31] 付表[xls]に個別製品売上 - ■製品Products BiCNU(R)(carmustine for injection) News RoomNews Releases [Investors -News Releasesを含む]

NCI -National Cancer Institute Success Story: Carmustine (BCNU, NSC 409962) NIH - National Institutes of Health SUBSTANCE PROFILES: bis(Chloroethyl) Nitrosourea CAS No. 154-93-8 NTIS -National Technical Information Services PubMed IARC:International Agency for Research on Cancer)














[1068]●製品: TEMODAR (Temozolomide) [Schering-Plough]テモゾロミド(テモダール)

 日本語版註)TEMODAR (Temozolomide) [Schering-Plough]テモゾロミド(テモダール)
 【別名】Methazolastone, CCRG81045, SCH52365, NSC362856, M&B 39831 【開発元】Schering-Plough Corporation  [DBR_ID]
 【化学名】3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide
 【承認】FDA申請=1998.8.2、FDA承認=1999.8.11,発売1999.9 ;【製剤】カプセル5 mg, 20 mg, 100 mg, or 250 mg 【適応】For the treatment of adult patients with refractory anaplastic astrocytoma, ie., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. 【用法用量】初回は28日間周期で、最初の5日間に1日1回150mg/m2経口投与する。 好中球と血小板数により用量を決定する 【作用】アルキル化剤 【特徴】 【製品情報】 【添付文書】http://www.fda.gov/cder/foi/label/1999/21029lbl.pdf 【EU】99.8.26付けEU 15カ国承認(星細胞腫; EMEA-CPMP答申99.5)、EUでは99.1 多形膠芽腫を承認済み。[http://www.sch-plough.com/news/business/1999/8-26-99.html] 【日本】テモダールカプセル[製造販売元/シェリング・プラウ株式会社]Temodal 申請2005.9.30 -06.9.15薬価収載 -06.9.15発売、2005.9.30優先審査品目に指定;2006.4.21薬食審医薬品第二部会審議通過。「テモダールカプセル20㎎、同100㎎」は、「悪性神経膠腫」を効能効果とする新有効成分医薬品。未承認薬使用問題検討会議において早期に承認申請を行うよう指示された薬剤で、優先審査品目に指定されている。原体・製剤は毒薬。再審査期間は10年。国内治験症例数が少ないため、承認条件として全例調査を行うよう指示された。  【製剤~日本】1カプセル テモゾロミド 50mg,100mg 【適応~日本】悪性神経膠腫 【用法用量~日本】[1. 初発の場合] 放射線照射との併用にて,通常,成人ではテモゾロミドとして1回75mg/m2(体表面積)を1日1回連日42日間,経口投与し,4週間休薬する。その後,本剤単独にて,テモゾロミドとして1回150mg/m2を1日1回連日5日間,経口投与し,23日間休薬する。この28日を1クールとし,次クールでは1回200mg/m2に増量することができる。 [2. 再発の場合] 通常,成人ではテモゾロミドとして1回150mg/m2(体表面積)を1日1回連日5日間,経口投与し,23日間休薬する。この28日を1クールとし,次クールで1回200mg/m2に増量することができる。 【製品情報~日本】 【添付文書~日本】テモダール添付文書 - [pdf] | インタビューフォーム 【その他】●Temozolomide Review ● ●1998年オーファン指定。臨床上利益評価のためのrandomized trialが承認条件。 既存薬無効の星細胞腫54例への臨床効果は完全反応9%,部分反応13%。[FDA APPROVES NEW DRUG FOR BRAIN CANCER] ●Oncologic Drugs Advisory Committee (ODAC) は、1999.1.12に11-0で承認勧告。 但し「星細胞腫」のみで「多形膠芽腫」は見送り。[Dr. Justice Response to temozolomide letters. FDA April 14, 1999]




●承認データ:FDA

●2004.5.1 以降 Drugs@FDA

Drug Name(s) =TEMODAR FDA Application No. =NDA # 021029 Active Ingredient(s)=TEMOZOLOMIDE Company =SCHERING Dosage Form/Route =CAPSULE; ORAL:100MG ;20MG ;250MG ;5MG Strength = - Approval Date=08/11/1999[000] :Label[添付文書]|Letter[承認書]|Review[承認] indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. - Approval Date=01/18/2002[004] :Label[添付文書]|Letter[承認書]|Review[ラベル更新] - Approval Date=03/11/2003[005] :Label[添付文書]|Letter[承認書]|[Efficacy Supplement with Clinical Data to Support] - Approval Date=03/15/2005[008] :Label[添付文書]|Letter[承認書]|[New or Modified Indication]
Electronic Orange Book

Application Number: 021029 Active Ingredient : TEMOZOLOMIDE Proprietary Name : TEMODAR [SCHERING] CAPSULE; ORAL:100MG ;20MG ;250MG ;5MG Approval Date : Aug 11, 1999 Exclusivity Data : ODE MAR 15,2012 I-450 MAR 15,2008 ODE AUG 11,2006 PED FEB 11,2007 Patent Data : 5260291 AUG 11,2013 Y Y U-619 5260291*PED FEB 11,2014
●EU承認

EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ※Temodal INN:Temozolomide (Rev. 5) - Published 12/12/05 Temodal [SP Europe] [Therapeutic Indication] Temodal capsiulesd are indicated for the treatment of patients with malignant glioma, such as glioblast oma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy ■[Enterprise and Industry DG] Directorate F - Consumer Goods -http://pharmacos.eudra.org/ ★The Community Register[承認製品リスト] - 医薬品は1995.10以降。 各製品データシートにリンク。 [医薬品]Community Register of medicinal products for human use - [年月別] - 取下げ・中断 - 却下 [総合索引~成分別]General index on active ingredient [総合索引~銘柄別]General index on brand name

情報ソース●FDA Drug Approvals List August 1999 Original Application #: 021029
Approval Date: 11-AUG-99
Trade Name: TEMODAR
Chemical Type: 1
Therapeutic Potential: P
Dosage Form: CAPSULE
Applicant: SCHERING CORP
Active Ingredient(s): TEMOZOLOMIDE
OTC/RX Status: RX
Indication(s): For the treatment of adult patients with refractory anaplastic astrocytoma, ie., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine.
October 22,1999

情報ソース●FDA Drug Approvals List February 1999 Original New Drug Applications
Original Application #: 021029
Approvable Date: 12-FEB-99
Trade Name: TEMODAL
Dosage Form: CAPSULE
Applicant: SCHERING CORP
Active Ingredient(s): TEMOZOLOMIDE
OTC/RX Status: RX
March 15., 1999



TEMODAR (temozolomide)添付文書

10-29-99, http://www.fda.gov/cder/foi/label/1999/21029lbl.pdf
[21p]から抜粋
TEMODAR (temozolomide) CAPSULES
derivative. The chemical name of temozolomide is
3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula is:
Each capsule contains 5 mg, 20 mg, 100 mg, or 250 mg of temozolomide.

INDICATIONS AND USAGE
TEMODAR (temozolomide) Capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine.
This indication is based on the response rate in the indicated population. No results are available from randomized controlled trials in recurrent anaplastic astrocytoma that demonstrate a clinical benefit resulting from treatment, such as improvement in disease-related symptoms, delayed disease progression, or improved survival.
★メモ
承認=99-08-11
Other Names: Methazolastone, CCRG81045, SCH52365, NSC362856, M&B 39831
アルキル化剤
TEMODAR (temozolomide)承認書
10-08-99, http://www.fda.gov/cder/foi/appletter/1999/21029ltr.pdf



FDA APPROVES NEW DRUG FOR BRAIN CANCER

 米国で脳腫瘍の新患は約1.8万人、うちグリオーマが50%。 1998年オーファン指定。臨床上利益評価のためのrandomized trialが承認条件。 既存薬無効の星細胞腫54例への臨床効果は完全反応9%,部分反応13%。
FDA TALK PAPER
 T99-37 Print Media: 301-827-6242 August 11, 1999
 Broadcast Media: 301-827-3434 Consumer Inquiries: 888-INFO-FDA

FDA has approved temozolomide, a cancer treatment for
adult patients diagnosed with a form of brain cancer --
anaplastic astrocytoma -- who have relapsed following
chemotherapy including a nitrosourea drug (carmustine or
lomustine) and procarbazine. The following may be used to
respond to questions.

Approximately 18,000 new cases of primary intracranial
(brain) cancer are diagnosed each year in the U.S. This
represents about 2 percent of all adult cancers. More than 50
percent of these are high-grade gliomas (i.e. glioblastoma
multiform and anaplastic astrocytoma tumors). Patients with
these tumors often suffer from severe disabilities such as
motor dysfunction, seizures, and vision abnormalities. The
approval of temozolomide gives patients another option for
treatment of their disease when they do not respond to initial
treatment with radiation and chemotherapy.

Temozolomide has been granted accelerated approval - a
regulatory mechanism that allows early approval for a product
for the treatment of serious or life-threatening conditions
for which no acceptable alternative treatments exist or which
provide a meaningful therapeutic benefit over existing
treatments. Accelerated approval is based on surrogate
markers of effectiveness such as shrinkage of a tumor rather
than a documented effect on clinical benefit such as survival
or quality of life.

Temozolomide's approval was supported by a single arm
multi-center trial in l62 patients who had anaplastic
astrocytoma at first relapse and who had received previous
radiation therapy and may also have received chemotherapy. In
the patients with tumors resistant to previous chemotherapy
with a nitrosourea and procarbazine, seven (7) out of 54
patients (13 percent) had partial shrinkage of their tumors
while nine percent or 5 out of 54 patients had a complete
response.

Side effects reported include headaches, nausea,
vomiting, fatigue and low blood counts. Patients with severe
vomiting may require antiemetic therapy before or during
temozolomide treatment.

FDA's approval follows the recommendation of the
Oncologic Drugs Advisory Committee for accelerated approval
of temozolomide to treat patients with anaplastic astrocytoma
tumors.
Temozolomide was granted orphan drug status in 1998.
Orphan status provides incentives to companies to develop
products for use in small patient populations.
The drug will be marketed under the name Temodar. As a
condition of approval, the manufacturer, Schering-Plough Corp,
Madison New Jersey will conduct a randomized trial to evaluate
clinical benefit.



Dr. Justice Response to temozolomide letters.

Oncologic Drugs Advisory Committee (ODAC) は、1999.1.12に11-0で承認勧告。 但し「星細胞腫」のみで「多形膠芽腫」は見送り。 FDA April 14, 1999
Dear Colleague:
Your letter is one of many received recently by the Food and Drug Administration (FDA) requesting approval of the drug temozolomide for the treatment of adult patients with malignant glioma at first relapse. Additionally, issues regarding advisory committees, the drug review process, reimbursement for pharmaceuticals, and information to physicians were raised in many of the letters. I hope that you will understand that I am unable to respond to each letter individually. Instead I will try to address in this letter all of the concerns that have been raised.
On January 12, 1999, the Oncologic Drugs Advisory Committee (ODAC) reviewed the safety and effectiveness data on temozolomide and recommended, by a vote of 11-0 with one abstention, that FDA not approve this drug for use in the treatment of glioblastoma multiforme at first relapse. At the same meeting, the committee recommended accelerated approval of temozolomide for treatment of relapsed anaplastic astrocytoma.

The primary role of an advisory committee is to provide independent expert advice to FDA in evaluating drugs. These outside experts include physicians, scientists, consumers and patient representatives from across the nation. The committees broaden FDA's perspective on important decisions, so that the agency's final decisions reflect a balanced evaluation. Hearing from the public during the public comment session of the meeting enhances the advisory committee process.
FDA is not required to follow a committee's recommendations, but FDA regulatory decisions are generally consistent with advisory committee recommendations. The FDA's decision whether or not to approve a new drug for marketing under the Federal Food, Drug and Cosmetic Act is based upon consideration of two questions:
Do the results from testing of the new drug provide substantial evidence of effectiveness for the condition being studied?
Do the results show that the product is safe under the conditions of use proposed in the labeling for the product?
Members of FDA staff involved in the process are currently evaluating available data to answer these two questions with respect to the use of temozolomide.
Enclosed are two articles that explain FDA's drug review process, and the underlying drug development process:
"The FDA, What Does It do For Cancer Patients?" and
"Understanding Clinical Trials from The Patient Perspective"
Also included is a copy of the Cancer Letter's coverage of the January 12, and 13, 1999 ODAC proceedings. This article is provided with the permission of the Cancer Letter. I hope the articles will help clarify issues for you.
As a matter of record, FDA cannot approve a drug on the basis of reimbursement-related considerations. The decision must be made on whether the drug has been shown to be safe and effective for its proposed use. Once a drug is approved, the Food and Drug Administration Modernization Act of 1997 provides a mechanism for manufacturers to disseminate reports from medical journals to physicians regarding other uses of a marketed medical product while the manufacturer pursues further development of those uses.
We appreciate the time you took to express your concerns and encourage active participation in this very important process. If you have any questions, you may contact Patty Delaney or JoAnn Minor with the FDA Office of Special Health Issues, Cancer Liaison Program at 301-827-4460.
Sincerely,
/s/
Robert L. Justice, M.D.
Acting Director
Division of Oncology Drug Products
Office of Drug Evaluation I
Center for Drug Evaluation and Research
Posted on the Web by:
Cancer Liaison Program
Office of Special Health Issues
Office of International and Constituent Relations
April 21, 1999
[Cancer Home Page]



■メーカーサイト

Schering-Plough Corporation

- http://www.sch-plough.com/schering_plough/index.jsp ●ProductsResearch Products in DevelopmentNews & MediaInvestor RelationsSEC Filings 10-K[pdf,173p;2005.3.9] Financial HighlightsAnnual/Quarterly Report 2004 Annual Report (Interactive) 2004 Annual Report (PDF) Press Releases Schering-Plough Reports Financial Results for 2004 Fourth Quarter, Full Year[2005.1.25] Schering-Plough Reports Financial Results for 2003 Fourth Quarter, Full Year[2004.1.26] Schering-Plough Reports Sales, Earnings for 2002 Fourth Quarter and Full Year[2003.1.23,pdf 12p] SCHERING-PLOUGH REPORTS SALES, EARNINGS FOR 2001 FOURTH QUARTER AND FULL YEAR[pdf;2002.1.24] Business.com :Schering-Plough
シェリング・プラウ

製品情報プレスリリース 悪性神経膠腫の治療薬 テモダール(R)カプセル(一般名:テモゾロミド)新発売 ―脳腫瘍関連の適応を持つ新規薬剤としては19年ぶりの新薬―[2006.9.15] - 発売2006.9.15;年間発生患者数2300人 テモダールRが膠芽腫新規診断患者の術後の生存期間を有意に改善[2005.11.7] 難治性脳腫瘍である悪性神経膠腫の治療薬、テモダールカプセル(一般名:テモゾロミド)の承認申請ならびに優先審査品目指定について[2005.10.31] 欧州連合(EU)、膠芽腫の新規診断患者の治療薬として TEMODALR(テモダール/一般名TEMOZOLOMIDE)を承認 [2005.6.22] ●医療関係者向け情報 テモダール添付文書 - [pdf] | インタビューフォームホットリンク

●Schering-Plough :TEMODAR (Temozolomide)プレスリリース

Schering-Plough Business Press Releases
Press Releases 1999
September 7, 1999
 Schering-Plough and British Biotech Announce Agreement to Develop Matrix Metalloproteinase Inhibitors (MMPIs) for Cancer
August 26, 1999
Schering-Plough Announces European Union Approval of TEMODAL for Recurrent Anaplastic Astrocytoma
August 11, 1999
Schering-Plough Announces FDA Approval Of TEMODAR (Temozolomide) Capsules for Patients with Refractory Anaplastic Astrocytoma
May 26, 1999
 Schering-Plough Announces European Union's CPMP Recommends Approval of TEMODAL for Treating Brain Tumors.
January 28, 1999
 Schering-Plough Announces European Union Approval of TEMODAL for Recurrent Glioblastoma Multiforme
=======================================================

Schering Plough Press Release: 8-26-99 SCHERING-PLOUGH ANNOUNCES EUROPEAN UNION APPROVAL  OF TEMODAL FOR RECURRENT ANAPLASTIC ASTROCYTOMA

 99.8.26付けEU 15カ国承認(星細胞腫; EMEA-CPMP答申99.5)、EUでは99.1 多形膠芽腫を承認済み。
MADISON, N.J., August 26, 1999 — Schering-Plough Corporation (NYSE: SGP) today announced that the European Union's (EU) Commission of the European Communities has granted marketing authorization to TEMODAL (temozolomide) Capsules for the treatment of patients with anaplastic astrocytoma, a type of brain cancer, showing recurrence or progression after standard therapy.

Commission approval of the centralized Type II variation for TEMODAL for anaplastic astrocytoma results in a single Marketing Authorization with unified labeling that is immediately valid in all 15 European Union-Member States. The Commission's decision follows the recommendation for approval of the Type II variation in May 1999 by the EU's Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA).

TEMODAL is currently marketed in the EU for the treatment of patients with glioblastoma multiforme, another type of brain cancer, showing recurrence or progression after standard therapy. The European Commission granted centralized marketing authorization to TEMODAL for this indication in January 1999.

TEMODAL (temozolomide), an oral cytotoxic, alkylating agent, is the lead compound in a new class of compounds known as imidazotetrazines. Schering-Plough has exclusive worldwide rights to market temozolomide through a licensing agreement with Cancer Research Campaign Technology, Ltd., of the United Kingdom.

Anaplastic astrocytoma and glioblastoma multiforme are among the most serious and aggressive types of malignant brain tumors, with median patient survival times ranging from one to three years from initial diagnosis. Despite intensive treatment with surgery, radiotherapy and chemotherapy, patients with these brain cancers almost invariably experience tumor recurrence, often within a year of completing first-line therapy. Median survival in patients with recurrent high-grade tumors ranges from only three to six months from the time of recurrence.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.
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SCHERING-PLOUGH ANNOUNCES FDA APPROVAL OF TEMODAR (TEMOZOLOMIDE) CAPSULES FOR PATIENTS WITH REFRACTORY ANAPLASTIC ASTROCYTOMA

20年ぶりの脳腫瘍化学療法剤。 99.9発売予定
First New Chemotherapy Agent for Brain Tumors in 20 Years

MADISON, N.J., Aug. 11, 1999 — Schering-Plough Corporation (NYSE: SGP) today announced that the U.S. Food and Drug Administration has granted accelerated approval to TEMODAR (temozolomide) Capsules for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse with disease progression on a nitrosourea- and procarbazine-containing drug regimen. TEMODAR is the first new chemotherapy agent for this type of brain tumor approved in the United States in 20 years. It will be available nationwide in early September.

"TEMODAR represents an important new treatment option in recurrent anaplastic astrocytoma, one of the most serious and aggressive types of malignant brain tumor," said W.K. Alfred Yung, M.D., chairman of the Neuro-Oncology Department at MD Anderson Cancer Center in Houston. "In addition, oral dosing with TEMODAR Capsules for 5 days in each 28-day treatment cycle is convenient for patients, enabling them to take medication in the comfort of their homes instead of at doctorsoffices or hospitals where intravenous treatments are administered," Yung said.

TEMODAR, an oral cytotoxic alkylating agent, is the lead compound in a new class of compounds known as imidazotetrazines. Cytotoxic agents are designed to prevent the replication of cells that divide rapidly, including those in tumors. Schering-Plough has exclusive worldwide rights to market temozolomide through a licensing agreement with Cancer Research Campaign Technology, Ltd., of the United Kingdom. In the European Union, temozolomide is approved under the name TEMODAL Capsules.

The median survival time for patients with anaplastic astrocytoma ranges from 2 to 3 years from the time of initial diagnosis. Despite intensive treatment with surgery, radiotherapy and chemotherapy, these patients almost invariably experience tumor recurrence, often within a year of completing first-line therapy. The annual incidence of anaplastic astrocytoma in the United States is one to 1.5 cases per 100,000 persons, with 2,000 to 3,000 new cases diagnosed per year.

CLINICAL TRIALS
A single-arm, multicenter clinical study with TEMODAR (temozolomide) Capsules was conducted in 162 patients who had anaplastic astrocytoma at first relapse. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Of the 162 patients in the study, 54 patients had disease progression on prior therapy with both a nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Patients in the study were given TEMODAR for the first 5 days of a 28-day treatment cycle at a starting dose of 150 mg/m2 per day.

In the refractory anaplastic astrocytoma population, the overall tumor response rate (complete response plus partial response) was 22 percent (12/54 patients) and the complete response rate was 9 percent (5/54 patients). A complete response equaled complete resolution of the tumor for 2 consecutive months as measured by gadolinium-enhanced magnetic resonance and clinical improvement. A decrease of more than 50 percent in the tumor area for 2 consecutive months constituted a partial response.

The median duration of all responses was 50 weeks (range of 16 weeks to 114 weeks) and the median duration of complete responses was 64 weeks (range of 52 weeks to 114 weeks). Progression-free survival at six months was 45 percent (95 percent confidence interval of 31 percent to 58 percent), progression-free survival at 12 months was 29 percent (95 percent confidence interval of 16 percent to 42 percent), and median progression-free survival was 4.4 months. Overall survival at six months was 74 percent (95 percent confidence interval of 62 percent to 86 percent), overall survival at 12 months was 65 percent (95 percent confidence interval of 52 percent to 78 percent), and median overall survival was 15.9 months.

TEMODAR (temozolomide) Capsules is indicated for the treatment of refractory anaplastic astrocytoma based on a demonstrated tumor response rate. No results are available from randomized, controlled trials in recurrent anaplastic astrocytoma that demonstrate a clinical benefit resulting from treatment, such as improvement in disease-related symptoms, delayed disease progression or improved survival.

In the clinical study, myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse event. The effect usually occurred within the first few cycles of therapy, was not cumulative and was resolved within 14 days. Hospitalization, blood transfusion and discontinuation of therapy due to myelosuppression occurred in less than 10 percent of patients treated with temozolomide. The most common side effects were nausea (53 percent), vomiting (42 percent), headache (41 percent), fatigue (34 percent) and constipation (33 percent). Each of these side effects was severe in 10 percent or less of patients, with nausea and vomiting readily controlled by standard antiemetic therapy.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.
For more information on brain tumors, please contact:
-- American Brain Tumor Association (1-800-886-2282)
-- Brain Tumor Society (1-800-770-8287)
-- National Brain Tumor Foundation (1-800-934-2873)



■一般ニュース

Clinical Trials and Noteworthy Treatments for Brain Tumors: Temozolomide

Last Updated:: Nov. 12, 1999
TEMODAR (The brand name of Temozolomide) gets FDA approval in the USA!!
Click here for the press release!
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Medicare Approves Temodar for Reimbursement! Details comming soon - but if you need Temodar and are on Medicare - ask the pharmacist to check into it for you! 
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Temodar is now available in many places around the USA! 
If your pharmacy can't get it, One place to get Temodar in the USA is from Biologics, Inc. 
They will deliver anywhere in the USA. Call 1-800-850-4306 .

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Temozolomide is also available - as the brand name drug Temodal - in the following countries now: 
Austria 
Australia 
Argentina 
France 
Germany 
Greece 
Italy (Not approved yet - but it is available while they decide!) 
Mexico 
Netherlands 
New Zealand 
Spain 
Sweden 
UK 
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Review Of Temozolomide (Updated 2/11/99) An easy to read paper reviewing the published reports on Temozolomide. 

American Society Of Clinical Oncology (ASCO) Abstracts: The following Temozolomide abstracts are to be presented at the next ASCO meeting, mid-May 1999.

Randomized Trial of Temodal (TEM) Vs. Procarbazine (PCB) in Glioblastoma Multiforme (GBM) at First Relapse. 
A Phase-2 trial of Temodal ョ (temozolomide) in Patients with Anaplastic Astrocytoma at First Relapse. 
Health-Related Quality of Life (HRQL) Benefits of Treatment with Temozolomide (TMZ) Vs Procarbazine (PCB) in Patients (PTS) with Glioblastoma Multiforme (GBM). 
Phase I Trials of GliadelTM Plus CPT-11 or Temodalョ (temozolomide)  
Phase II Treatment of Anaplastic Oligodendro-Glioma and Low Grade Glioma with Temodalョ  
Activity of Temozolomide in Recurrent Malignant Gliomas: A Phase II Study.  
Daily Temozolomide (TMZ) and Concomitant Radiotherapy Followed by Adjuvant TMZ for Newly Diagnosed Glioblastoma Multiforme (GBM). A Well Tolerated and Promising Regimen. 
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If you are having trouble paying for the drug, Schering Corp. has a program called "Committment to Care". This is a patient assistance program (helps with reimbursement and if no reimbursement options are available, patients are assessed for eligibility in cost share and free drug programs). Call them toll free at: 1-800-521-7157. 
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Disclosure Statement: Schering-Plough Research Institute - who are developing Temozolomide - is a sponsor of this website.
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Copyright (c) 1999 by The Musella Foundation 


Temozolomide Review

    Clinical Trials and Noteworthy Treatments for Brain Tumors: 
Temozolomide (Temodal) For Brain Tumors
By: 
Andrew James Parker
Dept. Biomedical Sciences
University of Sheffield
Sheffield, England
Last Updated: 2/11/99

Overview
Introduction
Molecular Structure
Pharmacokinetics
Mechanism Of Action
Effectiveness
Summary 
(Click on a reference number to see the reference and abstract!)

Generic Name: Temozolomide 
Brand Name: TemodalR 
Other Names: Methazolastone, CCRG81045, SCH52365, NSC362856, M&B 39831 
Classification: Oral cytotoxic agent. 
Brain tumor dosage: 
Adults: 150-200mg/m2/day Total dose: 750-1000mg/m2/cycle 
Children: 180-215mg/m2/day Total dose: 900-1075mg/m2/cycle 
Delivery: Oral tablet 
Schedule: Five consecutive days, repeated every 28 days. 
Side effects: Possibility of nausea and vomiting, controllable by anti-emetics. Less frequently: Headaches, rash, diarrhoea, constipation, alopecia, high blood sugar, myelosuppression and elevated liver function tests.
Availability: Experimental in the USA. (It is approved for brain tumors in a few other countries). Compassionate release of this drug may be sought from Schering -Plough. Contact their oncologist: Dr Uwe Fraas (USA) 908/298-7020

●Introduction
Temozolomide, or Temodal, is the result of almost forty years of chemical evolution. It is derived from a range of drugs developed principally for antitumor activity in melanoma but has shown to have activity with other cancers. Amongst these, Temodal has been noticeably effective (compared to other chemotherapeutic agents) in the treatment of glioma. Results have been particularly encouraging with astrocytomas. This report lists many of the recently published articles on Temodal and attempts to set them into the context of the development of Temodal.
On the 12th January 1999, the Schering-Plough Corporation issued two press releases concerning Temozolomide (Temodal). The first announced a submission to the European Unions European Medicines Evaluation Agency, seeking clearance to market Temodal for the treatment of patients with recurrent malignant gliomas such as glioblastoma multiforme (gbm) and anaplastic astrocytoma (aa). The second stated that the Oncologic Drugs Advisory committee to the U.S.F.D.A. had unanimously recommended accelerated approval of Temodal for the treatment of adults with aa but not for gbm. If given, approval will be significant because the FDA have approved only two other drugs for brain tumor treatment since the 1960s. Given that there are currently in excess of thirty chemotherapeutic agents being used or tested in such cases, what attributes make Temodal worthy of such distinction? This short essay will attempt to summarise the emergence of Temodal as a potential frontrunner in the treatment of primary brain tumors.

A detailed review of the development, chemistry and progression to clinical trials of Temodal has been published (1) and other papers (2,3) and reviews ( 4 , 5 , 6 , 7 ) have examined the position of Temodal as a relatively new anti-tumor agent. The journey from formula to formulation is usually an arduous one and the precursors of Temodal can be traced back to a group of compounds called triazines, which were developed in the 1960s. The progressive refinement of these molecules involving dacarbazine (DTIC) in the 1970s, and tetrazinones and mitozolomide in the 1980s serves as a paradigm for drug development, one that has been chronicled and likened to evolution ( 8 ). Possibly the hardest (and rate-limiting) step in drug development is from concept to condenser but once synthesised there are a number of stages which have to be followed:

(a) Structural and chemical analysis
(b) Pharmacokinetics studied
(c) Mechanisms of action researched
(d) Toxicity studies
(e) Screening in cell culture and animals
(f) Progression to clinical trials

Clinical trials are usually performed in three phases:

Phase (i) examines delivery and dosage in a small number of patients, usually less than 20.
Phase (ii) Determines if treatment works as expected. Normally in a larger group of about 20 - 50 patients.
Phase (iii) Compares treatment to the standard care. Larger numbers are involved and the trial is randomised.

This format seldom proceeds in such a linear fashion, but serves as an outline for study.

●Molecular Structure
The molecular formula of Temodal, C6H6N6O2, reveals little of its structure but the systematic name: 8-carbamoyl-3-methylidazo [5,l-d]- 1,2,3,5-tetrazin-4 (3H)-one gives an indication of its complexity. The syntheses of Temodal ( 9 , 10 , 11 , 12 ) structurally related molecules ( 13 , 14 , 15 ) and derivatives ( 16 ) have been described. In pharmacology, an analogue denotes a substance that is similar in appearance or function to another but different in origin or development. Temodal is the methyl analogue of mitozolomide and both molecules belong to a group classed as imidazotetrazinones. The structure of these bicyclic antitumor agents has been reported ( 17 , 18 , 19 ). Temodal is also an analogue of the anti-melanoma drug dacarbazine (DTIC) introduced into clinical practice in the 1970s. It was established that DTIC required metabolic activation to the triazene MTIC (20). Temodal and mitozolomide also yield this active metabolite, MTIC, by decomposition in solution ( 21 , 22 , 23 ) . Because it is the producer of the active metabolite, Temodal is termed a prodrug (24). The subsequent metabolism of Temodal, in vivo, from its first product MTIC to the final position of its constituent atoms has been fully described (1). High performance reversed-phase liquid chromatography (HPLC) has been used to quantify Temodal in plasma and urine of patients receiving Temodal (25). HPLC has also been used to analyse the biologically active degradation product MTIC in human plasma (26). Accurate measurements of drugs in biological fluids are essential to determine the action of drugs within the body - the pharmacokinetics.

●Pharmacokinetics
Pharmacokinetic studies of drugs include the routes and mechanisms of absorption, the rate at which a drugs action begins and the duration of the effect, the biotransformation of the substance in the body, and the effects and routes of excretion of the metabolites of the drug. These parameters are usually referred to as ADME factors; absorption, distribution, metabolism and excretion. Temodal is given as an oral tablet. Although it degrades rapidly in alkali conditions it is stable under acid conditions, which means it can tolerate stomach acidity. However, other administration routes have been studied ( 27 , 28 ). Additionally, Sparta pharmaceuticals have signed a licence agreement with Schering-Plough for the use of Spartajet with Temodal. Spartajet is a drug delivery system that allows poorly water-soluble and water insoluble compounds to be given by injection. This may enable intravenous administration for patients requiring higher concentrations or delivery to localized areas (Sparta press release). The distribution and pharmacokinetics of Temodal have been probed by NMR ( 27 ) and PET ( 29 ). Studies on Temodal metabolism ( 30 ) have given values for its half-life (t1/2) - the time taken to decrease plasma concentration to half its initial value - ranging from 0.42h in human plasma (30) to approximately one hour ( 27 , 31 ). Whereas t1/2 for the reactive metabolite MTIC has been estimated at between 88 min ( 31 ) and 1.9h ( 26 ). Excretion of Temodal has been shown to take place via the kidneys of mice and men ( 32 ). Pharmacological studies extend to consider analogues of Temodal ( 33 , 34 , 35 ) and interactions with other drugs ( 36 , 37 , 38 , 39 ). Such studies can give insights as to the mechanism of action of a drug an area that has received considerable attention for Temodal.

●Mechanism Of Action
The mechanism of action of Temodal is complex and involves more than one site of action. In certain cancer cells, Temodal has been shown to have an inhibitory action on enzymes such as esterase ( 40 ) and glyoxalase (41). However, the main cytotoxic (cell-killing) action of Temodal is effected by its role as an alkylating (or methylating) agent ( 42 , 43 , 44 ), specifically the alkylation of DNA. The active metabolite MTIC adds methyl residues to nucleotides in the DNA molecule. Temodal has been reported as not altering the methylation of genes such as c-myc and C-Ha-ras (45), genes containing many methylated sequences. A number of studies suggest Temodal may block cellular replication by indirectly inhibiting DNA methylation, cells not blocked having hypomethylated DNA ( 46 , 47 , 48 ). The majority of mechanistic studies have concluded that the antitumor activity of Temodal is due to the methylation of DNA but such damage is defended by three repair mechanisms:

(1) 06-alkylguanine-DNA alkyltransferase (ATase)
(2) DNA mismatch repair.
(3) Poly (ADP-ribose) polymerase.

The cytotoxic and mutagenic (causing genetic mutation) action of antitumor triazenes such as Temodal have been attributed to their ability to form DNA adducts (a combination of chemicals with DNA) by the methylation in the O6 position of the purine base guanine to form O6-methylguanine (49, 50 , 51 ). Repair of these methyl adducts is mediated by the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase (ATase) which removes alkyl adducts from DNA in a single step mechanism without co-factors. Temodal has been shown to decrease the activity of ATase ( 52 , 53 , 54 , 55 ) and inhibition of ATase enhances the action of Temodal (56). Conversely, high levels of ATase reduce the effect of Temodal ( 57 , 58 , 59 , 60 ) and high levels have been reported in human brain tumors (61). Depletion of ATase potentiates (enhances) the action of BCNU ( 54 , 62 , 63 ) and CCNU (53). The effect of Temodal is also potentiated by the presence of an ATase inactivating agent; O6- benzylguanine ( 64 , 65 , 66 , 67 , 68 , 69 ) this action has been reviewed (70)

Replication of DNA is usually accurate but there are occasional errors of base pairings. This is usually corrected by the "proofreading" DNA polymerases, however mismatched base pairs sporadically become incorporated into DNA. In normal cells such errors are corrected by the mismatch repair system (MRS), a group of seven proteins with the primary function of recognising and correcting mismatched base pairs within the DNA helix. When the O6-methylguanine produced by Temodal is processed by a normal MRS this leads to cytotoxicity. Unfortunately, loss of DNA MRS has been observed in a variety of cancers that can confer resistance to methylating agents such as Temodal ( 71 , 72 , 73 , 74 ) this process has been reviewed (75). Abnormalities in MRS have been demonstrated in gbm cells (76) but have been shown to be intact in human medulloblastoma (77). Further screening of brain tumor classes is evidently required.

It has been shown that Temodal causes adducts at the O6-position of guanine and that subsequent processing by an intact MRS leads to cytotoxicity. However, Temodal can induce methyl adducts at other positions, N7-guanine and N3-adenine. Another repair mechanism, the base excision repair mechanism is involved in the correction of such lesions. This repair mechanism can handle a variety of structural DNA defects and in mammalian cells many enzymes are involved in the process. Adenosine diphosphate (ADP) ribosylation is involved in DNA excision repair and the enzyme poly (ADP-ribose) polymerase (PARP) is activated by DNA strand breaks and mediates cellular responses to DNA damage ( 78 , 79 ). Inhibition of PARP has been shown to potentiate the cytotoxic effects of N7-methylguanine and N3-methylguanine ( 80 , 81 , 82 , 83 ) thus improving the action of Temodal. Similarly, PARP has been shown to utilise nicotinamide adenine dinucleotide (NAD) and low cell levels of NAD have been shown to enhance the effect of Temodal (84).

The molecular mechanisms of Temodal continue to be investigated but another factor that distinguishes Temodal from other agents is its ability to cross the blood-brain barrier (BBB). The BBB is a protective mechanism that ensures the stability of the brain environment. Homeostasis, the maintenance of stable conditions is essential in the brain, particularly with respect to ionic concentrations involved in the control of neuron function. Thus the BBB serves to permit water, nutrients and lipid-soluble substances such as anaesthetics, nicotine, and alcohol whilst prohibiting pathogens (bacteria and viruses), metabolic waste, proteins, toxins and most drugs. The action is one of retardation rather than complete exclusion and is effected by the relative impermeability of the brain capillaries, possibly in conjunction with glial cells. Many publications describe the ability of Temodal to cross the BBB but few offer citations to support this claim. There is a report of Temodal entering mouse brain (8) and a study on mitozolomide delivered intraperitoneally into mice found a rapid and extensive distribution although the brain contained the lowest drug level compared to other tissues (85). Indirect evidence for Temodal crossing the BBB can be derived from a study which added an angiogenesis inhibitor (TNP-470) as well as Temodal in a rat model of glioma (86). TNP-470 caused a reduction of capillary permeability and there was evidence to suggest that it decreased the uptake of Temodal by the tumor. This study highlights the caution that must be exercised with combinational chemotherapies. PET studies have revealed a greater distribution of Temodal in glioma than in normal brain (29) and has been shown to enter the CSF ( 37 ) but overall published supportive evidence is scant. It has been stated that the BBB breaks down around gliomas (87) but again this claim offers no supportive evidence. Even the existence of the BBB has been questioned and whether it can be blamed for the failure of many chemotherapeutic agents (88). It would seem that further investigation into the physiology of the BBB is merited.

●Effectiveness
Having considered the structure, chemistry, pharmacology and mechanism of action of Temodal, the next stage is to test its effectiveness. It would be irrational to test a novel cytotoxin on patients without discovering what dosage is required or whether any side effects outweigh benefits. Additionally, it is important to establish the schedule of administration of the drug since its pharmacokinetics, metabolism and clearance in vivo determine its potency. Consequently, toxicity and pathfinder experiments are performed in animals or increasingly in tissue culture. The technique of cell or tissue culture allows cells to be grown and maintained in physiological conditions and their response to drugs can be repeatedly monitored.

Clinical trials of mitozolomide revealed that it caused thrombocytopenia (89), a reduction in platelets caused by damage to bone marrow. Although disappointing this lead to the selection of Temodal due to its lower toxicity. Toxicity studies are perforce performed on animals or more commonly cell lines but such studies are frequently criticised. Cell culture can be said to be unrepresentative of the living milieu since factors such as tissue interaction and blood flow are absent and apart from moral complaints, animal models are often claimed to be unlike human beings. Such is the burden of the research worker attempting to alleviate disease. One approach that minimises criticism is that of the xenograft, a technique that transplants human tumors into animal hosts and the mouse has proven to be particularly suitable for this method.

In mice, Temodal has shown to have activity against lung cancer (90) by interfering with the action of protein kinase C, an enzyme active in brain tumor (91). Temodal has also shown inhibition of tumor cell growth in a dose-dependent manner in models of colon adenocarcinoma (92) and melanoma xenografts (93). This latter study also confirmed the importance of the schedule of Temodal delivery. An improved response was obtained when the initial dose was divided into five equal fractions and given on consecutive days. This approach had been suggested by an earlier study (30). Antitumor activity of Temodal has been demonstrated in rodents bearing human brain tumor xenografts. Temodal has been shown to improve the action of BCNU (94), was more effective than procarbazine (95) and works synergistically with O6-benzylguanine (O6-BG), the ATase inhibitor both in mice (96) and apes (69). Uptake of Temodal in a rat glioma model was diminished by the presence of an angiogenesis inhibitor (86)

The action of Temodal on tumor cell lines has been examined (97,98). The latter study evaluated the cytotoxic effect of Temodal on a panel of human tumor cell lines and a satisfactory cytotoxic action was observed with breast, ovarian and non-small cell lung cancers. Activity was also recorded in other cancer cell lines including; renal cell carcinoma, colon cancer, melanoma, sarcoma and prostatic and pancreatic carcinomas. Studies have also been undertaken on brain tumor cell lines. One report analysed the response of 14 human medulloblastoma and glioma derived cell lines to Temodal and streptozotocin (99). Although the cells responded similarly to these two agents, the action of O6-BG as an adjunct to treatment was found to be variable. A later study (100) combined Temodal with X-irradiation in a human gbm cell line and also in human colorectal adenocarcinoma (Mawi) cells. It was found that the gbm cell line was more sensitive to Temodal than the Mawi cells but significantly, the latter had far greater ATase activity that reduces the effect of Temodal. Other studies have reported a synergistic effect between Temodal and other drugs with gbm cell lines (130).

Since Temodal exhibited cytotoxicity to a variety of human cancer cell lines (98) and had been shown to have low toxicity in screening experiments (30), progression to clinical trials was logical and desirable. The efficacy of any drug in clinical trials becomes more apparent as increasing numbers are performed. In the interim, summation of trials is problematic. Each study will produce a range of responses that are often difficult to classify, e.g. some patients may report that a drug alleviates their symptoms but no clinical changes are observed. For the purposes of this essay, an examination of Temodals action in trials will first examine the performance in patients with cancers other than brain. Then a brief chronological summary of published clinical trials of Temodal in primary brain tumor will be presented.

During the 1990s, Temodal has been the subject of clinical trials for the treatment of many types of cancer. A review of systemic therapy of T-cell lymphomas (101) recommended larger phase II trials for (inter alia) Temodal. One such study in low grade non-Hodgkin's lymphoma only had a response in 1 of 18 patients (102), however all these patients had received previous treatment which may have affected the response to Temodal and further trials with different categories of lymphoma are indicated. Following good preclinical results with dacarbazine in leukemia, a group of workers in Italy have evaluated Temodal for leukemia with results suggesting it may have therapeutic potential ( 103, 104 , 105 ). Although showing potential against many human tumor cell lines (98) and xenografts (106), response to Temodal in patients with pancreatic cancer (107), renal cell carcinoma (108) and nasopharyngeal carcinoma (109) has been disappointing. However, it is considered to have potential in the treatment of breast cancer ( 110 , 111 ) and has shown antitumor activity in hepatocellular carcinoma (112). In the development of Temodal, it may be recalled that dacarbazine and mitozolomide were significant in its evolution. These molecules have shown activity against melanoma. Since Temodal transforms to MTIC, the active agent of dacarbazine, its action in melanoma has also been investigated. Antitumor activity was seen in phase I (113) and II (114) trials. Measurement of ATase levels prior to treatment were not found to be predictive of Temodal response (115) but reduction of ATase by O6-BG is advocated (116). Temodal did not produce a response in uveal melanoma (117). A review of the chemotherapy of melanoma (118) suggests that Temodal shows promise, especially in cases with brain metastases. The consensus opinion is that trials of Temodal should focus on melanoma and glioma.

To date, the greatest potential of Temodal has been manifest in the treatment of primary brain tumors. This intractable cancer has proven resistant to many promising avenues of treatment in the past and success is long overdue. It should be stressed that no final decision on Temodals efficacy has been made. Phase I and II trials are still taking place, with progression to randomised phase III trials being advocated. (87) and initiated. The present article will briefly outline results of clinical trials of Temodal on brain tumors published over the past eight years.

Phase I trials started in England in 1987 (119) examining the response to single dose (50 - 2000 mg/m2) given intravenously and oral dose repeated over five days (total: 750-1,200mg/m2). Although this trial only generated two partial responses in patients with recurrent high-grade glioma, it established the importance of the dosing schedule. Using that regimen, a later study (120) found major improvement in computer tomography (CT) scan in 5/10 patients with astrocytomas and major clinical improvement in a further patient. Reduction in size of the CT scan was observed in 4/7 patients with high-grade astrocytomas given 2-3 courses of Temodal prior to radiotherapy. A phase I study investigating toxicity (135) found that grade 4 thrombocytoenia was the dose-limiting toxicity in 2 of 3 patients at a dosage of 250mg/m2 for five days. Continuing work at the Charing Cross Hospital in London was described in 1996 (121`) in a study of 75 patients with malignant glioma. The overall objective response rate was 27% but the responses were of short duration. The authors suggested that quality-of-life evaluation should be included in such studies, even if a drug does not cure, any alleviation of symptoms must be considered. A phase II trial of 103 patients with recurrent high-grade gliomas (122) achieved an objective response in 11% and a further 47% had stable disease. Response rates were similar for aa (grade III) and gbm (grade IV). As in previous studies, myelosuppression was the major toxicity.

Investigation into alternative drug schedules reported in an abstract in 1997 (123) found an objective response in 7 of 15 patients (47%) receiving 75mg/m2/day over 6 or 7 weeks, thus permitting delivery of a total dose approximately double the conventional one and suggesting further investigations into alternative scheduling. In the same year, an American phase I trial (124) found a difference in response between patients with or without prior exposure to nitrosurea (NU). There were two complete responses (one glioma and one melanoma) in patients without NU. Differences between previously treated and chemotherapy naive subjects has been discussed (102). The study recommended increasing dosage to 225mg/m2/day for 5 days for patients previously treated with NU.

Further abstracts in 1997 reported pharmacokinetics of Temodal as studied by PET scans (125) and as influenced by cisplatin (126). The latter did not generate any significant cross-reaction. Two more American studies concluded in favor of Temodal. The first, of thirty three patients with newly diagnosed gbm and five with aa, conducted at Duke University (76), found 3 complete responses, 14 partial responses and 4 patients with stable disease. The second was a phase II multicenter study performed over 19 months at 32 centers evaluating 161 patients with aa (127). The overall response rate (complete and partial) was 42 % and as with other studies, toxicity was found to be mild with less than 6% experiencing some myelosuppression.

The Charing Cross Group in 1998 (128) published additional studies into alternative schedules. Twenty-four patients (17 gliomas) received daily doses of Temodal starting at 50mg/m2/day increasing to 100mg/m2/day for up to 7 weeks. Of the glioma patients, 41% demonstrated tumor responses. This new regimen was recommended for further studies.

Two phase I studies of paediatric patients have been published. The UK Childrens Cancer Study Group (131) evaluated 16 patients without prior NU or craniospinal irradiation (CSI) and used on 5 consecutive days doses ranging between 500 and 1200mg/m2 per cycle. Their recommended dose was 1000mg/m2 per cycle. Responses were noted in 2 out of 5 patients and one patient had stable disease. The report from the Childrens Cancer Group in Washington (129) evaluated a range of doses in 27 patients. The study recommended a maximum tolerated dose of Temodal in children of 215mg/m2 for those without prior craniospinal irradiation (CSI) and 180 mg/m2/day for 5 days for those with prior CSI. Ten patients had stable disease, 3 had partial response and one had complete response persisting over two years of follow up.

At an international meeting in Versailles on Sept. 15th 1998, results of a phase II/III clinical study were presented. Dr Yung, reported on an evaluation of Temodal in 225 gbm patients, randomised to receive either Temodal or procarbazine. On all parameters reported in the Schering Plough press release, Temodal performed better than procarbazine. Six-month survival being 60% in the Temodal group compared to 48% in the patients receiving procarbazine. At the same conference, Dr. Brada reported on a phase II study in 162 patients with aa at first relapse. Progression free survival at six months was 46 % and at twelve months 24 %. The overall objective response rate was 35 % and stable disease occurred in 27% of patients. A large proportion of patients had improved quality-of-life scores.

The most recent published information is in the form of abstracts and the full papers are yet to be published. Details of ongoing phase II trials can be obtained at this site.

●Summary
In summary, Temodal is not a novel drug but the result of some forty years refinement (1) and may not be the end product of the process. It is a prodrug (24) with excellent oral bioavailability and biodistribution that crosses the blood brain barrier ( 37, 85) and decomposes to the active metabolite MTIC (21) in alkaline conditions. Gliomas are reported to have an alkaline environment ( 132 , 133 ). The mechanism of action, although not fully understood, has been extensively analysed enabling biochemical enhancement ( 56 , 70 , 80 ) of its cytotoxicity. As a chemotherapeutic agent it has low toxicity with myelosuppression presenting the major challenge ( 122, 127). Although many studies have been performed to establish optimum dosage (119) and schedule (128), alternative regimens may yet be investigated. Interactions with other drugs merits further attention both in potentiation ( 53 , 94 ) and interference ( 37, 39, 85). Additionally, diminishment of Temodals action by other chemotherapeutic agents (124) and angiogenesis inhibitors (86) needs further study. The gulf between in vitro and in vivo studies is highlighted by demonstrable cytoxicity against human cancer cell lines ( 97, 98) failing to be matched in clinical trials ( 107, 108, 109). Early clinical trials have shown to be of benefit both in anaplastic astrocytoma and glioblastoma multiforme, not only in reduction of tumor size but also in extended progression free survival and improved quality of life (134). This essay may have indicated some aspects of the difficulties associated with the process of drug development. The rigours of the scientific method sometimes appear to hinder progress but they ensure that precious resources are not misdirected in the pursuit of drugs of minimal or irreproducible benefit. The long journey from test tubes in the 1960s to tablets in the 1990s has indeed been arduous but when a trial reports on a child with complete response to glioma lasting over 2 years after administration of Temodal ( 129), the first reaction is simply appreciation. Ultimately the clinical statistics will reveal the full story.
----------------------------------------------------------------------------
Copyright (c) 1999 by The Musella Foundation
 引用文献はオリジナルwebからは参照可。


●New Drug to Treat Recurring Brain Cancer

FDA Updates--November-December 1999 FDA Consumer magazine
Updates
New Drug to Treat Recurring Brain Cancer
Some adult brain cancer patients now have another option for treating their disease.
The oral treatment temozolomide (Temodar) was approved by FDA in August to treat a form of brain cancer called anaplastic astrocytoma in patients who relapsed following initial treatment with radiation and chemotherapy.
Temozolomide was granted accelerated approval, a process FDA applies to some drugs for serious or life-threatening conditions. In a single study of the drug, tumors resistant to previous chemotherapy with two other drugs partially shrank and disappeared in 7 out of 54 patients. The most common side effects of temozolomide included headaches, nausea, vomiting, fatigue, and low blood counts.
At least 18,000 new cases of brain cancer are diagnosed each year in the United States, a figure which represents about 2 percent of all adult cancers. More than 50 percent of brain cancer cases are tumors that can cause severe disabilities such as motor dysfunction, seizures, and vision abnormalities.
As a condition of approval, FDA is requiring the manufacturer, Schering-Plough Corp., Madison, N.J., to further study the drug's effects on patients' survival or quality of life.












[]●


[]●製品


 日本語版註)NovoTTF-100A System [NovoCure Ltd]
 【別名】 【開発元】NovoCure Ltd  [DBR_ID]
 【装置内容】(再発性GBM治療用のNovoTTF-100aシステムは、人体内部の腫瘍治療場(TTFields)と呼ばれる交流電界を形成する装置で、携帯用電池またはAC電源により作動する。 TTFieldsは、電気的に絶縁された表面電極により、患者に使用する。 TTFieldsは、癌細胞による急速な細胞分裂を阻害すると推論される。) The NovoTTF-100A System for the treatment of recurrent GBM is a portable battery or power supply operated device which produces alternating electrical fields, called tumor treatment fields ("TTFields") within the human body. TTFields are applied to the patient by electrically-insulated surface electrodes. The TTFields are inferred to disrupt the rapid cell division exhibited by cancer cells.

(NovoTTF-100Aシステムは、2つの主部品で構成される: (1)電場発生装置(NovoTTF-100A装置):(2)INE絶縁体電極(電極)。 さらに、以下のコンポーネントは、またNovoTTF-100A Treatment Kitに含まれる: 電源、携帯用電池、バッテリーラック、バッテリーチャージャー、接続ケーブルおよびキャリングケース。) The NovoTTF-100A System is comprised of two main components: (1) an Electric Field Generator (the NovoTTF-100A device); and (2) INE Insulated Electrodes (the electrodes). In addition, the following components are also included in the NovoTTF-100A Treatment Kit: power supply, portable battery, battery rack, battery charger, connection cable and carrying case.
Treatment parameters are preset by NovoCure such that there are no electrical output adjustments available to the patient. The patient must learn to change and recharge depleted device batteries and to connect to an external power supply overnight. In addition, the electrodes need to be replaced once to twice a week and the scalp re-shaved in order to maintain optimal contact. Patients carry the device in an over-the-shoulder bag or backpack and receive continuous treatment without changing their daily routine.
 【承認】FDA承認勧告=17-Mar-2011、FDA承認=8-Apr-2011、米国発売2-Dec-2011 ;
 【適応】(本装置は、組織学的な確認を受けた膠芽腫のある成人(22歳以上)患者に対する治療を適応とする。 但し、化学療法を受けた後、脳のテント上領域(運動感覚領野深部)で組織学的もしくは放射線学的に再発が確認された患者に限定する。 本装置は単独療法として使用するよう意図され、外科的および放射線の選択が排除された後、GBMへの標準的な治療に替わる選択肢として意図されたものである。) The NovoTTF-100A System is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM), following histologically- or radiologically-confirmed recurrence in the supra-tentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
 【用法用量】1日18時間以上の装着を推奨。(18h未満に比し、延命率が3ヵ月以上違う) 装着期間についての指示はない。
 【作用】(NovoTTF-100Aは、頭皮に装着した電極を通じて脳に作用し、癌細胞による急速な細胞分裂を阻害する交流電界を人体内に形成する。) The NovoTTF-100A produces alternating electrical fields within the human body that are inferred to disrupt the rapid cell division exhibited by cancer cells, with the alternating electrical fields applied to the brain through electrodes placed on the scalp.

(TTFieldsは、腫瘍細胞の増殖を阻止し、破壊する電場を結束する。 TTField技術は、分裂細胞の特性および幾何学的図形を利点とし、交流電気のTTFieldsの効果を受けやすくする。 これらの特殊な領域は、中間周波数(100-300kHzに属して)で腫瘍細胞極性を変える。 特定の治療法に使用される周波数は、細胞型に固有である(例: GBMには200kHz)。) TTFields harness electric fields to arrest the proliferation of tumor cells and to destroy them. The TTField technology takes advantage of the special characteristics and geometrical shape of dividing cells, which make them susceptible to the effects of the alternating electric TTFields. These special fields alter the tumor cell polarity at an intermediate frequency (on the order of 100-300 kHz). The frequency used for a particular treatment is specific to the cell type being treated (e.g., 200kHz for GBM).

In contrast, the TTFields have not been shown to have an effect on cells that are not undergoing division. Since most normal adult brain cells proliferate very slowly, if at all, they are hypothesized to be little affected by the TTFields. Testing demonstrates no differences between treated and control animals in histology of the major internal organs (including the brain), blood examination, cardiac rhythm, body temperature, or in animal behavior. In addition, because the fields alternate so rapidly, they have no effect on normal quiescent cells nor do they stimulate nerves and muscles. It is noted that, because TTFields are only applied to the brain, they have no effect on rapidly proliferating cells in the rest of the body. The intensities of the electric fields within the tissues are very small and do not result in any meaningful increase in tissue temperature Thus, TTField application has the advantage of being highly selective and is not expected to be associated with significant toxicity.

The above mechanisms of action are consistent with the extensive research regarding the effects of TTFields. These results demonstrate both disruption of cell division up to complete cessation of the process, as well as complete destruction of the dividing cells. It is important to note that all the described effects can be obtained by fields of low intensity such that they are not accompanied by any significant elevation of temperature.
 【特徴】TTFields - Tumor Treating Fields: Low intensity (1-3 V/cm), intermediate frequency (100-300 kHz), alternating electric fields, delivered using insulated electrodes to the region of the body inflicted with a solid tumor. The fields have been shown in vitro to arrest the replication of tumor cells by disrupting the proper formation of the microtubule spindle and by dielectrophoretic disruption of cell integrity during late telophase.(低強度(1-3 V/cm)、中間周波数(100-300 kHz)、交流電場は、絶縁体電極を用いて固体腫瘍の患部にまで届ける。 TTFieldsはin vitroで、微小管紡錘体の適切な形成を妨げることによって、および後期末期の間の細胞統合の誘電泳動破壊によって腫瘍細胞の複製を阻止することが分かった。) 
  【添付文書】NovoTTF-100A添付文書 【EU】The device has been available commercially in the European Union (EU) since the fourth quarter of 2009.

US Pharmacopeial Commission
AMA: United States Adopted Names
BIAM
 --- BIAM -ABC順|BIAM -会社順
NLM: MeSH HOme
 ---MeSH Online search


Yoram Palti is a Professor of Physiology and Biophysics at the Technion, Israel Institute of Technology and the Founder of NovoCure Ltd. He was formerly an Associate Professor of Physiology at the University of Maryland School of Medicine. He was also Head of the Rappaport Institute for Research in the Medical Sciences, the research arm of the Technion Medical School, for 12 years. Professor Palti is an expert in electrophysiology and biomedical engineering and is the author of more than 30 patents and 70 scientific papers.


●承認データ:FDA

FDA Newsroom - FDA Press Releases FDA approves new medical device for form of brain cancer[April 15, 2011 ] FDA approves new medical device for form of brain cancer[April 15, 2011 ] [FDA] Medical Devices Device Approvals and Clearances - April 2011 PMA Approvals PMA Original Approvals
APPLICATION NUMBER / DATE of APPROVALDEVICE TRADE NAMECOMPANY NAME CITY, STATE, & ZIPDEVICE DESCRIPTION / INDICATIONS
P1000345
4/8/11
NovoTTF-100A SystemNovoCure, Ltd.
Rye Beach, NH 03871
Approval for the NovoTTF-100A System. The device is indicated for treatment of adult patients (22 years of age or older) with histologically- confirmed glioblastoma multiforme, following histologically- or radiologically- confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
NovoTTF-100A System - P100034 Issued April 8, 2011 Approval Order Summary[pdf,39p] Labeling[pdf,74p] Other Consumer Information Updated May 6, 2011 ●Device Approvals and Clearances - January 2012 PMA Approvals PMA Supplemental Approvals
APPLICATION NUMBER / DATE of APPROVALDEVICE TRADE NAMECOMPANY NAME CITY, STATE, & ZIPDEVICE DESCRIPTION / INDICATIONS
P100034/S001
1/3/12
180-Day
NovoTTF-100A Treatment KitNovoCure, Ltd.
Rye Beach, NH 03871
Approval of the post-approval study protocol
Device Approvals and Clearances - 2011 Device Approvals
Device NameCategoryDate
NovoTTF-100A System - P10003438Tumor Treatment 04/08/11
NovoTTF-100A System - P100034

This is a brief overview of information related to FDA’s approval to market this product. See the links below to the Summary of Safety and Effectiveness Data (SSED) and product labeling for more complete information on this product, its indications for use, and the basis for FDA’s approval.

Product Name: NovoTTF-100A System
PMA Applicant: NovoCure Ltd.
Address: 15022 MATAM Center, Haifa 31905, Israel
Approval Date: April 8, 2011
Approval Letter: http://www.accessdata.fda.gov/cdrh_docs/pdf10/p100034a.pdf

What is it? The NovoTTF-100A System treats recurrent glioblastoma multiforme (GBM). The NovoTTF-100A System is a portable battery or power-supply operated device which produces changing electrical fields, called tumor treatment fields (“TTFields”) within the human body. TTFields are applied to the head of the patient by electrically-insulated surface electrodes.

How does it work? TTFields stop the growth of tumor cells resulting in cell death of the rapidly dividing cancer cells. The geometrical shape and scattering of the electrical charges within the dividing tumor cells allows TTF electrical fields to physically break up the tumor cell membrane. The frequency of the TTFields used for a particular treatment is specific to the size of the cell type being treated.

When is it used? The NovoTTF-100A System is intended as a treatment for adult patients (22 years of age or older) with confirmed glioblastoma multiforme, following confirmed recurrence in an upper region of the brain (supratentorial) after receiving chemotherapy. The device is intended to be used as a stand-alone treatment, and is intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted.

What will it accomplish? In the clinical study, subjects with previously diagnosed GBM who had a recurrence of their tumor or their condition worsened despite conventional therapy (surgery and chemo-radiotherapy followed by chemotherapy) were randomly assigned to receive either NovoTTF-100A stand-along treatment or the best standard of care effective chemotherapy (that is, the best effective chemotherapy treatment chosen for them by their physician).

The study showed that overall survival with the NovoTTF-100A System was comparable to that seen with active best standard of care chemotherapy. There was a slightly higher incidence of neurological adverse events in the NovoTTF-100A treated group (43.1% or 50 out of 116 subjects) compared to the best standard of care control group (36.3% or 33 out of 91 subjects). Mild to moderate skin irritation beneath the device electrodes was seen in 16% (18 out of 116 subjects) of NovoTTF-100A-treated subjects. NovoTTF-100A-treated subjects experienced a lower frequency of the classic adverse events as seen with chemotherapy (such as, gastrointestinal, hematological and infectious adverse events) with best standard of care. Quality of life surveys indicated an improved quality of life in the NovoTTF-100A recurrent GBM subjects compared to the best standard of care recurrent GBM subjects.

When should it not be used? The NovoTTF-100A System should NOT be used in patients with any of the conditions below that apply:

An active implanted medical device or a skull defect. Use of the device together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of the device together with implanted medical devices or skull defects (that is, missing bone with no replacement), a shunt, or bullet fragments has not been tested and may possibly lead to tissue damage or cause the device stimulation ineffective.

Examples of active electronic devices include: deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts

Any known sensitivities to conductive hydrogels like the gel used on electrocardiogram (ECG) stickers or TENS (transcutaneous electrical nerve stimulation) electrodes. In this case, skin contact with the electrode gel used with this device may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure.

Additional information: Summary of Safety and Effectiveness and labeling are available online.

Other Resources:
NIH - MedlinePlus-Brain Tumor-Primary-Adults









●FDA Advisory Committees

参考●ML資料:FDA諮問委員会~議題 FDA Advisory Committees CDRH■Neurological Devices Panel - http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/default.htm 2012 | 2011 | 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003 | 2002 | 2001
ML開催日議題備考
 2011.03.17P100034/NovoTTF-100A System for Recurrent Glioblastoma Multiforme (GBM) NovoCure 
※資料FDA Executive Summary (DOC - 1.1MB) | NovoCure Panel Pack (PDF - 3.2MB) | 議事要旨24 Hour Meeting Summary | 議事録Trascripts※【審議結果】[安全性]Y=12,N=0,保留=0 [効果]Y=7,N=6,保留=0 [ベネフィット]Y=7,N=3,保留=2 
NovoTTF-100A
Table 1. Summary of Mechanism of Action Studies (From SBA)
Test Purpose Results Conclusions
Time-lapse microphotography of malignant cell cultures (BI6Fl) exposed to TTFields for 24h [1]Identify structural changes to mitotic cells exposed to TTFieldsMembrane breakdown and blebbing seen only in cells which enter telophase "Hourglass" shape of cells during telophase leads to dielectrophoretic movement of organelles and macromolecules
Immuno-histochemical staining for Tubulin, DNA and Actin in malignant cells after 24h exposure to TTFields [1]Identify what part of the mitotic apparatus is damaged during exposure to TTFieldsAbnormal mitotic figures seen in all mitotic cells exposed to TTFields for 24hTTFields interfere with the proper alignment of tubulin dimers and lead to the formation of ineffective mitotic spindles
Annexin staining of HeLa cells exposed to TTFieldsIdentify whether the mechanism of cell death due to TTFields is apoptosis versus necrosisAnnexin staining seen only in mitotic cells exposed to TTFieldsTTFields-mediated cell death is through apoptosis

Table 14. Device-Related AEs (From SBA)
NovoTTF-100A
Adverse Event [N=116](%)
Medical device site reaction 18 (16)
Headache 4(3)
Malaise 2 (2)
Muscle twitching 1 (1)
Fall 1 (1)
Skin ulcer 1 (1)

Figure 2. Primary Effectiveness Endpoint Analysis: ITT population (From SBA)
TTF
(n=120)
BSC
(n=117)
Death10597
Lost-to-Follow610
Still Alive910
Median(months)
95% CI
6.3
(5.6,7.8)
6.4
(5.2,7.4)

Primary Effectiveness Endpoint - Overall Survival

Vital status is known for 221 (93%) subjects at the end of the study; 202 subjects were known to have died and 19 subjects (Novo-TTF=9, BSC=10) were still alive at the end of the study (6 months after the last subject had been randomized). Sixteen (7%) subjects (Novo-TTF=6, BSC= 10) were lost to vital status follow-up.
The majority of subjects lost to follow-up were subjects who never started the assigned treatment after randomization (Novo-TTF=1, BSC=8). The remaining 7 subjects (Novo-TTF=5, BSC=2) were lost to follow-up during the study due to non-compliance with the follow up protocol.

In the ITT population including all randomized subjects (Novo-TTF=120, BSC=117), there was no significant difference in overall survival (OS) between the two treatment groups (median OS Novo-TTF=6.3 vs. BSC=6.4 months; Logrank p=0.98, Hazard Ratio (HR) = 1.0, 95% Confidence Interval of HR: 0.76, 1.32). The Kaplan-Meier survival curves (Fig. 2) for the two treatment groups appeared to be very similar during first 12 months of follow-up, where 80% of the events occurred in both groups. Between 12 and 24 months, the survival curves separated in favor of the BSC control group. After 24 months, the number of subjects remaining may be too small to reliably estimate the long term survival outcome.

Table 15. Summary of Secondary Endpoints (except Quality of Life) (From SBA)
Secondary EndpointsTreatment Group
NovoTTF-100A BSC
Total Number of Patients120117
One-Year Survival21.9%
(25/114)
22,1%
(23/104)
PFS6
CEC adjudicated21.4%
(22/103)
15.2%
(14/92)
Core radiology review17.0%
(17/100)
19.4%
(13/67)
Radiological Response Rate
Investigator assessment14.0%
(14/100)
9.6%
(7/73)
Core radiology review4.1%
(4/97)
6.8%
(5/73)
Median TTP (weeks)
CEC adjudicated9.39.6
Core radiology review9.912.1

Secondary Effectiveness Endpoints

The secondary effectiveness endpoints for the NovoTTF- 100A trial support the primary endpoint results, in that they show the NovoTTF-100A device is clinically comparable to the BSC control among the evaluable subjects (Table 15). One-year-survival in the NovoTTF-100A group (evaluable number of subjects = 114) was very similar to that in the BSC chemotherapy group (evaluable = 104) 21.9% vs. 22.1%, respectively. According to the Clinical Events Committee's (CEC) adjudication of the investigator's assessment of tumor progression, which considered both clinical and radiological information, progression free survival at 6 months (PFS6) was 21.4% for the Novo-TTF- 100A group (evaluable = 103) vs. 15.2% for the BSC group (evaluable = 92) and median time to progression (TIP) was 9.3 weeks for NovoTTF-100A vs. 9.6 weeks for BSC. Based on the unblinded investigator's assessment, radiological response rates were reported as 14% for the NovoTTF-100A group (evaluable = 100) compared to 9.6% for the BSC group (evaluable = 73).

However, based on core radiology review, limited to MRI review, PFS6, radiological response rate and median TTP appeared to be better among the evaluable subjects in the BSC group than in the NovoTTF-100A group.







NovoCure Ltd

- http://www.novocure.com/ ;登記本社the Jersey Isle; Standen Ltd.子会社 本社 イスラエル、米国Portsmouth, NH Founded by Dr. Yoram Palti in 2000 Novocure is a commercial-stage oncology company dedicated to the advancement of TTF therapy for patients with solid tumors. ●TTF therapy Pipeline Clinical Trials
試験名称実施責任者規模期間試験方法備考
多型性神経膠芽腫に対するNovoTTF-100AとTemozolomide併用の有効性NovoCure Ltd700人Jun 2009~Apr 2015予RCT Open
有効性
Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme (GBM)[NCT00916409]
Primary Outcome Measures:~Progression Free Survival (PFS) time [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Secondary Outcome Measures~•Overall survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
NovoCure Ltd~予
[]
Publications & Presentations Press Releases Novocure announces first sites trained to treat patients with NovoTTF-100A System[2011.2.2] Updated survival data for phase III trial for recurrent glioblastoma tumors presented at SNO[2011.11.20] Novocure announces supply agreement[2011.8.4] FDA approves the NovoTTF-100A System for the treatment of recurrent GBM[2011.4.15] FDA Neurological Devices Advisory Committee[2011.3.17] Results from phase II trial for advanced NSCLC presented at ESMO[2010.10.9] Results from phase III trial for recurrent glioblastoma tumors presented at ASCO[2010.6.5] Results from phase I/II trial for newly diagnosed glioblastoma presented at SNO[2008.11.18] Results from pilot study in breast cancer presented at AACR[2008.4.14] Data from phase I/II trial for recurrent glioblastoma tumors published in PNAS[2007.5.18]
●各種

Novocure brings brain cancer therapeutic device to U.S. sites[2-Dec-2011]

Novocure Ltd., a medical device company in Portsmouth, N.H., has announced that its new brain tumor therapeutic device is going to be used at four clinical sites in the U.S., including Beth Israel Deaconess Medical Center in Boston.

In the U.S., the TTFields device will see use at the four initial clinical sites by the following doctors: Dr. Eric T. Wong, Beth Israel Deaconess Medical Center in Boston; Dr. Jay-Jiguang Zhu, Mischer Neuroscience Institute in the Memorial Hermann Hospital and The University of Texas Health Science Center, Houston; Dr. Joseph Landolfi, New Jersey Neuroscience Institute at JFK, Edison, N.J.; and Dr. Herbert Engelhard, University of Illinois Hospital in Chicago.

Undergoing training on the devices so they can be ready to use it by the end of 2011 are: Dr. Andrew Lassman, Columbia University Medical Center at New York – Presbyterian Hospital, New York City; Dr. Lisa DeAngelis, Memorial Sloan Kettering Cancer Center, New York City; and Dr. Santosh Kesari, University of California San Diego Moores Cancer Center, San Diego.


非侵襲的脳腫瘍治療デバイス「NovoTTF-100A」が米国で承認獲得[日経メディカルオンライン 2011.4.21]

NovoTTF-100A - New Treatment of Brain Tumors, Breast, and, Other Cancers[Examiner 2011.6.13]
Management of Recurrent or Progressive Glioblastoma Multiforme with Low-intensity, Medium-frequency Alternating Electric Fields
Yoram Palti
Professor of Physiology and Biophysics, Technion, Israel Institute of Technology
Touch Briefings 2007
European Oncological Diseases 2007
FDA Approves the NovoTTF-100A System for the Treatment of Patients With Recurrent Glioblastoma Multiforme (GBM) Brain Tumors[2011.4.15]







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関連●MLリソース:膀胱癌治療薬[1049_ADD]
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1068★15/26★99.12.17★123★難治性未分化星細胞腫治療薬テモゾロミド/2p1068追加メモ[脳腫瘍治療薬]
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1035★14/19★98.09.11★092★脳腫瘍の治療に対するGliadel wafer/1p1035追加メモ>
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作成:2000.1.17 最終更新:2008.5.15 小菅博之
The Medical Letter日本語版
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On Drugs and Therapeutics

このページは[The Medical Letter日本語版]の補足データとして添付しています。 [The Medical Letter]は新薬の厳正な評価誌であり、ここに収録される製品は新しくFDA承認された新薬に対する評価を中心としています。
 企画意図の第一は、収録製品についての米国内・世界での背景情報です。 例えば、各製品の承認関連データ、競合品との、あるいは市場での位置づけ、疫学データなど。 第二は、日本での該当製品や市場の情報。 市場の主要製品売上、開発中の治験薬等。 調査項目としては、■製品■解説■データ■臨床ガイドラインなど■総説記事・文献■ニュース・トピックス■リンク■主要サイト