JP6856657B2 - 血液学的悪性疾患および固形腫瘍の処置のためのidh1阻害剤 - Google Patents
血液学的悪性疾患および固形腫瘍の処置のためのidh1阻害剤 Download PDFInfo
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- JP6856657B2 JP6856657B2 JP2018544835A JP2018544835A JP6856657B2 JP 6856657 B2 JP6856657 B2 JP 6856657B2 JP 2018544835 A JP2018544835 A JP 2018544835A JP 2018544835 A JP2018544835 A JP 2018544835A JP 6856657 B2 JP6856657 B2 JP 6856657B2
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Description
IDH1またはIDH2の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする血液学的悪性疾患および固形腫瘍を含む悪性疾患を処置する方法が、本明細書で提供される。一実施形態では、悪性疾患を処置するための方法は、FLT3経路を標的にする1つまたは複数の化合物と組み合わせてIDH1阻害剤またはIDH2阻害剤を投与するステップを含み、悪性疾患は、IDH1またはIDH2それぞれの変異体対立遺伝子および変異体FLT3の存在を特徴とする。
イソクエン酸デヒドロゲナーゼ(IDH)は、イソクエン酸の2−オキソグルタル酸(即ち、α−ケトグルタル酸)への酸化的脱炭酸反応を触媒する。これらの酵素は、2つの別個のサブクラスに属し、そのうち一方は、電子受容体としてNAD(+)を利用し、他方はNADP(+)を利用する。5つのイソクエン酸デヒドロゲナーゼが報告されている:ミトコンドリアマトリックスに局在化する3つのNAD(+)依存的イソクエン酸デヒドロゲナーゼ、およびそのうち一方はミトコンドリア性であり、他方は優勢にサイトゾル性である、2つのNADP(+)依存的イソクエン酸デヒドロゲナーゼである。各NADP(+)依存的アイソザイムはホモダイマーである。
イソクエン酸+NAD+(NADP+)→α−KG+CO2+NADH(NADPH)+H+
において、イソクエン酸のα−ケトグルタル酸(α−KG)への酸化的脱炭酸反応を触媒し、それによって、NAD+(NADP+)をNADH(NADPH)に還元する。
一実施形態では、対象に治療有効量の変異体IDH1阻害剤を投与することによって血液悪性疾患を処置する方法であって、血液悪性疾患が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする、方法が本明細書で提供される。一実施形態では、血液悪性疾患は、進行した血液悪性疾患である。一実施形態では、血液悪性疾患は急性骨髄球性白血病(AML)である。一実施形態では、AMLは、再発性または難治性である。血液悪性疾患を処置する方法における使用のための変異体IDH1阻害剤であって、血液悪性疾患が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする、変異体IDH1阻害剤もまた本明細書で提供される。
以下の説明中に示されるまたは図面中に例示される構成要素の構築および配置の詳細は、限定であることを意味しない。本発明を実施するための他の実施形態および異なる方法は、明白に含まれる。また、本明細書で使用される言い回しおよび専門用語は、説明を目的としており、限定とみなすべきではない。本明細書での「含む(including)」、「含む(comprising)」または「有する(having)」、「含む(containing)」、「含む(involving)」およびそれらのバリエーションの使用は、その後ろに列挙された項目およびそれらの等価物、ならびにさらなる項目を包含することを意味する。
定義:
化合物
A.化合物1
形態1
形態2
形態3
形態4
形態5
形態6
B.化合物2
形態I
形態II
FLT3標的化化合物
組成物および投与経路
化合物2の固体分散物
固体分散物を調製するためのプロセス
a)化合物2、1つまたは複数のポリマー(単数または複数)および1つまたは複数の溶媒(単数または複数)の混合物を形成するステップ;ならびに
b)溶液から溶媒(単数または複数)を迅速に除去して、化合物2および1つまたは複数のポリマー(単数または複数)を含む固体アモルファス分散物を形成するステップ
を含む。1つまたは複数のポリマー(単数または複数)および1つまたは複数の溶媒(単数または複数)は、本明細書に開示されるもののいずれかであり得る。
a)化合物2、ポリマーおよび溶媒の混合物を形成するステップ;ならびに
b)混合物を噴霧乾燥して、化合物2およびポリマーを含む固体分散物を形成するステップ
を含む。
化合物2の固体分散物を含む医薬組成物
使用の方法
患者集団
(実施例1)
IDH2変異を持つ進行性血液悪性疾患を有する対象における経口投与された化合物1の、フェーズ1/2、多施設、オープンラベル、用量漸増および拡大の、安全性、薬物動態学、薬力学および臨床活性試験
1.対象は、18歳以上でなければならない。
2.対象は、以下の進行性血液悪性疾患を有していなければならない:
フェーズ1/用量漸増:
・世界保健機関(WHO)の基準に従ったAMLの診断;
・難治性または再発性疾患(骨髄中5%より多い芽球の再出現として定義される)。
・年齢60歳以上で、担当医師(treating physician)に従って、かつ医療監視者の承認を得た、年齢、パフォーマンスステータス、および/または有害リスク因子により標準療法の候補でない未処置のAML;
・WHO分類に従った過剰芽細胞を伴う不応性貧血(サブタイプRAEB−1またはRAEB−2)を有する、または改訂国際予後スコアリングシステム(International Prognostic Scoring System、IPSS−R)により高リスク、つまり反復性または難治性であるとみなされるMDSの診断、または担当医師に従って、かつ医療監視者の承認を得た、その状態に臨床上有用であることが公知の確立された治療に耐用性がない対象(つまり、臨床上有用であることが公知のレジメンの候補にならない対象)。(他の再発性および/または原発性難治性血液がん、例えばCMMLを有し、選択/除外基準を満たす対象は、医療監視者の承認を得て、ケースバイケースで検討されうる。)
フェーズ1/パート1拡大:
・アーム1:年齢60歳以上で再発性もしくは難治性AML、または年齢に関係なくBMT後に再発したAMLを有する任意の対象。
・アーム2:年齢60歳未満の再発性または難治性AML。ただし、BMTの後に再発したAMLを有する対象を除く。
・アーム3:標準治療の化学療法を断っている年齢60歳以上で未処置のAML。
・アーム4:アーム1〜3に対して適格でないIDH2変異進行性血液悪性疾患。
フェーズ2:
・世界保健機関(WHO)基準によるAML、および以下によって定義される再発性または難治性の疾患の診断:
・同種移植後に再発する対象;
・第2のまたは後の再発である対象;
・初期誘導または再誘導処置に難治性である対象;
・初期処置の1年以内に再発する対象。ただし、NCCNガイドラインに従って良好なリスク状態の患者を除く。良好なリスクの細胞遺伝学:inv(16)、+(16;16)、t(8;21)、t(15;17)。
3.対象は、IDH2遺伝子変異疾患を文書化しておかなければならない:
・用量漸増フェーズおよびパート1拡大における対象について、IDH2変異は、地方の評価に基づくものでもよい(中央の検査が遡及的に実行される)。
4.治験のフェーズ2部分の対象について、骨髄穿刺液および末梢血の試料におけるIDH2変異の中央検査が、適格性を確認するために、スクリーニング中に要求される。対象は、試験中に、連続骨髄サンプリング、末梢血サンプリングおよび尿サンプリングに適していなければならない。
・AMLまたはMDSの診断および評価は、骨髄穿刺および生検によってなされる。穿刺液が取得できない場合(つまり、「ドライタップ」)、診断は、コア生検からなされてもよい。
・骨髄穿刺液および末梢血試料のスクリーニングは、全ての対象に必要とされる。十分な穿刺が達成できない場合、骨髄生検が回収されなければならないが、以下の場合はこの限りではない:
・骨髄穿刺液および生検は、試験処置の開始の前28日以内に標準治療の一部として実行した;および
・骨髄穿刺液、生検および染色末梢血塗抹標本のスライドは、地方および中央の病理レビューアの両方が利用可能である;
5.対象は、インフォームドコンセントを理解することができ、進んで署名しなければならない。法的に権限がある代理人は、現場および/または現場の治験審査委員会(IRB)/独立倫理委員会(IEC)によって受け入れられ、承認が得られる場合、代理人によらなければインフォームドコンセントを提出できない対象に代わって、同意してもよい。
6.対象は、0〜2のECOG PSを有していなければならない。
7.血小板数が20,000/μL以上(このレベルを達成するための輸血は許可される)。基礎の悪性疾患によりベースライン血小板数が20,000/μL未満である対象は、医療監視者の承認を得て適格である。
8.対象は、以下によって証明される十分な肝機能を有していなければならない:
・Gilbert疾患、UGT1A1における遺伝子変異、または白血病の臓器の関与によると考えられない限り、医療監視者の承認を得て、血清総ビリルビンが1.5×正常上限(ULN)以下;
・白血病の臓器の関与によると考えられない限り、アスパラギン酸アミノトランスフェラーゼ(AST)、アラニンアミノトランスフェラーゼ(ALT)、およびアルカリホスファターゼ(ALP)が、3.0×ULN以下。
9.対象は、以下によって証明される十分な腎機能を有していなければならない:
・血清クレアチニンが、2.0×ULN以下、または
・Cockroft−Gault糸球体濾過率(GFR)推定:(140−年齢)×(重量kg)×(女性の場合0.85)/72×血清クレアチニンに基づいて、クレアチニンクリアランスが40mL/分より大きい
10.対象は、任意の先行の外科手術、放射線療法、またはがんの処置のための他の治療のいずれかの臨床的に関連する毒性影響から回復していなければならない。(残留のグレード1の毒性を有する対象、例えばグレード1の末梢性ニューロパチーまたは残留脱毛症を有する対象は、医療監視者の承認を得て、認められる。)
11.生殖能力を有する女性対象は、試験薬を開始する前に、医学的監督下の妊娠検査を受けることに同意しなければならない。最初の妊娠検査は、スクリーニング時(最初の試験薬投与の前7日間以内)および最初の試験薬投与の日に実行され、投薬前および全てのその後のサイクルの投薬前1日目に陰性であると確認される。
12.生殖能力を有する女性対象は、治療の開始前7日間以内に血清妊娠検査で陰性でなければならない。生殖能力を有する対象は、子宮摘出術、両側卵巣摘出術または卵管閉塞術を受けていない、性的に成熟した女性、または少なくとも連続する24カ月にわたり自然閉経後(つまり全く月経がなかった)ではない(つまり、先行の連続する24カ月の任意の時点で月経期を有していた)、性的に成熟した女性として定義される。生殖能力を有する女性ならびに生殖可能な男性および生殖能力を有する女性である彼らのパートナーは、インフォームドコンセントを提出した時点から、試験の間、および化合物1の最終投薬後120日まで、性交を避けること、または2つの極めて有効な避妊形態を使用することに同意しなければならない(女性および男性)。避妊の極めて有効な形態は、ホルモン経口避妊薬、注射剤、パッチ、子宮内デバイス、二重障壁法(例えば、合成コンドーム、ダイアフラム、または殺精子泡を有する子宮頸部キャップ、クリーム、またはゲル)または男性パートナー避妊法として定義される。
13.試験訪問スケジュール(つまり、特定の試験訪問についての他の断りがない限り、試験現場での診療所訪問は必須である)および他のプロトコール要件に準拠することができる
以下の基準のいずれかを満たす対象は、試験に登録されない:
1.化合物1の最初の投薬の60日以内に造血幹細胞移植(HSCT)を受けた対象、またはスクリーニング時にHSCT後免疫抑制療法中である対象、または臨床的に意義のある移植片対宿主病(GVHD)を有する対象。(HSCT後の経口ステロイドおよび/または進行中の皮膚GVHDのためのステロイド外用剤の安定な用量の使用は、医療監視者の承認を得て、許容される。)
2.試験薬投与の最初の日の前14日間未満に、全身性抗がん療法または放射線療法を受けた対象。(登録前、および白血球増加症(白血球[WBC]数が30,000/μLより多い)である対象における末梢白血病性芽球の制御のための化合物1の開始後のヒドロキシ尿素は、許可される)。
3.試験薬投与の最初の日の前14日間未満に、低分子治験薬を受けた対象。加えて、化合物1の最初の投薬は、その治験薬の5半減期以上の期間が経過する前は行うべきではない。
4.治療範囲を狭める以下の感受性CYP基質薬品を服用している対象は、投薬前の5半減期以上の期間内に他の薬品へ移行することができない限り、試験から除外される:パクリタキセル(CYP2C8)、ワルファリン、フェニトイン(CYP2C9)、S−メフェニトイン(CYP2C19)、チオリダジン(CYP2D6)、テオフィリンおよびチザニジン(CYP1A2)。
5.P−gpおよびBCRPトランスポーター感受性基質ジゴキシンおよびロスバスタチンを服用している対象は、投薬前の5半減期以上の期間内に他の薬品へ移行することができない限り、試験から除外されるべきである。
6.治癒する可能性のある抗がん療法が利用可能である対象。
7.妊娠中または授乳中である対象。
8.スクリーニング訪問中または試験薬投与の最初の日に、抗感染療法が必要とされる活動性の重度の感染を有する対象、または説明できない38.5℃より高い発熱を有する対象(治験担当医師の裁量で、腫瘍発熱を有する対象は登録される場合がある)。
9.化合物1の構成要素のいずれかに対して既知の過敏症を有する対象。
10.C1D1のおよそ28日以内に、ニューヨーク心臓協会(New York Heart Association、NYHA)クラスIIIまたはIVうっ血性心不全または心エコー(ECHO)もしくはマルチゲート収集(MUGA)スキャンによりLVEFが40%未満であると認められた対象。
11.スクリーニングの最後の6カ月以内に心筋梗塞の既往を有する対象。
12.スクリーニング時に制御されていない高血圧(収縮期血圧[BP]が180mmHgより高いまたは拡張期BPが100mmHgより高い)を有する対象は除外される。高血圧を制御するために2つまたはそれよりも多くの薬品を必要とする対象は、医療監視者の承認を得て適格である。
13.不安定なまたは制御されていない既知の狭心症を有する対象。
14.重度のおよび/または制御されていない既知の心室性不整脈の既往を有する対象。
15.スクリーニング時にQTcF(Fridericiaの式に基づいて補正されたQT)間隔が450ミリ秒以上の対象またはQT延長もしくは不整脈イベントのリスクを増加させる他の要因(例えば、心不全、低カリウム血症、QT延長症候群(long QT interval syndrome)の家族歴)を有する対象。脚ブロックおよび長期QTc間隔を有する対象は、選択の可能性について、医療監視者によって再検討を受けるべきである。
16.投薬前の5半減期以上の期間内に他の薬品へ移行することができない限り、QT間隔を延長することが公知の薬品を服用している対象。
17.ヒト免疫不全ウイルス(HIV)または活性B型肝炎もしくはC型肝炎を有する既知の感染症を有する対象。
18.インフォームドコンセントに署名し、協力し、または試験に参加する対象の能力を阻害する可能性があると治験担当医師によって認められた任意の他の医学的または精神学的状態を有する対象。
19.経口投与された薬物の摂取または胃腸吸収を制限する、既知の嚥下障害、短腸症候群、胃不全麻痺または他の状態を有する対象。
20.活性な中枢神経系(CNS)白血病または既知のCNS白血病が示唆される臨床症状を有する対象。脳脊髄液の評価は、スクリーニング中に白血病によるCNS関与が臨床的に疑われる場合にのみ必要である。
21.制御不能な出血、低酸素症もしくはショックを伴う肺炎、および/または播種性血管内凝固などの、直ちに生命を脅かす重度の白血病の合併症を有する対象。
22.治験のフェーズ2部分のみについて、IDH阻害剤で従前に処置を受けていた対象。
・全ての対象が化合物1を用いた処置を中止し、その後少なくとも12カ月間、生存が追跡されたか、もしくは死亡したか、追跡調査不能になったか、もしくは追跡調査の少なくとも12カ月より前に同意を撤回した時点、または
・プロトコールおよび/もしくは統計解析計画(SAP)で予め指定されるように、主要、副次および/もしくは外挿解析のために必要とされる最後の対象からの最後のデータ点の受領日
のいずれか遅い方の日の時点として定義される。
(実施例2)
IDH1変異を持つ進行性血液悪性疾患を有する対象における経口投与された化合物2の、フェーズ1、多施設、オープンラベル、用量漸増の、安全性、薬物動態学的、薬力学的および臨床活性試験
移植後に再発する対象;
第2のまたは後の再発である対象;
初期誘導または再誘導処置に難治性である対象。
初期処置の1年以内に再発する対象。ただし、NCCNガイドライン、バージョン1.2015に従って良好なリスク状態の患者を除く。
医療監視者の承認を得た、低メチル化剤(単数または複数)の失敗後の反復性または難治性である骨髄異形成症候群。
医療監視者の承認を得た、再発性および/または原発性難治性慢性骨髄単球性白血病[CMML]。
治験担当医師に従って、かつ医療監視者の承認を得て、標準治療に失敗した、または利用可能な標準治療処置選択肢がない、他の非AML IDH1変異再発性および/または難治性進行性血液悪性疾患。
対象は、試験に登録されるために、以下の基準を全て満たさなければならない:
対象は、年齢が18歳以上でなければならない。
対象は、以下の進行性血液悪性疾患を有していなければならない。
世界保健機関(WHO)基準によって定義される再発性および/もしくは原発性難治性AML;または
年齢60歳以上で、担当医師に従って、かつ医療監視者の承認を得た、年齢、パフォーマンスステータスおよび/もしくは有害リスク因子により標準療法の候補でない未処置のAML;
過剰芽細胞を伴う不応性貧血(サブタイプRAEB−1またはRAEB−2)を有する、または改訂国際予後スコアリングシステム(International Prognostic Scoring System、IPSS−R)Greenbergら、Blood. 2012年;120巻(12号):2454〜65頁、により高リスク、つまり反復性または難治性であるとみなされる骨髄異形成症候群、または担当医師に従ってかつ医療監視者の承認を得て、その状態に臨床上有用であることが公知の確立された治療に耐用性がない対象(つまり臨床上有用であることが公知のレジメンの候補にならない対象)。
(他の再発性および/または原発性難治性血液がん、例えばCMMLを有し、選択/除外基準を満たす対象は、医療監視者の承認を得て、ケースバイケースで考えることができる。)
移植後に再発する対象;
第2のまたは後の再発である対象;
初期誘導または再誘導処置に難治性である対象。
初期処置の1年以内に再発する対象。ただし、NCCNガイドライン、バージョン1.2015に従って良好なリスク状態の患者を除く。
医療監視者の承認を得た、低メチル化剤(単数または複数)の失敗後の反復性または難治性である骨髄異形成症候群。
医療監視者の承認を得た、再発性および/または原発性難治性CMML
治験担当医師に従って、かつ医療監視者の承認を得て、標準治療に失敗し、利用可能な標準治療処置選択肢がない、他の非AML IDH1変異再発性および/または難治性進行性血液悪性疾患。
用量漸増フェーズにおける対象について、IDH1変異は、地方の評価に基づくものでもよい。(中央の検査が遡及的に実行される。)
拡大フェーズの対象について、IDH1遺伝子変異疾患の中央検査が、適格性の確認のため、スクリーニング中に必要とされる。
AMLまたはMDSの診断および評価は、骨髄穿刺および/または生検により行われうる。穿刺液が取得できない場合(つまり、「ドライタップ」)、診断は、コア生検からなされてもよい。
Gilbert疾患または白血病の関与によると考えられない限り、血清総ビリルビンが、1.5×正常上限(ULN)以下;
白血病の関与によると考えられない限り、アスパラギン酸アミノトランスフェラーゼ(AST)、アラニンアミノトランスフェラーゼ(ALT)、およびアルカリホスファターゼ(ALP)が、3.0×ULN以下。
血清クレアチニンが、2.0×UL以下、または
Cockroft−Gault糸球体濾過率(GFR)推定:(140−年齢)×(重量kg)×(女性の場合0.85)/72×血清クレアチニンに基づいて、クレアチニンクリアランスが40mL/分より大きい
本発明は、例えば、以下の項目を提供する。
(項目1)
対象において血液学的悪性疾患を処置する方法であって、前記対象に、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)を投与するステップを含み、前記血液学的悪性疾患が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする悪性疾患である、方法。
(項目2)
対象において固形腫瘍を処置する方法であって、前記対象に、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)を投与するステップを含み、前記固形腫瘍が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする、方法。
(項目3)
対象において血液学的悪性疾患を処置する方法であって、前記対象に、FLT3阻害剤と組み合わせて、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)を投与するステップを含み、前記血液学的悪性疾患が、IDH1の変異体対立遺伝子および変異体FLT3の存在を特徴とする悪性疾患である、方法。
(項目4)
対象において固形腫瘍を処置する方法であって、前記対象に、FLT3阻害剤と組み合わせて、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)を投与するステップを含み、前記固形腫瘍が、IDH1の変異体対立遺伝子および変異体FLT3の存在を特徴とする、方法。
(項目5)
IDH1変異がIDH1 R132X変異である、項目1から4のいずれか一項に記載の方法。
(項目6)
前記IDH1変異が、IDH1 R132H、R132C、R132L、R132V、R132SまたはR132G変異である、項目5に記載の方法。
(項目7)
前記FLT3阻害剤が、キザルチニブ(AC220)、スニチニブ(SU11248)、ソラフェニブ(BAY 43−9006)、ミドスタウリン(PKC412)、レスタウルチニブ(CEP−701)、クレノラニブ(CP−868596)、PLX3397、E6201、AKN−028、ポナチニブ(AP24534)、ASP2215、KW−2449、ファミチニブおよびDCC−2036から選択される、項目3から6のいずれか一項に記載の方法。
(項目8)
前記悪性疾患が、各々がIDH1の変異体対立遺伝子の存在を特徴とする、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、骨髄増殖性腫瘍(MPN)、慢性骨髄単球性白血病(CMML)、B細胞急性リンパ球性白血病(B−ALL)またはリンパ腫(例えば、T細胞リンパ腫)であり、前記方法が、前記対象に治療有効量の化合物2を投与するステップを含む、項目1または3に記載の方法。
(項目9)
前記悪性疾患が、IDH1の変異体対立遺伝子の存在を特徴とする急性骨髄性白血病(AML)である、項目8に記載の方法。
(項目10)
前記固形腫瘍が、各々がIDH1の変異体対立遺伝子の存在を特徴とする、神経膠腫、黒色腫、軟骨肉腫、胆管癌(肝内胆管癌(IHCC)を含む)、前立腺がん、結腸がんまたは非小細胞肺がん(NSCLC)であり、前記方法が、前記対象に治療有効量の化合物2を投与するステップを含む、項目2または4に記載の方法。
(項目11)
化合物2の用量が、約20〜約2000mg/日の用量で投与される、項目1から10のいずれか一項に記載の方法。
(項目12)
化合物2の用量が、約50〜約500mg/日の用量で投与される、項目1から10のいずれか一項に記載の方法。
(項目13)
IDH1阻害剤による処置に適切ながん対象を同定する方法であって、(a)がんを有する対象から生物学的試料を取得するステップ;(b)IDH1変異およびFLT3変異について、前記生物学的試料をスクリーニングするステップ;ならびに(c)前記がんが、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする場合、前記対象を、IDH1阻害剤による処置に適切ながん対象であると同定するステップを含む、方法。
(項目14)
前記IDH1阻害剤が化合物2である、項目13に記載の方法。
(項目15)
IDH1阻害剤およびFLT3経路阻害剤の組合せによる処置に適切ながん対象を同定する方法であって、(a)がんを有する対象から生物学的試料を取得するステップ;(b)IDH1変異およびFLT3変異について、前記生物学的試料をスクリーニングするステップ;ならびに(c)前記がんが、IDH1の変異体対立遺伝子および変異体FLT3の存在を特徴とする場合、前記対象を、IDH1阻害剤およびFLT3阻害剤の併用治療による処置に適切ながん対象であると同定するステップを含む、方法。
(項目16)
前記IDH1阻害剤が化合物2である、項目15に記載の方法。
(項目17)
前記FLT3阻害剤が、キザルチニブ(AC220)、スニチニブ(SU11248)、ソラフェニブ(BAY 43−9006)、ミドスタウリン(PKC412)、レスタウルチニブ(CEP−701)、クレノラニブ(CP−868596)、PLX3397、E6201、AKN−028、ポナチニブ(AP24534)、ASP2215、KW−2449、ファミチニブおよびDCC−2036から選択される、項目15または16に記載の方法。
(項目18)
前記がんが、固形腫瘍または血液悪性疾患である、項目13から17のいずれか一項に記載の方法。
(項目19)
前記血液悪性疾患がAMLである、項目18に記載の方法。
(項目20)
前記AMLが、再発性または難治性である、項目19に記載の方法。
(項目21)
前記変異体FLT3が、FLT3−ITDまたはFLT3−KDMである、項目1から20のいずれか一項に記載の方法。
(項目22)
前記変異体FLT3がFLT3−ITDである、項目1から21のいずれか一項に記載の方法。
(項目23)
対象において血液学的悪性疾患を処置する方法における使用のための化合物であって、前記化合物が、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)であり、前記血液学的悪性疾患が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする悪性疾患である、使用のための化合物。
(項目24)
対象において固形腫瘍を処置する方法における使用のための化合物であって、前記化合物が、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)であり、前記固形腫瘍が、IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在を特徴とする、使用のための化合物。
(項目25)
対象において血液学的悪性疾患を処置する方法における使用のための化合物であって、前記化合物が、FLT3阻害剤と組み合わせた、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)であり、前記血液学的悪性疾患が、IDH1の変異体対立遺伝子および変異体FLT3の存在を特徴とする悪性疾患である、使用のための化合物。
(項目26)
対象において固形腫瘍を処置する方法における使用のための化合物であって、前記化合物が、FLT3阻害剤と組み合わせた、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド:
または薬学的に許容されるその塩、溶媒和物、互変異性体、立体異性体、アイソトポログ、プロドラッグ、代謝物もしくは多形体(化合物2)であり、前記固形腫瘍が、IDH1の変異体対立遺伝子および変異体FLT3の存在を特徴とする、使用のための化合物。
(項目27)
前記IDH1変異が、IDH1 R132H、R132C、R132L、R132V、R132SまたはR132G変異である、項目23から26のいずれか一項に記載の使用のための化合物。
(項目28)
前記FLT3阻害剤が、キザルチニブ(AC220)、スニチニブ(SU11248)、ソラフェニブ(BAY 43−9006)、ミドスタウリン(PKC412)、レスタウルチニブ(CEP−701)、クレノラニブ(CP−868596)、PLX3397、E6201、AKN−028、ポナチニブ(AP24534)、ASP2215、KW−2449、ファミチニブおよびDCC−2036から選択される、項目25から27のいずれか一項に記載の使用のための化合物。
(項目29)
前記悪性疾患が、各々がIDH1の変異体対立遺伝子の存在を特徴とする、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、骨髄増殖性腫瘍(MPN)、慢性骨髄単球性白血病(CMML)、B細胞急性リンパ球性白血病(B−ALL)またはリンパ腫(例えば、T細胞リンパ腫)であり、前記方法が、前記対象に治療有効量の化合物2を投与するステップを含む、項目23または25に記載の使用のための化合物。
(項目30)
前記悪性疾患が、IDH1の変異体対立遺伝子の存在を特徴とする急性骨髄性白血病(AML)である、項目29に記載の使用のための化合物。
(項目31)
前記AMLが、再発性または難治性である、項目30に記載の使用のための化合物。
(項目32)
前記固形腫瘍が、各々がIDH1の変異体対立遺伝子の存在を特徴とする、神経膠腫、黒色腫、軟骨肉腫、胆管癌(肝内胆管癌(IHCC)を含む)、前立腺がん、結腸がんまたは非小細胞肺がん(NSCLC)であり、前記方法が、前記対象に治療有効量の化合物2を投与するステップを含む、項目24または26に記載の使用のための化合物。
(項目33)
化合物2の用量が、約20〜約2000mg/日または約50〜約500mg/日である、項目23から32のいずれか一項に記載の使用のための化合物。
(項目34)
前記変異体FLT3が、FLT3−ITDまたはFLT3−KDMである、項目25から33のいずれか一項に記載の使用のための化合物。
(項目35)
前記変異体FLT3がFLT3−ITDである、項目25から34のいずれか一項に記載の使用のための化合物。
Claims (27)
- 対象において急性骨髄性白血病(AML)を処置するための組成物であって、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- IDH1変異がIDH1 R132X変異である、請求項1または2に記載の組成物。
- 前記IDH1変異が、IDH1 R132H、R132C、R132L、R132V、R132SまたはR132G変異である、請求項3に記載の組成物。
- 前記変異体FLT3が、FLT3−ITDまたはFLT3−KDMである、請求項2から4のいずれか一項に記載の組成物。
- 前記変異体FLT3がFLT3−ITDである、請求項5に記載の組成物。
- 前記AMLが、再発性または難治性である、請求項1から6のいずれか一項に記載の組成物。
- 化合物2の用量が、約20〜約2000mg/日である、請求項1から7のいずれか一項に記載の組成物。
- 化合物2の用量が、約50〜約500mg/日である、請求項1から7のいずれか一項に記載の組成物。
- 化合物2の用量が、約500mg/日である、請求項1から7のいずれか一項に記載の組成物。
- IDH1の変異体対立遺伝子の存在およびFLT3変異の非存在をIDH1阻害剤による処置に適切な急性骨髄性白血病(AML)対象の指標とする方法であって、IDH1変異およびFLT3変異について、AMLを有する対象から取得された生物学的試料をスクリーニングするステップを含み、前記試料におけるIDH1の変異体対立遺伝子の存在およびFLT3変異の非存在は、前記AML対象がIDH1阻害剤による処置に適切であることを示すことを特徴とし、前記IDH1阻害剤が、以下の式を有する(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- IDH1の変異体対立遺伝子およびFLT3の変異体対立遺伝子の存在をIDH1阻害剤およびFLT3経路阻害剤の組合せによる処置に適切な急性骨髄性白血病(AML)対象の指標とする方法であって、IDH1変異およびFLT3変異について、AMLを有する対象から取得された生物学的試料をスクリーニングするステップを含み、IDH1の変異体対立遺伝子および変異体FLT3の存在は、前記AML対象がIDH1阻害剤およびFLT3阻害剤の併用治療による処置に適切であることを示すことを特徴とし、前記IDH1阻害剤が、以下の式を有する(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- 前記AMLが、再発性または難治性である、請求項11または12に記載の方法。
- 前記変異体FLT3が、FLT3−ITDまたはFLT3−KDMである、請求項12または13に記載の方法。
- 前記変異体FLT3がFLT3−ITDである、請求項14に記載の方法。
- 対象において急性骨髄性白血病(AML)を処置するための組み合わせ物であって、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- 前記IDH1変異が、IDH1 R132H、R132C、R132L、R132V、R132SまたはR132G変異である、請求項16に記載の組み合わせ物。
- 前記AMLが、再発性または難治性である、請求項16または17に記載の組み合わせ物。
- 化合物2の用量が、約20〜約2000mg/日または約50〜約500mg/日である、請求項16から18のいずれか一項に記載の組み合わせ物。
- 化合物2の用量が約500mg/日である、請求項16から18のいずれか一項に記載の組み合わせ物。
- 前記変異体FLT3が、FLT3−ITDまたはFLT3−KDMである、請求項16から20のいずれか一項に記載の組み合わせ物。
- 前記変異体FLT3がFLT3−ITDである、請求項16から20のいずれか一項に記載の組み合わせ物。
- 請求項12に記載の方法により特定された急性骨髄球性白血病(AML)対象におけるAMLを処置するための、IDH1阻害剤を含む組成物であって、前記組成物はFLT3阻害剤と組み合わせて投与されることを特徴とし、前記IDH1阻害剤は、以下の式を有する(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- 前記AMLが再発性または難治性AMLである、請求項23または24に記載の組成物。
- 請求項12に記載の方法により特定された急性骨髄球性白血病(AML)対象におけるAMLを処置するための、IDH1阻害剤およびFLT3阻害剤を含む組み合わせ物であって、前記IDH1阻害剤は、以下の式を有する(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
- 対象において急性骨髄性白血病(AML)を処置するための組成物であって、キザルチニブ(AC220)、スニチニブ(SU11248)、ソラフェニブ(BAY 43−9006)、ミドスタウリン(PKC412)、レスタウルチニブ(CEP−701)、クレノラニブ(CP−868596)、PLX3397、E6201、AKN−028、ポナチニブ(AP24534)、ASP2215、KW−2449、ファミチニブおよびDCC−2036から選択されるFLT3阻害剤を含み、前記組成物は、以下の式を有する変異体イソクエン酸デヒドロゲナーゼ1(IDH1)阻害剤(S)−N−((S)−1−(2−クロロフェニル)−2−((3,3−ジフルオロシクロブチル)アミノ)−2−オキソエチル)−1−(4−シアノピリジン−2−イル)−N−(5−フルオロピリジン−3−イル)−5−オキソピロリジン−2−カルボキサミド(化合物2):
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IL261333B (en) | 2022-03-01 |
AU2016393870A1 (en) | 2018-10-18 |
CA3015753A1 (en) | 2017-08-31 |
AU2016393869A1 (en) | 2018-09-20 |
US20170246174A1 (en) | 2017-08-31 |
WO2017146794A1 (en) | 2017-08-31 |
MX2021007790A (es) | 2021-08-11 |
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KR20180113540A (ko) | 2018-10-16 |
US10137130B2 (en) | 2018-11-27 |
CA3015757A1 (en) | 2017-08-31 |
KR20180114202A (ko) | 2018-10-17 |
CN109069410A (zh) | 2018-12-21 |
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