JP2016522212A5 - - Google Patents
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- JP2016522212A5 JP2016522212A5 JP2016517058A JP2016517058A JP2016522212A5 JP 2016522212 A5 JP2016522212 A5 JP 2016522212A5 JP 2016517058 A JP2016517058 A JP 2016517058A JP 2016517058 A JP2016517058 A JP 2016517058A JP 2016522212 A5 JP2016522212 A5 JP 2016522212A5
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Claims (31)
- PI3Kモジュレーター又はその医薬として許容し得る形態を、単独で又は1以上の他の治療剤と組み合わせて含む医薬組成物であって、1以上のBTK阻害剤、抗CD20抗体、プロテアソーム阻害剤、又はアルキル化剤による前治療に対する耐性を生じた対象、又は該耐性を生じたとして同定された対象における癌又は血液悪性腫瘍の治療に使用するための、前記医薬組成物。
- PI3Kモジュレーター又はその医薬として許容し得る形態を、単独で又は1以上の他の治療剤と組み合わせて含む医薬組成物であって、1以上のBTK阻害剤、抗CD20抗体、プロテアソーム阻害剤、又はアルキル化剤による前治療に再発性若しくは不応性である対象、又は該再発性若しくは不応性として同定された対象における癌又は血液悪性腫瘍の治療又は管理に使用するための、前記医薬組成物。
- 前記前治療が、1以上のBTK阻害剤による治療である、請求項1又は2記載の医薬組成物。
- 前記BTK阻害剤が、イブルチニブ、AVL-292、RN-486、GDC-0834、CGI-560、CGI-1746、HM-71224、ONO-4059、ACP-196、CNX-774、又はLFM-A13である、請求項3記載の医薬組成物。
- 前記前治療が、1以上の抗CD20抗体による治療であり、該抗CD20抗体が、オビヌツズマブ、トシツモマブ、131Iトシツモマブ、90Yイブリツモマブ、111Iイブリツモマブ、又はオファツムマブである、請求項1又は2記載の医薬組成物。
- 前記前治療が、1以上のプロテアソーム阻害剤、又はアルキル化剤による治療である、請求項1又は2記載の医薬組成物。
- 前記対象から取得される生体試料において、下記から選択される1以上の突然変異の存在が検出されている、請求項1〜6のいずれか一項記載の医薬組成物：
BTKの残基481におけるシステインからセリンへの突然変異(C481S)、BTKの残基481におけるシステインからフェニルアラニンへの突然変異(C481F)、PLCγ2遺伝子の残基665におけるアルギニンからトリプトファンへの突然変異(R665W)、PLCγ2遺伝子の残基257におけるヒスチジンからロイシンへの突然変異(H257L)、PLCγ2遺伝子の残基1141におけるメチオニンからアルギニンへの突然変異(M1141R)、PLCγ2遺伝子の残基707におけるセリンからフェニルアラニンへの突然変異(S707F)、PLCγ2遺伝子の残基845におけるロイシンからフェニルアラニンへの突然変異(L845F)、PLCγ2遺伝子の残基707におけるセリンからチロシンへの突然変異(S707Y)、PLCγ2遺伝子の残基244におけるヒスチジンからアルギニンへの突然変異(H244R)、及びWHIM様CXCR4突然変異。 - 前記PI3Kモジュレーター及び1以上の他の治療剤が、別々の組成物中での同時投与、別々の組成物中での異なる時間での投与、又は該PI3Kモジュレーター及び1以上の他の治療剤が存在する1つの組成物中での投与のために、製剤化されている、請求項1〜7のいずれか一項記載の医薬組成物。
- PI3Kモジュレーター又はその医薬として許容し得る形態を含む、癌又は血液悪性腫瘍を有する対象の治療に使用するための医薬組成物であって、
該対象が、BTKの残基481におけるシステインからセリンへの突然変異(C481S)、BTKの残基481におけるシステインからフェニルアラニンへの突然変異(C481F)、PLCγ2遺伝子の残基665におけるアルギニンからトリプトファンへの突然変異(R665W)、PLCγ2遺伝子の残基257におけるヒスチジンからロイシンへの突然変異(H257L)、PLCγ2遺伝子の残基1141におけるメチオニンからアルギニンへの突然変異(M1141R)、PLCγ2遺伝子の残基707におけるセリンからフェニルアラニンへの突然変異(S707F)、PLCγ2遺伝子の残基845におけるロイシンからフェニルアラニンへの突然変異(L845F)、PLCγ2遺伝子の残基707におけるセリンからチロシンへの突然変異(S707Y)、PLCγ2遺伝子の残基244におけるヒスチジンからアルギニンへの突然変異(H244R)、及びWHIM様CXCR4突然変異から選択される1以上の突然変異を有するとして同定される、前記医薬組成物。 - 前記PI3Kモジュレーター又はその医薬として許容し得る形態が、1以上の他の治療剤と組み合わせて、前記1以上の突然変異を有すると同定された対象に投与される、請求項9記載の医薬組成物。
- 前記対象が、該対象から生体試料を取得すること、並びにBTKの残基481におけるシステインからセリンへの突然変異(C481S)、BTKの残基481におけるシステインからフェニルアラニンへの突然変異(C481F)、PLCγ2遺伝子の残基665におけるアルギニンからトリプトファンへの突然変異(R665W)、PLCγ2遺伝子の残基257におけるヒスチジンからロイシンへの突然変異(H257L)、PLCγ2遺伝子の残基1141におけるメチオニンからアルギニンへの突然変異(M1141R)、PLCγ2遺伝子の残基707におけるセリンからフェニルアラニンへの突然変異(S707F)、PLCγ2遺伝子の残基845におけるロイシンからフェニルアラニンへの突然変異(L845F)、PLCγ2遺伝子の残基707におけるセリンからチロシンへの突然変異(S707Y)、PLCγ2遺伝子の残基244におけるヒスチジンからアルギニンへの突然変異(H244R)、及びWHIM様CXCR4突然変異から選択される1以上の突然変異を該試料中で検出することにより同定された、請求項9又は10記載の医薬組成物。
- 前記検出することが、ポリメラーゼ連鎖反応(PCR)又はハイブリダイゼーションを実施して、前記1以上の突然変異を検出する、請求項11記載の医薬組成物。
- 癌又は血液悪性腫瘍を有すると診断された対象を治療有効量のPI3Kモジュレーター又はその医薬として許容し得る形態による治療の候補として選択する方法であって:
(a)BTKの残基481におけるシステインからセリンへの突然変異(C481S)、BTKの残基481におけるシステインからフェニルアラニンへの突然変異(C481F)、PLCγ2遺伝子の残基665におけるアルギニンからトリプトファンへの突然変異(R665W)、PLCγ2遺伝子の残基257におけるヒスチジンからロイシンへの突然変異(H257L)、PLCγ2遺伝子の残基1141におけるメチオニンからアルギニンへの突然変異(M1141R)、PLCγ2遺伝子の残基707におけるセリンからフェニルアラニンへの突然変異(S707F)、PLCγ2遺伝子の残基845におけるロイシンからフェニルアラニンへの突然変異(L845F)、PLCγ2遺伝子の残基707におけるセリンからチロシンへの突然変異(S707Y)、PLCγ2遺伝子の残基244におけるヒスチジンからアルギニンへの突然変異(H244R)、及びWHIM様CXCR4突然変異から選択される1以上の突然変異の有無を、該対象から取得された試料中で検出すること(ここで、該突然変異のうちの1つ又は複数の存在は、該対象が治療有効量のPI3Kモジュレーター又はその医薬として許容し得る形態による治療の候補であることを示す);並びに
(b)該突然変異のうちの1つ又は複数が該試料中に存在するとき、該対象を、該PI3Kモジュレーター又はその医薬として許容し得る形態による治療のために選択すること；
を含む、前記方法。 - 前記対象が、1以上の他の治療剤による治療のために選択される、請求項13記載の方法。
- 前記突然変異のうちの1つ又は複数が前記試料中に存在するとき、前記対象に、PI3Kモジュレーター又はその医薬として許容し得る形態が投与される、請求項13又は14記載の方法。
- 前記他の治療剤が、化学療法剤又は治療抗体であり、該化学療法剤が、任意に有糸分裂阻害剤、アルキル化剤、代謝拮抗薬、プロテアソーム阻害剤、挿入抗生物質、成長因子阻害剤、細胞周期阻害剤、酵素、トポイソメラーゼ阻害剤、生物応答修飾物質、抗ホルモン薬、血管新生阻害剤、及び抗アンドロゲン薬から選択され、かつ該治療抗体が、任意に抗CD37抗体、抗CD20抗体、及び抗CD52抗体から選択される、請求項1〜12のいずれか一項記載の医薬組成物。
- 前記他の治療剤が、リツキシマブ、オビヌツズマブ、トシツモマブ、131Iトシツモマブ、90Yイブリツモマブ、111Iイブリツモマブ、又はオファツムマブから選択される抗CD20抗体である、請求項16記載の医薬組成物。
- 前記PI3Kモジュレーターと前記他の治療剤とのモル比が、約500:1、約250:1、約100:1、約50:1、約25:1、約20:1、約19:1、約18:1、約17:1、約16:1、約15:1、約14:1、約13:1、約12:1、約11:1、約10:1、約5:1、約4:1、約3:1、約2:1、又は約1:1である、請求項1〜12又は16〜17のいずれか一項記載の医薬組成物。
- 前記PI3Kモジュレーターが、約0.1mg〜約150mg、約1mg〜約100mg、約5mg〜約75mg、約5mg〜約60mg、約10mg〜約60mg、約20mg〜約60mg、約30mg〜約60mg、約40mg〜約60mg、約45mg〜約55mg、約10mg、約20mg、もしくは約50mgの1日1回の投薬量で;又は約0.1mg〜約75mg、約1mg〜約75mg、約5mg〜約75mg、約5mg〜約60mg、約5mg〜約50mg、約5mg、約10mg、約20mg、約25mg、もしくは約50mgの1日2回の投薬量で投与されるために製剤化され;かつ
前記他の治療剤が、約0.1mg〜約10,000mg、約0.1mg〜約7500mg、約0.1mg〜約5000mg、約1mg〜約2500mg、約1mg〜約1500mg、約10mg〜約1000mg、約500mg〜約1000mg、約750mg〜約1000mg、約800mg〜約1000mg、約900mg〜約1000mg、又は約1000の1日1回の投薬量で投与されるために製剤化されている、請求項1〜12又は16〜17のいずれか一項記載の医薬組成物。 - 前記PI3Kモジュレーターが、約1000ng/mL〜約5000ng/mL、約1000ng/mL〜約4000ng/mL、約1000ng/mL〜約3000ng/mL、約1000ng/mL〜約2500ng/mL、又は約1400ng/mL〜約2200ng/mLの定常状態での最大血漿濃度(Cmaxss)に達する量で投与されるために製剤化され;かつ
前記他の治療剤が、約100ng/mL〜約1000ng/mL、約250ng/mL〜約1000ng/mL、約500ng/mL〜約1000ng/mL、約600ng/mL〜約1000ng/mL、約700ng/mL〜約1000ng/mL、約740ng/mL〜約1000ng/mL、約750ng/mL〜約1000ng/mL、約750ng/mL〜約900ng/mL、又は約750ng/mL〜約800ng/mLのCmaxssに達する量で投与されるために製剤化されている、請求項1〜12又は16〜17のいずれか一項記載の医薬組成物。 - 前記PI3Kモジュレーターが、約5000ng/mL*時〜約10000ng/mL*時、約5000ng/mL*時〜約9000ng/mL*時、約6000ng/mL*時〜約9000ng/mL*時、約7000ng/mL*時〜約9000ng/mL*時、約7000ng/mL*時、約7500ng/mL*時、約8000ng/mL*時、約8500ng/mL*時、約8600ng/mL*時、約8700ng/mL*時、又は約8800ng/mL*時の定常状態での血漿濃度-時間曲線下面積(AUCss)に達する量で投与されるために製剤化され;かつ
前記他の治療剤が、約1000ng/mL*時〜約5000ng/mL*時、約2000ng/mL*時〜約5000ng/mL*時、約3000ng/mL*時〜約5000ng/mL*時、約4000ng/mL*時〜約5000ng/mL*時、又は約4000ng/mL*時〜約4500ng/mL*時のAUCssに達する量で投与されるために製剤化されている、請求項1〜12又は16〜17のいずれか一項記載の医薬組成物。 - 前記PI3Kモジュレーターが、化合物292又はその医薬として許容し得る形態であり、前記他の治療剤が、オビヌツズマブである、請求項1〜12又は16〜17のいずれか一項記載の医薬組成物。
- 化合物292とオビヌツズマブのモル比が、約500:1、約250:1、約100:1、約50:1、約25:1、約20:1、約19:1、約18:1、約17:1、約16:1、約15:1、約14:1、約13:1、約12:1、約11:1、約10:1、約5:1、約4:1、約3:1、約2:1、又は約1:1である、請求項22記載の医薬組成物。
- 化合物292が、約0.1mg〜約150mg、約1mg〜約100mg、約5mg〜約75mg、約5mg〜約60mg、約10mg〜約60mg、約20mg〜約60mg、約30mg〜約60mg、約40mg〜約60mg、約45mg〜約55mg、約10mg、約20mg、もしくは約50mgの1日1回の投薬量で;又は約0.1mg〜約75mg、約1mg〜約75mg、約5mg〜約75mg、約5mg〜約60mg、約5mg〜約50mg、約5mg、約10mg、約20mg、25mg、もしくは約50mgの1日2回の投薬量で投与されるために製剤化され;かつ
オビヌツズマブが、約0.1mg〜約10,000mg、約0.1mg〜約7500mg、約0.1mg〜約5000mg、約1mg〜約2500mg、約1mg〜約1500mg、約10mg〜約1000mg、約500mg〜約1000mg、約750mg〜約1000mg、約800mg〜約1000mg、約900mg〜約1000mg、又は約1000mgの1日1回の投薬量で投与されるために製剤化されている、請求項22記載の医薬組成物。 - 化合物292が、約1000ng/mL〜約5000ng/mL、約1000ng/mL〜約4000ng/mL、約1000ng/mL〜約3000ng/mL、約1000ng/mL〜約2500ng/mL、又は約1400ng/mL〜約2200ng/mLのCmaxssに達する量で投与されるために製剤化され;かつ
オビヌツズマブが、約100ng/mL〜約1000ng/mL、約250ng/mL〜約1000ng/mL、約500ng/mL〜約1000ng/mL、約600ng/mL〜約1000ng/mL、約700ng/mL〜約1000ng/mL、約740ng/mL〜約1000ng/mL、約750ng/mL〜約1000ng/mL、約750ng/mL〜約900ng/mL、又は約750ng/mL〜約800ng/mLのCmaxssに達する量で投与されるために製剤化されている、請求項22記載の医薬組成物。 - 化合物292が、約5000ng/mL*時〜約10000ng/mL*時、約5000ng/mL*時〜約9000ng/mL*時、約6000ng/mL*時〜約9000ng/mL*時、約7000ng/mL*時〜約9000ng/mL*時、約7000ng/mL*時、約7500ng/mL*時、約8000ng/mL*時、約8500ng/mL*時、約8600ng/mL*時、約8700ng/mL*時、又は約8800ng/mL*時のAUCssに達する量で投与されるために製剤化され;かつ
オビヌツズマブが、約1000ng/mL*時〜約5000ng/mL*時、約2000ng/mL*時〜約5000ng/mL*時、約3000ng/mL*時〜約5000ng/mL*時、約4000ng/mL*時〜約5000ng/mL*時、又は約4000ng/mL*時〜約4500ng/mL*時のAUCssに達する量で投与されるために製剤化されている、請求項22記載の医薬組成物。 - PI3Kモジュレーター又はその医薬として許容し得る形態を含む、血液悪性腫瘍を有する対象におけるBTK耐性の予防に使用するための医薬組成物であって、該対象が、BTK阻害剤で治療されている、前記医薬組成物。
- 前記癌又は血液悪性腫瘍が、CLL、ワルデンストレームマクログロブリン血症(WM)、マントル細胞、NHL、iNHL、びまん性大細胞型B細胞リンパ腫、又はT細胞リンパ腫である、請求項1〜12又は16〜27のいずれか一項記載の医薬組成物。
- 前記癌又は血液悪性腫瘍が、濾胞性リンパ腫である、請求項1〜12又は16〜27のいずれか一項記載の医薬組成物。
- 前記PI3Kモジュレーターが、PI3K阻害剤である、請求項1〜12又は16〜29のいずれか一項記載の医薬組成物。
- 前記PI3Kモジュレーターが、化合物292である、請求項1〜12、16〜21及び27〜30のいずれか一項記載の医薬組成物。
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