JP2007510721A - マントル細胞リンパ腫を処置するためのcci−779 - Google Patents
マントル細胞リンパ腫を処置するためのcci−779 Download PDFInfo
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- JP2007510721A JP2007510721A JP2006539565A JP2006539565A JP2007510721A JP 2007510721 A JP2007510721 A JP 2007510721A JP 2006539565 A JP2006539565 A JP 2006539565A JP 2006539565 A JP2006539565 A JP 2006539565A JP 2007510721 A JP2007510721 A JP 2007510721A
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- cci
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- cell lymphoma
- mantle cell
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Abstract
Description
本発明は、マントル細胞リンパ腫(MCL)の処置または阻害における、3−ヒドロキシ−2−(ヒドロキシメチル)−2−メチルプロピオン酸とのラパマイシン42−エステル(CCI−779)の使用に関する。
本発明は、対象におけるマントル細胞リンパ腫の処置または阻害のための医薬の製造におけるCCI−779の使用を提供する。
従って、本発明は、マントル細胞リンパ腫の処置または阻害に有用な方法およびキットを提供する。
マントル細胞リンパ腫は、結果としてホスファチジルイノシトール3キナーゼ(PI3K)経路の一員であるサイクリンD1の過剰発現を生じるt(11;14)により特徴付けられる。本治験は、ラパマイシンの哺乳動物標的(mTOR)のレベルでPI3K経路を阻害するCCI−779が、MCLを有する患者における腫瘍応答をもたらすことができるかどうかを試験した。
本研究は、North Central Cancer Treatment Group(NCCTG)の共同グループにより行われた。患者は、以前に治療を受け、かつ再発しているならば、本試験を受ける資格があった。従前の治療の回数は制限しなかった。すべての組織像を、病理中央診断(central pathology review)によりマントル細胞リンパ腫であることを確認した。免疫組織化学によるサイクリンD1陽性またはFISHによるt(11;14)検出が必要とされた。患者は、>2cmのリンパ節または腫瘤を有する測定可能な疾患、またはALC>5,000を有する悪性リンパ球増加症;>3ヶ月の平均余命、0、1、または2のECOG全身状態(performance status);>1,000の絶対好中球数(ANC);>75,000の血小板;>8g/dLのヘモグロビン;<2×正常値の上限(UNL)の血清クレアチニン;<1.5UNLの血清ビリルビン;<350mg/dLの血清コレステロール;および、<400mg/dLのトリグリセリドを有することが必要とされた。患者は、分かっている中枢神経系介入またはHIV感染を有してはならなかった。
全部で35名の患者をこの治験に登録した。1名の患者は、組織像がMCLと一致したが、サイクリンD1染色が陰性であったため、病理学的レビューの後、不適格と証明された。患者は平均年齢70歳(範囲:38−89歳)で高齢者の傾向であった。ほとんどの患者(91%)がステージIVの疾患を有し、平均3回の以前の治療で激しく前処置されていた(平均4;1−11の範囲)。患者のほとんどは、リツキシマブ、シクロホスファミドなどのアルキル化剤、およびドキソルビシンなどのアントラサイクリンで不成功に終わった。患者の半数以上がプリンヌクレオシド類似体を受けた。
全奏功率(ORR)は38%(13/34;90%CI:24%−54%)であり、1名のCRと12名のPRであった。腫瘍応答は急速に起こり、応答までの時間の中央値は1ヶ月(範囲、1−8)であった。第一サイクル評価後に8名の応答が起こり、3サイクル後に3名が記載され、4ヶ月および8ヶ月評価後に各々1名が記録された。13応答者の応答期間の中央値は5.7ヶ月(95%CI:4−13.2ヶ月)であった。これらの解析の時点で、3名の患者が処置中であった。
35名の患者すべてを安全性および認容性の解析に含んだ。30分間の点滴中、CCI−779は十分認容性であり、起こった著しい毒性はなかった。血小板減少症が用量低下のほとんどの原因であり、典型的に1週間の遅延のみで、薬剤で急速に回復した。3名の患者のみが血小板輸血を必要とし、4名の患者が赤血球細胞輸血を必要とした。13名の患者が好中球減少症の合併なしで、グレード3感染を経験した;2名の患者が熱性好中球減少症を経験し、3名が好中球減少症を合併した感染(グレード3)を経験した。1名の患者が右下部運動神経顔面神経麻痺(ベル麻痺)と精神状態変化を発症し、MRIスキャンと脳脊髄液分析を行ったが、MCLの関与の証拠はなかった。この結論は、これは特発性ベル麻痺であり、実際、それは最終的に消失した。CCI−779との関連の可能性は確立の除外もされていない。目のかすみを経験した患者は、サイトメガロウイルス(CMV)感染による網膜炎と診断された。この患者は、本治験参加前にCMV網膜炎の病歴があったが、治験参加時に感染の証拠はなかった。
MCLを有する11名の患者(4名は難治性、7名は再発性。55から85歳の範囲)を、CCI−779のフェーズII試験に登録し、実施例1におけるよりも10倍低い用量、すなわち、25mg/週を受けた以外は上記の実施例1のとおりに処置した。8名の患者(73%)はステージIVにあり、2名(18%)はステージIIIにあり、そして4人(36%)は、>2の節外病変を有した。患者は、中央値3(範囲、1−7)の前処置を受けており、そして3名は、彼らの直前の処置で難治性であった。
すべての応答率は、7名のPRで64%(7/11)であった(64%)。
35名の患者すべてを安全性および認容性の解析に含んだ。30分間の点滴中、CCI−779は十分認容性であり、起こった著しい毒性はなかった。血小板減少症が用量低下のほとんどの原因であり、典型的に1週間の遅延のみで、薬剤で急速に回復した。3名の患者のみが血小板輸血を必要とし、4名の患者が赤血球細胞輸血を必要とした。13名の患者が好中球減少症の合併なしで、グレード3感染を経験した;2名の患者が熱性好中球減少症を経験し、3名が好中球減少症を合併した感染(グレード3)を経験した。1名の患者が右下部運動神経顔面神経麻痺(ベル麻痺)と精神状態変化を発症し、MRIスキャンと脳脊髄液分析を行ったが、MCLの関与の証拠はなかった。この結論は、これは特発性ベル麻痺であり、実際、それは最終的に消失したことである。CCI−779との関連の可能性は確立も除外もされていない。目のかすみを経験した患者は、サイトメガロウイルス(CMV)感染による網膜炎と診断された。この患者は、本治験参加前にCMV網膜炎の病歴があったが、治験参加時に感染の証拠はなかった。
Claims (12)
- 哺乳動物においてマントル細胞リンパ腫を処置または阻害する方法であって、それを必要とする該哺乳動物に有効量のCCI−779を供すること含む方法。
- 前記CCI−779を静脈内投与する請求項1に記載の方法。
- 前記CCI−779を1から12ヶ月間週1回投与する請求項1に記載の方法。
- 前記CCI−779を、1週間あたり10から100mgの用量で投与する、請求項1に記載の方法。
- 前記CCI−779を、1週間あたり25mgの用量で静脈内投与する、請求項1に記載の方法。
- 前記CCI−779を、1週間あたり100mgから250mgの用量で経口投与する、請求項1に記載の方法。
- 対象においてマントル細胞リンパ腫を処置または阻害するための医薬の製造におけるCCI−779の使用。
- 前記CCI−779が静脈内投与のために製剤されている、請求項7に記載の使用。
- 前記CCI−779が静脈内投与のために製剤されている、請求項7に記載の使用。
- マントル細胞リンパ腫の処置または阻害を必要とする哺乳動物におけるその処置または阻害に有用な医薬組成物であって、薬学的に許容される担体と一緒に単位投与量形態でCCI−779を含んでなる組成物。
- 一個体の哺乳動物に対するマントル細胞リンパ腫の1クールの処置剤を含む医薬パックであって、単位投与量形態で1単位のCCI−779を有する容器を含んでなるパック。
- 該パックが1から4単位のCCI−779を含んでなる、請求項11に記載の医薬パック。
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PCT/US2004/035900 WO2005046681A1 (en) | 2003-11-04 | 2004-10-28 | Cci-779 for treating mantle cell lymphoma |
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