JP2019522032A - 前立腺癌の治療方法 - Google Patents
前立腺癌の治療方法 Download PDFInfo
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- JP2019522032A JP2019522032A JP2019504790A JP2019504790A JP2019522032A JP 2019522032 A JP2019522032 A JP 2019522032A JP 2019504790 A JP2019504790 A JP 2019504790A JP 2019504790 A JP2019504790 A JP 2019504790A JP 2019522032 A JP2019522032 A JP 2019522032A
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Abstract
Description
該当なし。
本発明は、安全かつ/又は有効量のニラパリブをヒトに投与することによるヒトにおける転移性ホルモン未治療前立腺癌の治療に関する。
アンドロゲンは、標的組織の細胞内でアンドロゲン受容体(AR)という特定の受容体に結合する。ARは身体の多くの組織で発現し、テストステロン(T)及びジヒドロテストステロン(DHT)などの内因性のアンドロゲンリガンドの生理学的及び病理生理学的作用が発現する受容体である。構造的には、ARは、リガンド結合ドメイン(LBD)、DNA結合ドメイン、及びアミノ末端ドメインの3つの主な機能ドメインで構成されている。ARに結合し内因性のARリガンドの作用を模倣する化合物がARアゴニストと呼ばれるのに対して、内因性のARリガンドの作用を阻害する化合物はARアンタゴニストと呼ばれる。受容体へのアンドロゲンの結合は、受容体を活性化させ、受容体を標的遺伝子に隣接したDNA結合部位に結合させる。ここから受容体は補助活性化因子タンパク質及び基本転写因子と相互作用して遺伝子の発現を制御する。したがって、その受容体を介して、アンドロゲンは細胞内の遺伝子発現に変化を生じさせる。これらの変化は、細胞の代謝産物、分化、又は増殖に標的組織の生理学的状態において目に見える結果を最終的にもたらす。前立腺において、アンドロゲンは、アンドロゲン感受性組織の細胞質中に存在するARに結合することにより、前立腺組織及び前立腺癌細胞の増殖を刺激する。
内因性ホルモン(例えばテストステロン)の作用を阻害する薬剤(抗アンドロゲン剤)は極めて効果的であり、前立腺癌の治療に日常的に用いられている(アンドロゲン除去療法)。これらのアンドロゲン除去療法は、初期には腫瘍増殖の抑制に効果的であるが、ほとんどすべての症例で最終的には効果を失い、CRPCにつながる。すべてではないが大部分の前立腺癌細胞は、初期にはアンドロゲン除去療法に反応する。しかしながら、前立腺癌細胞はアンドロゲン除去療法によって作り出される選択圧に応答してきており、その時点で治療に反応しなくなっているため、時間の経過とともに前立腺癌細胞の生存集団が生じる。原発癌は用いられる療法に反応しなくなっているばかりか、癌細胞が原発腫瘍から分離し血流中を移動して、疾患を離れた部位(特に骨)に転移させ得る。これは、転移性去勢抵抗性前立腺癌(「mCRPC」)として知られる。他の作用の中でも、これは患者に顕著な痛み、更に骨の脆弱性を生じる。
ヒト前立腺腫瘍株におけるニラパリブのインビトロ細胞毒性
ニラパリブの細胞毒性を複数のヒト前立腺腫瘍株においてインビトロで試験した。いずれの腫瘍株も、BRCA−1又はBRCA−2欠損として知られているものではない。
ニラパリブのインビトロ細胞毒性を5つの前立腺癌細胞株C4−2B、LNCaP、LNCaP AR.TB、VCaP、及び22Rv1で評価した。C4−2B、LNCaP、LNCaP AR.TB、及び22Rv1細胞株は、10%熱不活化ウシ胎児血清(FBS)(Life Technologies #16140−071)及び非必須アミノ酸(NEAA)(Life Technologies #11140−050)を添加したRPMI1640+GlutaMAX(商標)−I培地(Life Technologies #61870−036)中で増殖させ、VCaP細胞は、10% FBS及びNEAAを添加したDMEM+GlutaMAX(商標)−I培地(Life Technologies ##10569−010)中で増殖させた。VCaP細胞は7日間ごとに継代培養し、他の株は3〜4日ごとに株分けした。
細胞毒性アッセイの結果を図1及び表1に示す。各細胞株の増殖は、ニラパリブの濃度を増大させることにより用量依存的に低下した。C4−2B細胞はEC50値が約1.2μMであり、感受性が最も高いようであった。VCaP細胞はEC50値が4.1μMであり、感受性が最も低いようであった。
ニラパリブによるPAR形成の阻害
ポリ(ADP)リボース(PAR)の形成を阻害するニラパリブの能力を2つのヒト前立腺腫瘍株でインビトロで試験した。いずれの腫瘍株も、BRCA−1又はBRCA−2欠損として知られているものではない。
ニラパリブを用いたPAR阻害を、C4−2B及びVCaPの2つのヒト前立腺癌細胞株で評価した。C4−2B細胞株は10% FBS及びNEAAを添加したRPMI1640+GlutaMAX(商標)−I培地中で増殖させ、3〜4日ごとに株分けした。VCaP細胞は、FBS及びNEAAを添加したDMEM+GlutaMAX(商標)−I培地中で増殖させ、7日間ごとに継代培養した。
PARアッセイの結果を図2に示す。PARは、各細胞株でニラパリブの濃度を増大させることにより用量依存的に低下した。
ニラパリブは、ヒト前立腺腫瘍株にインビトロでγ−H2AXを誘導する
DNAに二本鎖切断を誘導するニラパリブの能力を、22RV1、LNCaP AR.TB、及びC4−2Bの3つのヒト前立腺癌株で測定した。DNAの二本鎖切断に続いて、隣接するヒストンγ−H2AXのリン酸化が起きるが、このリン酸化は抗体染色及びフローサイトメトリーによって測定することができる。
22RV1、LNCaP AR.TB、及びC4−2B細胞株を上記で概略を述べたようにして増殖させた。細胞株を3〜4日ごとに継代した。
異なる濃度のニラパリブの影響を示した22RV1細胞株の代表的なヒストグラムを図3に示す。薬剤で処理した試料をビヒクル及び培地のコントロールと比較し、図4にグラフで示す。γ−H2AXシグナルがビヒクルコントロールを有意に上回る最低濃度を表2に示す。これらの結果は、各前立腺腫瘍株でニラパリブがγ−H2AXを用量依存的に誘導することを示すものである。
ニラパリブは、マウスにおいてC4−2Bヒト前立腺腫瘍の増殖を阻害する。
ビヒクルは、4℃の暗所で調製し保持した0.5%メチルセルロース(Methocel(商標)F4M)とした。すべての配合物は体重1kg当たり体積10mLを投与するように作られた。NSG雄性マウス(Jackson Laboratories社)を使用した。実験手順を実施するのに先立って動物を1週間馴化した。マウスを、12時間の明暗周期下で、温度19〜22℃、湿度35〜40%の使い捨てのIVCケージ(Innovive、San Diego,CA,USA)にグループ分けして収容した(ケージ当たり5匹ずつ)。マウスにオートクレーブした高脂質(6%)の実験動物用飼料及び水を自由摂取させた。
グループ2:0.5%メトセルF4Mに加えた25mg/kgのニラパリブを1日1回経口投与。
グループ3:0.5%メトセルF4Mに加えた50mg/kgのニラパリブを1日1回経口投与。
ビヒクルで処理したマウスは、実験およそ22日目から腫瘍体積の倫理的な限界値に達し始めた(個々の腫瘍体積については図5を参照)。腫瘍体積データを、実験24日目まで示した(10匹のビヒクル処理マウスのうち9匹が実験に残った)。処理の18、22、及び24日後、50mg/kgのニラパリブを毎日経口投与したグループ3は、腫瘍増殖の有意な阻害/遅延を示し、これらの期間の腫瘍増殖阻害(TGI)値は約40%であった。腫瘍増殖の有意差は、18、22及び24日目で認められた(*p<0.05、**p<0.01、***p<0.001)。25mg/kgのニラパリブを投与したマウスは、有意な腫瘍増殖阻害を示さなかったが、約12%のある程度のTGIが22及び24日目に認められた。
多施設共同のオープン試験を行って、少なくとも1ラインのタキサンによる化学療法及び少なくとも1ラインの抗アンドロゲン療法(例えば、アビラテロン酢酸塩、エンザルタミド、アパルタミド)を受けたことのあるmCRPC及びDNA修復異常を有する18才以上の男性被験者において、300mgのニラパリブの1日1回投与の有効性及び安全性を評価する。試験は、およそ100人の被験者で行う。被験者は、試験期間中、及び試験薬の最後の投与の30日後まで安全性について監視を行う。治療は、疾患の進行、許容されない毒性、死亡、又はスポンサーが試験を中止するまで継続する。
事前スクリーニングフェーズでは、可能性のある被験者がDNA修復異常についてバイオマーカー陽性であるかを評価する。すべての被験者は、事前スクリーニングフェーズのための特定のICFに署名し、ベースラインとなる人口統計学的特性及び疾患特異的な病歴を提供することが求められる。事前スクリーニングフェーズは、スクリーニングフェーズの前の任意の時点で行うことができる。
被験者は事前スクリーニングのICFに署名する。被験者が以前にFoundationOne(登録商標)遺伝子パネルによる腫瘍組織の分析を行っている場合、被験者の承諾の後、FoundationOne(登録商標)のデータを検討して表1に定義される基準に基づいて適性を判定することができる。被験者がバイオマーカー陽性である場合、スクリーニングフェーズに入る適性を有するものとする。被験者が以前にFoundationOne(登録商標)遺伝子パネルによる腫瘍組織の分析を行っていない場合、被験者は、スポンサーにより承認された試験によってバイオマーカー陽性について分析された、保管された腫瘍組織又は最近採取された(推奨される)腫瘍組織のいずれかを有していなければならない。被験者がバイオマーカー陽性である場合、スクリーニングフェーズに入る適性を有するものとする。
被験者は事前スクリーニングのICFに署名する。被験者の血液を採取し、バイオマーカー陽性についての分析用に送付する。被験者が以前にFoundationOne(登録商標)遺伝子パネルによる腫瘍組織の分析を行っている場合、被験者の承諾の後、FoundationOne(登録商標)のデータを検討して表1に定義される基準に基づいて適性を判定することができる。被験者がバイオマーカー陽性である場合、被験者はスクリーニングフェーズに入る適性を有するものとし、血液に基づいた分析の結果を待つ必要はない。FoundationOne(登録商標)遺伝子パネルが陰性である場合、被験者は、血液に基づいたアッセイによりバイオマーカー陽性であると判定されれば、依然として適性を有するものとみなすことができる。被験者が以前にFoundationOne(登録商標)遺伝子パネルによる腫瘍組織の分析を行っておらず、保管された組織が利用可能である場合、保管された腫瘍組織を取得及び分析する要請が開始される。血液に基づいたアッセイの結果がバイオマーカー陽性である場合、被験者はスクリーニングフェーズに入る適性を有するものとし、保管された腫瘍組織に基づいた分析の結果を待つ必要はない。保管された腫瘍組織に基づいた分析の結果が利用可能である場合、これを血液に基づいた結果と併せて一致及びブリッジング試験に用いることができる。
すべてのバイオマーカー陽性の被験者は、スクリーニングフェーズでのあらゆる試験関連の手順の実施に先立って主要試験のICFに署名しなければならない。このフェーズでは、適性の基準を再検討し、「時間及び事象のスケジュール」に示されるようにして完全な臨床評価を行う。特に指定されないかぎり、スクリーニング手順はサイクル1の1日目の35日前までに行われる。イメージングはサイクル1の1日目の8週間前まで許容される。スクリーニングによる臨床的安全性の臨床検査評価は、サイクル1の14日目以内に行われるならサイクル1の1日目の評価で使用することができる。
治療フェーズは、サイクル1の1日目に始まり、試験薬剤が中断されるまで継続する。試験薬剤の投与前又はスクリーニングの際のサイクル1の1日目に測定された最後の測定値(どちらか最後の値)が、ベースライン値として定義される。各サイクルの来院は、特に指定されないかぎり、±3日の範囲を有する。試験の来院は、サイクル1の1日目の日付から計算する。被験者には、画像を要する来院の±7日以内にイメージングを行うことができる。治療フェーズの間の治療来院及び評価については、「時間及び事象のスケジュール」を参照されたい。
治療終了時の来院は、試験薬剤の最後の投与後30日以内又は新たな抗前立腺癌治療薬の投与前(どちらか早い方)に予定されなければならない。被験者がEoT来院のために検査所に来院することができない場合、被験者には試験薬剤の最後の投与後30日以内に生じるAEを収集するために連絡が取られなければならない。
被験者が治療フェーズを完了した時点で、生存フォローアップ及びSSEを、来診、電話での問診、カルテ審査、又はその他の都合のよい方法によって3ヶ月ごとに実施する。因果関係にかかわらず死亡例及び試験薬剤に関連すると考えられるSAEは、事象の発見又は通知の24時間以内に収集し報告する。フォローアップ情報が電話での連絡により得られる場合、ソースドキュメントでの検討を行うために通話内容を書き取った記録がなければならない。
被験者がバイオマーカー陽性であるかを評価するため、被験者にとってより便利でありながら、バイオマーカー陽性状態を決定するための組織に基づいた分析よりも速やかな方法を提供する、血液に基づいたアッセイが試験期間中に利用できるようになり得る。血液に基づいたアッセイが利用可能となる前に、腫瘍組織(保管されているか、又は最近採取されたもの)の分析を行う必要がある。どの時点で試験に入ったかにかかわらず、すべての被験者が分析(すなわち、一致試験及びブリッジング試験)に使用できる同じバイオマーカーデータを有するように、腫瘍組織及び血液試料の両方を事前スクリーニングのインフォームドコンセントフォーム(ICF)に署名したすべての被験者から得る。バイオマーカー陽性を判定するためのプロセスは、血液に基づいたアッセイが利用可能となる前に事前スクリーニングフェーズに入る被験者では、血液に基づいたアッセイが利用可能となった後で事前スクリーニングフェーズに入る被験者と比較して異なる。しかしながら、腫瘍組織及び血液の両方におけるバイオマーカー陽性の状態はすべての被験者について評価を行う。
血液試料を「時間及び事象のスケジュール」に示された時点でCellsaveチューブに採取する。CTCの計数は、中央臨床検査室で評価して試験薬剤への反応を評価する。
全血試料をPaxgeneチューブに採取する。前立腺腫瘍に見られる複数のリボ核酸(RNA)転写産物がRNA中で検出可能であり、これらの試料の分析は、ニラパリブによって生じ得る抵抗性の潜在的な機序の評価を可能とする。
治療過程で採取した血漿試料を用いて、循環腫瘍DNA(ctDNA)により経時的に観察されるDNA修復異常のレベル又は種類の変化についてスクリーニングし、ニラパリブに対する抵抗性の潜在的なマーカーについて監視する。
Claims (11)
- 前立腺癌の治療を要するヒトの前立腺癌を治療する方法であって、前記ヒトに安全かつ有効量のニラパリブを投与することを含む、方法。
- 前記前立腺癌が、去勢抵抗性前立腺癌又は転移性去勢抵抗性前立腺癌である、請求項1に記載の方法。
- 前記前立腺癌が抗アンドロゲン抵抗性である、請求項2に記載の方法。
- 前記ヒトが、BRCA−1、BRCA−2、FANCA、PALB2、CHEK2、BRIP1、HDAC2、及びATMからなる群から選択される少なくとも1つのDNA修復異常を有する、請求項3に記載の方法。
- 前記DNA修復異常が、BRCA−1又はBRCA−2である、請求項4に記載の方法。
- 前記前立腺癌が、去勢抵抗性前立腺癌である、請求項5に記載の方法。
- 前記前立腺癌が、転移性去勢抵抗性前立腺癌である、請求項5に記載の方法。
- ニラパリブが、約30mg/日〜約400mg/日の量で投与される、請求項6に記載の方法。
- 前記投与されるニラパリブの量が、約300mg/日である、請求項8に記載の方法。
- ニラパリブが、3つの100mgの経口剤形での1日1回の経口投与として投与される、請求項9に記載の方法。
- ヒトの去勢抵抗性前立腺癌及び抗アンドロゲン抵抗性前立腺癌を治療する方法であって、前記ヒトに3つの100mgの経口剤形のニラパリブを1日1回投与することを含む、方法。
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