JP2014513089A - アフリバーセプト、フォリン酸、5−フルオロウラシル(5−fu)及びイリノセタン(フォルフィリ)を含む組成物 - Google Patents
アフリバーセプト、フォリン酸、5−フルオロウラシル(5−fu)及びイリノセタン(フォルフィリ)を含む組成物 Download PDFInfo
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Abstract
Description
a)包装材料;
b)アフリバーセプト;及び
c)前記包装材料内に収容されており、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと組み合わせたアフリバーセプトがCRCの治療のために有効であることを示すラベルまたは添付文書;
を含む製品を特徴とする。
a)アフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンからなるリストから選択される少なくとも1つの化合物;及び
b)キット内に収容されており、アフリバーセプトはフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタン(フォルフィリ)と一緒に使用されるべきであり、またはフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタン(フォルフィリ)はアフリバーセプトと一緒に使用されるべきであることを示すラベルまたは添付文書;
を含むCRC患者を治療するためのキットを特徴とする。
EFC10262は、オキサリプラチンに基づくレジメンに失敗した後の転移性大腸癌(MCRC)患者に対する第二選択治療として、2週間毎に静脈投与したイリノテカンと5−フルオロウラシル配合剤(フォルフィリ)と組み合わせた4mg/kgのアフリバーセプトをプラセボに対して比較するランダム化二重盲検多施設研究として計画された。各ランダム化患者は病気の進行、死亡または許容できない毒性まで治療した。
患者にイリノテカン、5−FU及びロイコボリン(フォルフィリレジメン)を投与した直後に、患者に割り当てたアームに応じてアフリバーセプトまたはプラセボのいずれかを投与した。
アームA,アフリバーセプト:4mg/kgを1日目に1時間かけて、2週間毎にIV投与する。または
アームB,プラセボ:4mg/kgを1日目に1時間かけて、2週間毎にIV投与する。
アフリバーセプト/プラセボの投与直後に、すべての患者に
−Yラインを用いてバッグで、500mLの水中5% デキストロース溶液(D5W)中180mg/m2のイリノテカンを90分間かけてIV注入し、同時に400mg/m2の右旋性−左旋性(dl)ロイコボリンを2時間かけてIV注入した後、
−400mg/m2の5−FUを2〜4分間かけてIVボーラス投与した後、
−500mLのD5W(推奨)中2400mg/m2の5−FUを46時間かけて連続IV注入した。
人口統計及びベースライン特性
患者人口統計及びベースライン特性は2治療アームで類似であった(表1)。
全体で、ランダム化患者の30.4%が前ベバシズマブ階層に割り当てられた(表3)。
全研究治療暴露中央値(すなわち、研究薬物のアフリバーセプト/プラセボとフォルフィリの両方、または一方のみ)は、プラセボ及びアフリバーセプト治療アームにおいてそれぞれ8.0及び9.0サイクルであった(表4)。
1.全生存期間
ITT母集団の締切日(2011年2月7日)での追跡期間中央値は22.28ヶ月であった(図2及び表8)。本研究はその主要エンドポイントを満たし、全生存期間の点でプラセボに比してアフリバーセプトが優位な有意差を立証した(層別化HR:0.817,95.34% CI:0.713〜0.937;p=0.0032)。ハザード比は、プラセボに比して18.3%のアフリバーセプトでの死亡リスクの減少に変換される(95.34 CI:6.3%〜28.7%)。ランダム化から12及び18ヶ月後、存命している推定可能性はプラセボアームにおいて50.3%及びアフリバーセプトアームにおいて56.1%であり、プラセボアームにおいて30.9%及びアフリバーセプトアームにおいて38.5%であった。全生存期間中央値は、アフリバーセプト及びプラセボ治療アームにおいてそれぞれ13.50ヶ月対12.06ヶ月であった。感度解析及び部分集団解析は非常に一致した治療効果を示し、主要エンドポイントに対する結果のロバストネスが確認された。
部分集団解析は、治療アームと層別化因子間で(両側10%レベルで)有意な相互作用を示さず、治療効果が部分集団で一致していた。このことを表9、並びに図3、4及び5に示す。
PFSについての最終解析をOSの第2中間解析時(すなわち、締切日=2010年5月6日)に実施した。無増悪生存期間(PFS)の改善は、プラセボ治療アームの患者に比してアフリバーセプト治療アームの患者において実証された(層別化HR:0.758,99.99% CI:0.578〜0.995;p=0.00007)。PFS中央値は、アフリバーセプトアームにおいて6.90ヶ月、プラセボアームにおいて4.67ヶ月であった(表11)。
無増悪生存期間(PFS)を表12及び図6に示した部分集団において解析した。治療アームと層別化因子間で相互作用は見られなかった(表12)。
IRC検討した全奏効率は、プラセボ治療アームと比較したときアフリバーセプト治療アームにおいて有意に高かった:それぞれ19.8%(95% CI:16.4%〜23.2%)対11.1%(95% CI:8.5%〜13.8%)(p=0.0001)(表13)。
両治療群における患者の全体60%が追加的抗癌治療を受けた(表14)。
有害事象
両治療アーム中の患者のほぼ100%ですべてのグレードの治療下で発現する有害事象が報告され、グレード3〜4の事象の発生はアフリバーセプト治療アームにおいて高かった(83.5%対62.5%)。
本研究は、プラセボと比較したときアフリバーセプトアームにおける全生存期間の有意な改善でその主要エンドポイントを満たした。
Claims (32)
- 治療を要する患者に対して治療有効量のアフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンを投与することを含む前記患者の大腸癌(CRC)または大腸癌(CRC)症状を治療する方法。
- CRCに苦しんでいる患者に対して治療有効量のアフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンを投与することを含む前記患者の全生存期間(OS)を延長させる方法。
- CRCに苦しんでいる患者に対して治療有効量のアフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンを投与することを含む前記患者の無増悪生存期間(PFS)を延長させる方法。
- CRCに苦しんでいる患者に対して治療有効量のアフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンを投与することを含む前記患者の全奏効率(ORR)を上昇させる方法。
- 安全且つ有効である、請求項1〜4のいずれか1項に記載の方法。
- 前記患者は既にCRCまたはCRC症状に対する治療を受けている、請求項1〜5のいずれか1項に記載の方法。
- 前記患者は前に化学療法、放射線療法または手術の治療を受けている、請求項1〜6のいずれか1項に記載の方法。
- 前記患者は前にオキサリプラチンまたはベバシズマブに基づく治療を受けている、請求項1〜7のいずれか1項に記載の方法。
- 前記患者は化学療法、放射線療法または手術に失敗している、請求項7または8に記載の方法。
- CRCは転移性CRCである、請求項1〜9のいずれか1項に記載の方法。
- 患者に対してフォリン酸を約200mg/m2〜約600mg/m2の用量で、5−フルオロウラシル(5−FU)を約2000mg/m2〜約4000mg/m2の用量で、イリノセタンを約100mg/m2〜約300mg/m2の用量で、アフリバーセプトを約1mg/kg〜約10mg/kgの用量で投与する、請求項1〜10のいずれか1項に記載の方法。
- 患者に対してフォリン酸を約400mg/m2の用量で、5−フルオロウラシル(5−FU)を約2800mg/m2の用量で、イリノセタンを約180mg/m2の用量で、アフリバーセプトを約4mg/kgの用量で投与する、請求項1〜11のいずれか1項に記載の方法。
- フォリン酸を約400mg/m2の用量で静脈内投与し、5−フルオロウラシル(5−FU)を約2800mg/m2の用量で静脈内投与し、イリノセタンを約180mg/m2の用量で静脈内投与し、アフリバーセプトを約4mg/kgの用量で静脈内投与し、配合剤を2週間毎に投与する、請求項1〜12のいずれか1項に記載の方法。
- フォリン酸、5−フルオロウラシル(5−FU)、イリノセタン及びアフリバーセプトを2週間毎に9〜18週の期間静脈内投与する、請求項1〜13のいずれか1項に記載の方法。
- アフリバーセプトの投与直後にフォリン酸を静脈内投与する、請求項1〜14のいずれか1項に記載の方法。
- アフリバーセプトの投与直後にフォリン酸を約2時間かけて静脈内投与する、請求項1〜15のいずれか1項に記載の方法。
- アフリバーセプトの投与直後にイリノセタンを静脈内投与する、請求項1〜16のいずれか1項に記載の方法。
- アフリバーセプトの投与直後にイリノセタンを約90分間かけて静脈内投与する、請求項1〜17のいずれか1項に記載の方法。
- アフリバーセプトの投与直後に5−フルオロウラシル(5−FU)を投与する、請求項1〜18のいずれか1項に記載の方法。
- アフリバーセプトの投与直後に第1量の5−フルオロウラシル(5−FU)を静脈内投与し、第1量の後に連続注入で第2量の5−FUを静脈内投与する、請求項1〜19のいずれか1項に記載の方法。
- アフリバーセプトの投与直後に約400mg/m2の5−フルオロウラシル(5−FU)を2〜4分間かけて静脈内投与し、400mg/m2を投与した後に連続注入で2400mg/m2の5−FUをほぼ46時間かけて静脈内投与する、請求項1〜20のいずれか1項に記載の方法。
- 前記患者は肝転移を有している、請求項1〜21のいずれか1項に記載の方法。
- CRC患者を治療するための治療有効量のアフリバーセプトをフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと一緒に含む組成物であって、前記組成物は同時投与用である前記組成物。
- CRC患者を治療するための、治療有効量のアフリバーセプトをフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと一緒に含む組成物であって、前記組成物は逐次投与用である前記組成物。
- CRC患者を治療するための治療有効量のアフリバーセプトをフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと一緒に含む組成物であって、前記組成物は配合剤の最大効果が得られるように一定期間にわたって間隔をあけて投与するためである前記組成物。
- a)包装材料;
b)アフリバーセプト;及び
c)前記包装材料内に収容されており、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと組み合わせたアフリバーセプトがCRCの治療のために有効であることを示すラベルまたは添付文書;
を含む製品。 - 前記CRCの治療は全生存期間(OS)の改善を含む、請求項26に記載の製品。
- 前記CRCの治療は無増悪生存期間(PFS)の改善を含む、請求項26に記載の製品。
- 前記CRCの治療は全奏効率(ORR)の改善を含む、請求項26に記載の製品。
- CRC患者を治療するための、治療有効量のアフリバーセプトをフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンと一緒に含み、医薬的に許容され得る担体を含む組成物。
- a)アフリバーセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンからなるリストから選択される少なくとも1つの化合物;
b)キット内に収容されており、アフリバーセプトをフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタン(フォルフィリ)と一緒に使用すべきであること、またはフォリン酸、5−フルオロウラシル(5−FU)及びイリノセタン(フォルフィリ)をアフリバーセプトと一緒に使用すべきであることを示すラベルまたは添付文書;
を含むCRC患者を治療するためのキット。 - (1)アフリバーセプトを含む医薬組成物、(2)フォリン酸を含む医薬組成物、(3)5−フルオロウラシル(5−FU)を含む医薬組成物、及び(4)イリノセタンを含む医薬組成物を含む患者のCRCの治療において併用するための医薬組成物を別々の容器中に含むキット。
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