JP2022024031A - 白血病に罹患している対象の治療レジメンを選択するためのアッセイ及び方法 - Google Patents
白血病に罹患している対象の治療レジメンを選択するためのアッセイ及び方法 Download PDFInfo
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Abstract
Description
本出願は、2015年11月11日に出願された米国仮出願62/254,109号の優先権を主張する。この文書の内容は本明細書中に参照により組み込まれる。
前記対象由来の癌細胞を、細胞培養物中でCPX-351処理にex vivoで曝露すること、及び
前記細胞の前記処理に対する応答性を測定すること、を含み;
ここで、その細胞が前記処理に応答性を示す対象が、CPX-351による治療が有効である可能性が高い対象として同定される、方法に関する。応答性は、例えば、IC50若しくはIC90の決定を用いた細胞毒性として、又はCPX-351の取り込みを測定することにより測定することができる。
本発明は、例えば以下の実施形態を包含する:
[実施形態1]FLT-3中に活性化変異を示す血液由来癌を有する対象におけるCPX-351による治療の有効性を増強させる方法において使用するためのFLT阻害剤及びCPX-351の組合せであって、前記方法は、CPX-351と組み合わせて有効量のFLT-3阻害剤を投与することを含み、ここで、CPX-351及びFLT-3阻害剤は、同時に投与されるか、又はCPX-351は、FLT-3阻害剤による治療の前に投与される、組合せ。
[実施形態2]CPX-351及びFLT-3阻害剤が同じ組成物中で投与される、実施形態1に記載の組合せ。
[実施形態3]血液由来癌が、急性骨髄性白血病(AML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性新生物(MPN)、及びリンパ腫からなる群から選択される、実施形態1に記載の組合せ。[実施形態4]FLT-3阻害剤が、キザルチニブ、ミドスタウリン、タンヅチニブ、ソラフェニブ、スニチニブ、レスタウルチニブ、クレノラニブ、ギルテリチニブ、AST-487、ドビチニブ、又はリニファニブである、実施形態1~3のいずれかに記載の組合せ。
[実施形態5]FLT-3中に活性化変異を示す血液由来癌を有する対象におけるCPX-351による治療の有効性を増強させる方法であって、CPX-351と組み合わせて有効量のFLT-3阻害剤を投与することを含み、ここで、CPX-351及びFLT-3阻害剤が、同時に投与されるか、又はCPX-351が、FLT-3阻害剤による治療の前に投与される、方法。
[実施形態6]CPX-351及びFLT-3阻害剤が同じ組成物中で投与される、実施形態5に記載の方法。
[実施形態7]血液由来癌が、急性骨髄性白血病(AML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性新生物(MPN)、及びリンパ腫からなる群から選択される、実施形態5に記載の方法。
[実施形態8]FLT-3阻害剤が、キザルチニブ、ミドスタウリン、タンヅチニブ、ソラフェニブ、スニチニブ、レスタウルチニブ、クレノラニブ、ギルテリチニブ、AST-487、ドビチニブ、又はリニファニブである、実施形態5~7のいずれかに記載の方法。
[実施形態9]血液由来癌を有するヒト対象の、CPX-351による治療に対する感受性を決定する方法であって、前記対象の生体サンプルをアッセイして以下を決定することを含む方法:
a)前記対象におけるFms様チロシン受容体キナーゼ3(FLT-3)遺伝子における変異の存在又は非存在;及び/又は
b)前記対象におけるヌクレオフォスミン1(NPM-1)遺伝子における変異の存在又は非存在;及び/又は
c)前記対象におけるCCAATエンハンサー結合タンパク質アルファ(CEBPα)遺伝子における変異の存在又は非存在;及び/又は
d)好適リスク、中間-I、中間-II又は有害リスクとしての前記対象の遺伝子型。[実施形態10]血液由来癌が、急性骨髄性白血病(AML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性新生物(MPN)、及びリンパ腫からなる群から選択される、実施形態9に記載の方法。[実施形態11]前記生体サンプルが血液、血清、血漿、唾液、又は芽球を含む、実施形態9に記載の方法。
[実施形態12]前記対象におけるFms様チロシン受容体キナーゼ3(FLT-3)遺伝子における変異の存在又は非存在を決定することを含む、実施形態9~11のいずれかに記載の方法。
[実施形態13]前記変異がFLT-3活性化変異である、実施形態12に記載の方法。[実施形態14]前記変異がFLT-3-ITD又はFLT-3-TKDである、実施形態12に記載の方法。
[実施形態15]前記対象においてヌクレオフォスミン1(NPM-1)遺伝子における変異の存在又は非存在を決定することを含む、実施形態9~11のいずれかに記載の方法。
[実施形態16]前記対象においてCCAATエンハンサー結合タンパク質アルファ(CEBPα)遺伝子における変異の存在又は非存在を決定することを含む、実施形態9~11のいずれかに記載の方法。
[実施形態17]前記対象の遺伝子型を好適リスク、中間-I、中間-II又は有害リスクとして決定することを含む、実施形態9~11のいずれかに記載の方法。
[実施形態18]血液由来癌を有するヒト対象の、CPX-351による治療に対する応答性を決定する方法であって、
(a)前記対象由来の血液由来癌細胞を、細胞培養物中のCPX-351にex vivoで曝露すること、及び
(b)前記細胞の前記曝露に対する応答性を測定すること
を含む、方法。
[実施形態19]前記細胞の応答性が、前記細胞培養物中の細胞のCPX-351のIC50又はIC90を測定することによって決定される、実施形態18に記載の方法。
[実施形態20]前記細胞の応答性が、前記細胞培養物中の細胞によるCPX-351の取り込みを測定することによって決定される、実施形態18に記載の方法。
[実施形態21]前記血液由来癌が、急性骨髄性白血病(AML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性新生物(MPN)、及びリンパ腫からなる群から選択される、実施形態18~20のいずれかに記載の方法。
[実施形態22]ヒト対象において血液由来癌を治療する方法であって、
(a)前記対象におけるFms様チロシン受容体キナーゼ3(FLT-3)遺伝子における変異の存在又は非存在を決定すること、及び
(b)前記FLT-3遺伝子に変異を示す対象に有効量のCPX-351を投与すること、ならびに/又は
(c)前記対象におけるヌクレオフォスミン1(NPM-1)遺伝子における変異の存在又は非存在を決定すること、及び
(d)前記NPM-1遺伝子に変異を示す対象に有効量のCPX-351を投与すること、ならびに/又は
(e)前記対象におけるCCAATエンハンサー結合タンパク質アルファ(CEBPα)遺伝子における変異の存在又は非存在を決定すること、及び
(f)前記CEBPα遺伝子に変異を示す対象に有効量のCPX-351を投与すること、ならびに/又は
(g)前記対象の遺伝子型を好適リスク、中間-I、中間-II、若しくは有害リスクとして決定すること、及び
(h)その遺伝子型が有害リスク若しくは中間-IIである対象に治療上有効な量のCPX-351を投与すること
を含む、方法。
[実施形態23](a)前記対象においてFms様チロシン受容体キナーゼ3(FLT-3)遺伝子における変異の存在又は非存在を決定すること、及び
(b)前記FLT-3遺伝子に変異を示す対象に有効量のCPX-351を投与することを含む、実施形態22に記載の方法。
[実施形態24]変異がFLT-3活性化変異である、実施形態23に記載の方法。
[実施形態25]変異がFLT-3-ITD又はFLT-3-TKDである、実施形態24に記載の方法。
[実施形態26](a)前記対象においてヌクレオフォスミン1(NPM-1)遺伝子における変異の存在又は非存在を決定すること、及び
(b)前記NPM-1遺伝子に変異を示す対象に有効量のCPX-351を投与することを含む、実施形態22に記載の方法。
[実施形態27](a)前記対象においてCCAATエンハンサー結合タンパク質アルファ(CEBPα)遺伝子における変異の存在又は非存在を決定すること、及び
(b)前記CEBPα遺伝子に変異を示す対象に有効量のCPX-351を投与することを含む、実施形態22に記載の方法。
[実施形態28](a)前記対象の遺伝子型を好適リスク、中間-I、中間-II、又は有害リスクとして決定すること、及び
(b)その遺伝子型が有害リスク又は中間-IIである対象に治療上有効な量のCPX-351を投与することを含む、実施形態22に記載の方法。
[実施形態29]ヒト対象における血液由来癌を治療する方法であって、
(a)前記対象由来の血液由来癌細胞を、細胞培養物中のCPX-351にex vivoで曝露すること;及び
(b)前記細胞の前記曝露に対する応答性を測定すること;及び
その細胞が前記曝露に対して応答を示す対象に治療上有効な量のCPX-351を投与すること
を含む、方法。
[実施形態30]前記細胞の応答性が、前記細胞培養物中の細胞のCPX-351のIC50又はIC90を測定することによって決定される、実施形態29に記載の方法。
[実施形態31]前記細胞の応答性が、前記細胞培養物中の細胞によるCPX-351の取り込みを測定することによって決定される、実施形態29に記載の方法。
[実施形態32]血液由来癌が、急性骨髄性白血病(AML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性新生物(MPN)、及びリンパ腫からなる群から選択される、実施形態29~31のいずれかに記載の方法。
CPX-351製剤及び単純な調製
CPX-351(シタラビン:ダウノルビシンの注射用リポソーム)は、50mLのバイアル中に、無菌的で発熱物質を含まない紫色の凍結乾燥製品として供給されている。1単位を1.0mgのシタラビン+0.44mgのダウノルビシン(ベースとして)とすると、各バイアルは100単位を含有する。これらの物質は19mLの注射用水で再構成し、室温で10分間穏やかに回旋させた。再構成した生成物の作業用アリコートは、-20℃で12カ月を超えない期間、凍結保存した。
薬物感受性試験を、標準の既知の方法によって実施した。簡潔には、患者骨髄検体からの単核細胞を、10―4Mの2-メルカプトエタノール(Sigma)を添加したR10(10%FBS(Atlanta Biologicals、ジョージア州Lawrenceville)、L-グルタミン、ペニシリン/ストレプトマイシン(Invitrogen、カリフォルニア州Carlsbad)、及びFungizone(登録商標)(Invitrogen)を添加したRPMI-1640培地)中で培養した。リンパ系白血病サンプルからの細胞を、10―4Mの2-メルカプトエタノール(Sigma)及びインスリン-トランスフェリン-亜セレン酸ナトリウム(Invitrogen)を添加したR20(20%FBS(Atlanta Biologicals、ジョージア州Lawrenceville)、L-グルタミン、ペニシリン/ストレプトマイシン(Invitrogen、カリフォルニア州Carlsbad)、及びFungizone(登録商標)(Invitrogen)を添加したRPMI-1640培地)中で培養した。
より高いCPX-351の効力が、FLT3-ITD表現型を有するAML患者の芽球で観察される。FMS様チロシン受容体キナーゼ(FLT3)は正常な造血及び白血病誘発において重要な役割を果たし、ほとんどのAML芽球中で発現している。AML患者の20%~25%で、FLT3遺伝子はFLT3の膜近傍ドメイン内に内部タンデム複製(FLT3-ITD)を獲得し、患者の予後不良に関連している。FLT3-ITDの状態が既に判明している、実施例1の研究の42人のAML患者のうち、14人の患者がFLT3-ITD変異を保有すると特定され、残りの28人はFLT3-ITD陰性であった。ex vivo細胞毒性の結果は、FLT3-ITDの陽性が、驚くべきことに、CPX-351誘導性の細胞毒性へのより高い感受性に関連していることを示している(図3A参照)。具体的には、FLT3-ITDを示す白血病芽球は、FLT3-ITD陰性患者の芽球サンプル(IC50=1.32:0.26μmol)と比較して十分に低いIC50値(0.29:0.058μmol)を示した。FLT3-ITD陽性と陰性のサンプル間の、CPX-351細胞毒性に対する応答の相違は統計的に有意であった(p=0.047)。また、FLT3-ITD陽性患者は、白血球数(WBC)の平均値が91,000/mm3であり、診断時の平均の29,000/mm3に対して有意に(p=0.0002)多いことも注目された。
前臨床の白血病動物モデルにより、CPX-351を注射した際、これらの動物に移植した骨髄中の白血病細胞は、シタラビン及びダウノルビシンを大部分は相乗的な薬物比を維持するインタクトなリポソーム形態で素早く取り込むことができ、その結果、遊離薬物のカクテル投与と比較して白血病細胞中での薬物蓄積が増加し長期化することが実証された。以下のデータは、遊離薬物と比較して増強されたCPX-351の取り込みを示す。したがって、ex vivoでのCPX-351の取り込み及び細胞毒性は、臨床的なCPX-351の成功の予測に用いることができる。
本実施例では、FLT-3遺伝子に活性化変異を有するかどうかを決定するようにAML患者をスクリーニングして、第3相臨床試験を行った。活性化変異AML-ITD+を持つことが判明したAML患者には、3用量のCPX-351を、1日目に1回目の投与ステップ、3日目に2回目の投与ステップ、及び5日目に3回目の投与ステップからなる投与サイクルで投与した。CPX-351を用いた治療プロトコルは米国特許第8,092,828号に記載されている。血漿及び/又は骨髄サンプルの分析を含む患者の応答性を測定及びモニタリングし、応答率及び生存率を測定した。NPM1及び/又はCEBPαの変異が陽性であった患者の亜群も含まれていた。初期研究はFLT-3の変異に焦点をあて、NPM-1及びCEBPαの変異を持つ個体も含まれていた。研究に参加した患者を表3に示す。
本実施例では、細胞生存率、及びフローサイトメトリーによって決定されたダウノルビシン蛍光に基づく細胞内取り込みを、実施例1及び3に記載のとおり測定した。
Claims (1)
- FLT-3中に活性化変異を示す血液由来癌を有する対象におけるCPX-351による治療の有効性を増強させる方法において使用するためのFLT阻害剤及びCPX-351の組合せであって、前記方法は、CPX-351と組み合わせて有効量のFLT-3阻害剤を投与することを含み、ここで、CPX-351及びFLT-3阻害剤は、同時に投与されるか、又はCPX-351は、FLT-3阻害剤による治療の前に投与される、組合せ。
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