JP6895956B2 - 悪性腫瘍を治療するための併用療法 - Google Patents
悪性腫瘍を治療するための併用療法 Download PDFInfo
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- JP6895956B2 JP6895956B2 JP2018519352A JP2018519352A JP6895956B2 JP 6895956 B2 JP6895956 B2 JP 6895956B2 JP 2018519352 A JP2018519352 A JP 2018519352A JP 2018519352 A JP2018519352 A JP 2018519352A JP 6895956 B2 JP6895956 B2 JP 6895956B2
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Description
本願は、2015年10月15日に出願された米国仮特許出願第62/242,218号の優先権の利益を主張するものであり、その開示は、その全体を参照として本明細書に援用する。
本明細書では、血液悪性腫瘍及び固形腫瘍を治療するための併用療法を提供する。一実施形態では、治療は、IDH2阻害剤及びDNA脱メチル化剤による治療を含む。
イソクエン酸+NAD+(NADP+)→α−KG+CO2+NADH(NADPH)+H+。
一実施形態では、変異型IDH2阻害剤とDNA脱メチル化剤とを被験者に併用投与することによって血液悪性腫瘍を治療する方法を、本明細書において提供する。
以下の説明または図面に示す構成要素の構築及び配置の詳細は、限定することを意図するものではない。本発明を実施するための他の実施形態及び異なる方法が明白に含まれる。また、本明細書中で使用する表現及び用語は、説明のためのものであって、限定するものとみなすべきではない。本明細書中の「含む(including)」、「含む(comprising)」、または「有する(having)」、「含む(containing)」、「含む(involving)」、及びそれらの変形の使用は、その後に列挙するアイテム及びその均等物ならびに追加のアイテムを包含することを意味する。
用語「変異型IDH2阻害剤」または「IDH2変異体(複数可)阻害剤」とは、分子、例えば、ポリペプチド、ペプチド、もしくは小分子(例えば、1,000ダルトン未満の分子)、またはアプタマーを意味し、IDH2変異体サブユニットに結合し、例えば二量体、例えば変異型IDH2サブユニットのホモ二量体または変異型及び野生型サブユニットのヘテロ二量体の形成を阻害することにより、新規活性を阻害する。いくつかの実施形態では、変異型IDH2阻害剤の非存在下での活性に比べて、新規活性の阻害は、少なくとも約60%、70%、80%、90%、95%または99%である。一実施形態では、変異型IDH2阻害剤は化合物1である。
用語「骨髄異形成症候群」とは、血液の細胞成分(赤血球、白血球(リンパ球以外)及び血小板(またはそれらの前駆細胞である巨核球)のうちの1つ以上の産生異常を特徴とする血液学的状態を指す。
用語「再発」とは、治療後に、AMLを含む癌が寛解した患者が、再び癌細胞を有するようになる状況を指す。
用語「難治性または耐性」とは、集中治療後であっても、患者が、体内に残存する癌細胞を有する状況を指す。
障害を治療するのに有効な、薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、またはその多形体を含む化合物の量、または「治療有効量」または「治療有効用量」とは、障害を有する被験者を、そのような治療の非存在下で予想される以上に、治癒、軽減、緩和または改善する際の、被験者への単回または複数回用量の投与に有効な、薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、またはその多形体を含む、化合物の量を指す。
白血病、特にAMLの治療に対する奏効は、AMLの国際ワーキンググループ奏効基準に基づいて評価することができる(Cheson et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes,and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21(24):4642−9)。
MDSの自然経過を変更するための修正国際ワーキンググループ奏効基準
ヘモグロビンをg/dLからg/Lに変換するには、g/dLを10倍する。
MDSは骨髄異形成症候群を示す;Hgb、ヘモグロビン;CR、完全寛解;HI、血液学的改善;PR、部分寛解;FAB、French−American−British;AML、急性骨髄性白血病;PFS、無増悪生存;DFS、無病生存。
*異形成の変化は、正常範囲の異形成の変化を考慮する必要がある(変更点)。41
†IWG奏効基準に対する変更点。
‡いくつかの状況では、プロトコール療法は、4週間の期間より前にさらなる治療(例えば、地固め、維持)の開始を必要とする場合がある。そのような患者は、治療開始時点で適合する奏効カテゴリーに含めることができる。反復化学療法コース中の一時的な血球減少は、前回のコースを上回るカウント数に回復する限りにおいては、奏効の持続性を阻むものとみなすべきではない。
血液学的改善のための修正国際ワーキンググループ奏効基準
ヘモグロビンレベルをg/dLからg/Lに変換するには、g/dLを10倍する。
Hgbはヘモグロビンを示す;RBC、赤血球;HI、血液学的改善。
*前処置は、≧1週間離した(変更点)少なくとも2回の測定の平均をカウントしている(輸血に影響を受けない)。
†IWG奏効基準に対する変更点
‡急性感染、反復化学療法(変更点)、消化管出血、溶血などの別の説明がなされない場合。個々の奏効パターンだけでなく、2種類の赤血球及び血小板の奏効を全体として報告することが推奨される。
一実施形態では、化合物1は、以下の式:
一実施形態では、化合物1の単結晶形態である形態1を、図10に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表1に示すデータによって特徴付ける。特定の実施形態では、表1に示すように、多形体を、図10から得られる1つ以上のピークによって特徴付けることができる。例えば、多形体を、表1に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つまたは9つのピークによって特徴付けることができる。
表1
一実施形態では、化合物1の単結晶形態である形態2を、図11に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表2に示すデータによって特徴付ける。特定の実施形態では、表2に示すように、多形体を、図11から得られるピークの1つ以上によって特徴付けることができる。例えば、多形体を、表2に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つまたは9つのピークによって特徴付けることができる。
表2
一実施形態では、化合物1の単結晶形態である形態3を、図12に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表3に示すデータによって特徴付ける。特定の実施形態では、表3に示すように、多形体を、図12から得られる1つ以上のピークによって特徴付けることができる。例えば、多形体を、表3に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つまたは9つのピークによって特徴付けることができる。
表3
一実施形態では、化合物1の単結晶形態である形態4を、図13に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表4に示すデータによって特徴付ける。特定の実施形態では、表4に示すように、多形体を、図13から得られる1つ以上のピークによって特徴付けることができる。例えば、多形体を、表4に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つまたは9つのピークによって特徴付けることができる。
表4
一実施形態では、化合物1の単結晶形態である形態5を、図14に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表5に示すデータによって特徴付ける。特定の実施形態では、表5に示すように、多形体を、図14から得られる1つ以上のピークによって特徴付けることができる。例えば、多形体を、表5に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つまたは9つのピークによって特徴付けることができる。
表5
一実施形態では、化合物1の単結晶形態である形態6を、図15に示すX線粉末回折(XRPD)パターン、及びCuKα線を用いて得られる表6に示すデータによって特徴付ける。特定の実施形態では、表6に示すように、多形体を、図15から得られる1つ以上のピークによって特徴付けることができる。例えば、多形体を、表6に示す1つまたは2つまたは3つまたは4つまたは5つまたは6つまたは7つまたは8つのピークによって特徴付けることができる。
表6
一実施形態では、本明細書において提供する方法は、1つ以上のDNA脱メチル化剤の投与または併用投与を含む。一実施形態では、DNA脱メチル化剤はシチジン類似体である。特定の実施形態では、シチジン類似体はアザシチジンである)か、または5−アザ−2′−デオキシシチジン(デシタビン)である。特定の実施形態では、シチジン類似体はアザシチジンである。特定の実施形態では、シチジン類似体は、5−アザ−2′−デオキシシチジン(デシタビン)である。特定の実施形態では、シチジン類似体は、例えば:1−β−D−アラビノフラノシルシトシン(シタラビンまたはara−C);プソイドイソシチジン(psi ICR);5−フルオロ−2′−デオキシシチジン(FCdR);2′−デオキシ−2′,2′−ジフルオロシチジン(ゲムシタビン);5−アザ−2′−デオキシ−2′,2′−ジフルオロシチジン;5−アザ−2′−デオキシ−2′−フルオロシチジン;1−β−D−リボフラノシル−2(1H)−ピリミジノン(ゼブラリン);2′,3′−ジデオキシ−5−フルオロ−3′−チアシチジン(エムトリバ);2′−シクロシチジン(アンシタビン);1−β−D−アラビノフラノシル−5−アザシトシン(ファザラビンまたはara−AC);6−アザシチジン(6−アザ−CR);5,6−ジヒドロ−5−アザシチジン(dH−aza−CR);N4−ペンチルオキシ−カルボニル−5′−デオキシ−5−フルオロシチジン(カペシタビン);N4−オクタデシル−シタラビン;またはエライジン酸シタラビンである。特定の実施形態では、シチジン類似体は、シチジンまたはデオキシシチジンに構造的に関連し、シチジンまたはデオキシシチジンの作用を機能的に模倣及び/または拮抗する任意の化合物を含む。
一実施形態では、治療有効量の変異型IDH2阻害剤及びDNA脱メチル化剤を含む医薬組成物を本明細書において提供する。一実施形態では、変異型IDH2阻害剤は化合物1である。
一実施形態では、変異型IDH2阻害剤とDNA脱メチル化剤を併用して被験者に投与することによる血液悪性腫瘍の治療方法を本明細書において提供する。いくつかのそのような実施形態において、血液悪性腫瘍は、進行性の血液悪性腫瘍である。
細胞株
IDH2/R140Q対立遺伝子または空ベクター対照TF−1/pLVXを過剰発現する改変型TF−1赤白血病細胞において、細胞分化、細胞増殖及び細胞死の測定値を評価した(Wang et al.,Science 340:622−626,2013)。HEPES及びL−グルタミン(Lonza 12−115F)、10%FBS(HyClone SH30088.03)、Pen/Strep(Life Technologies 15070−063)、G418:終濃度500μg/ml(Life Technologies 10131−027);GM−CSF:終濃度5ng/ml(R&D 215−GM−050)を含有するRPMI中で細胞を増殖させた。新たに増殖した細胞のみを用いた。細胞を継代するたびに培地に新鮮なG418及びGM−CSFを加えた。細胞をペレット化し、新鮮な培地に再懸濁するか、10mlの新鮮な培地に2mlの細胞を加えることにより、2〜3日ごとに培地を交換した。細胞を化合物で処理する場合、細胞をペレット化して培地を交換し、化合物の適切な濃度を確保した。
化合物1はDMSO中の10mMストック溶液として得られた。このストックを20μlのバッチとして等分し、−20℃で保存した。ランニングストックを解凍し、室温で暗所に保ち、進行中の実験に使用した。
エリスロポエチン(EPO)分化アッセイ
F1/pLVX及びTF1 IDH2/R140Q細胞(100,000細胞/ml)を化合物1、アザシチジンまたはその組合せで7日間前処理し(培地を2日ごとに交換した)、PBSで洗浄して残留GM−CSFを除去した。細胞を化合物1の存在下または非存在下でEPO(2ユニット/ml)を用いて分化誘導した。誘導を7日間継続し、細胞ペレットを採取し、ヘモグロビン形成量(血液系への分化の代用指標)について画像化した。
RNA easyキット(Qiagenから入手)により細胞からRNAを単離した。500ngのRNAを使用してcDNAを作製し、これをリアルタイムqPCRに供し、胎児ヘモグロビン(HBG)及びKLF−1遺伝子発現を検出した。RNA easyキットはQiagenから入手した。cDNAはSuperscript VILOキット(Life technologies)から作製した。TaqmanプローブはApplied Biosciencesから入手した。
細胞を10×BSA中でブロックし、MACSリンス溶液で15分間、1×濃度に希釈した(染色緩衝液、BD Biosciences)。上清を遠心分離によって除去した。10μlの抗CD34 FITC及び抗CD38 APC抗体(それぞれ染色緩衝液中)を添加した。マウスIgG2a FITC及びIgG2a APCをアイソタイプ対照として用いた。細胞を暗所で10分間染色し、溶液を遠心分離して上清を除去し、細胞を染色緩衝液300μlに再懸濁し、蛍光標識細胞分取(FACS)へ進行する。
EPO誘導分化の促進
細胞分化、細胞増殖及び細胞死の測定値を、図1に示すin vitro EPO分化アッセイ及び用量スケジュールパラダイムを用いて、TF1−R140Q細胞において評価した。細胞を、ビヒクル、アザシチジン単独、化合物1単独、またはアザシチジンと化合物1の組合せで処理した。連続スケジュールでは、化合物1を添加する前に細胞をアザシチジンで3日間前処理した。同時スケジュールでは、アッセイを通して細胞をアザシチジンと化合物1で同時処理した。
造血幹(CD34+/CD38−)及び前駆(CD34+/CD38+)細胞集団を、EPO分化アッセイの終了時に定量した(図3及び8)。単剤としてのアザシチジン及び化合物1のいずれによっても、CD34+/CD38+(図3i)及びCD34+/CD38−(図3ii)細胞集団は減少した。アザシチジンと化合物1の併用によって、相加的、または相加的よりも大きな減少が得られた。例えば、単剤としての化合物1(0.2μM)及びアザシチジン(0.1μM)により、連続治療で造血前駆細胞(CD34+/CD38+)がそれぞれ32%及び7%減少したが、一方、アザシチジン(0.1μM)と化合物1(0.2μM)の併用により、造血前駆細胞集団が64%減少した(図3i)。
EPO分化アッセイの終わりにアネキシンV/7−AADフローサイトメトリーを介して細胞死を分析した(図4及び9)。連続投与スケジュール計画では、単剤による細胞死の誘導(アネキシンV+及び/または7AAD+)はなかった(<2倍)。同時投与スケジュール計画では、単剤としてのアザシチジン及び化合物1により、アネキシンV+及び/または7AAD+細胞の割合がそれぞれ3.4倍及び3.5倍(用量濃度にわたる平均値)増加した。連続または同時治療レジメンのいずれかを使用する薬剤の併用では、細胞死の促進はなかった。
[適応症]:集中的導入化学療法(IC)を受ける候補者ではない、IDH1またはIDH2変異を有する新たに診断された急性骨髄性白血病(AML)を有する18歳以上の患者の治療。
被験者は、治験に登録するために以下の基準を満たさなければならない:
[適応症]:集中的誘導化学療法(IC)を受ける候補者ではない、IDH1またはIDH2変異を有する新たに診断された急性骨髄性白血病(AML)を有する18歳以上の患者の治療。
被験者は、治験に登録するために以下の基準を満たさなければならない:
実施例4、工程1:6−トリフルオロメチル−ピリジン−2−カルボン酸の調製
ジエチルエーテル(4.32L)及びヘキサン(5.40L)をN2雰囲気下で反応容器に加え、−75℃〜−65℃まで冷却した。−65℃未満、N2雰囲気下で、n−ブチルリチウム(1.6Mヘキサン中3.78L)を滴下した後、ジメチルアミノエタノール(327.45g、3.67mol)を滴下し、10分後、2−トリフルオロメチルピリジン(360g、2.45mol)を滴下した。約2.0〜2.5時間、温度を−65℃未満に維持しながら、反応物をN2下で撹拌した。粉砕したドライアイス上にN2下で反応混合物を注ぎ、次いで撹拌しながら(約1.0〜1.5時間)0〜5℃の温度にした後、水(1.8L)を添加した。反応混合物を5〜10分間撹拌し、5〜10℃に温めた。混合物がpH1.0〜2.0に達するまで6N HCl(900mL)を滴下し、次いで混合物を5〜10℃で10〜20分間撹拌した。25〜35℃において反応混合物を酢酸エチルで希釈し、次いでブライン溶液で洗浄した。反応物を濃縮し、n−ヘプタンですすぎ、次いで乾燥して、6−トリフルオロメチル−ピリジン−2−カルボン酸を得た。
アセトン(435.0mL)及び2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール(87.0g、0.184mol)を20〜35℃で反応容器に加えた。別の容器で、撹拌しながら冷(0〜4℃)アセトン(191.4mL)にメタンスルホン酸を10分間かけて添加してメタンスルホン酸溶液を調製した。ミクロンフィルターを通過させながら、新たに調製したメタンスルホン酸溶液を反応混合物に滴下した。得られたスラリーをヌッチェフィルターで濾過し、アセトンで洗浄した。濾過した物質を、真空を用いて30〜40分間乾燥して、2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ]−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オールメタンスルホネートを得た。
形態3への結晶化は以下の塩形成によって達成した:1)結晶化装置にアセトン(500ml、4.17vol)を入れ、次いで混合物を10分間攪拌し(550rpm)、2)2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール(120.0g、253.5mmol)を、固形チャージャーを介して結晶化装置に45分間かけて充填し;3)固形チャージャーをアセトン(100ml、0.83vol)ですすぎ;4)反応物を攪拌し(550rpm)、35℃に加熱して透明な溶液を得て(10分で)、5)MSA/アセトン溶液(0.3mol/L、18.1ml、3.8ml/分)の第1の部分(2%)を、ピストンポンプを介して5分間にわたって添加し、次いでポンプのパイプラインをアセトン(5ml、0.04vol)で洗浄し、6)溶液を透明に保ちながら、混合物を35℃で10〜15分間エージングさせ、7)2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オールメタンスルホネートシード(実施例2で生成したように2.4g、2wt%)を透明な溶液に加え、8)MSA/アセトン溶液(0.3mol/L、444ml、3.7ml/分)の第2の部分(49%)を2時間にわたって加え、9)混合物を35℃で30分間エージングさせ、10)MSA/アセトン溶液(0.3mol/L、444ml、7.4ml/分)の第3の部分(49%)を1時間にわたって加え、11)混合物を35℃で2時間エージングさせ、12)混合物を1時間、20℃まで冷却し、13)混合物を濾過し、ケーキをアセトンで洗浄し(240mlで2回)、17)ならびに30℃で真空乾燥し;形態3の結晶を得た。
本件出願は、以下の構成の発明を提供する。
(構成1)
変異型イソクエン酸デヒドロゲナーゼ2(IDH2)阻害剤及びDNA脱メチル化剤を被験者に投与することを含む血液悪性腫瘍の治療方法であって、前記変異型IDH2阻害剤が、以下の式:
(化1)
を有する2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくは多形体(化合物1)であり、前記血液悪性腫瘍が、IDH2の変異型対立遺伝子の存在を特徴とする悪性腫瘍である、前記治療方法。
(構成2)
前記IDH2変異が、IDH2 R140QまたはR172K変異である、構成1に記載の方法。
(構成3)
前記悪性腫瘍が、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、慢性骨髄単球性白血病(CMML)、骨髄肉腫、多発性骨髄腫、リンパ腫(例えば、T細胞リンパ腫またはB細胞リンパ腫)、血管免疫芽球性T細胞リンパ腫(AITL)または芽球性形質細胞様樹状細胞新生物である、構成1または2に記載の方法。
(構成4)
前記悪性腫瘍が急性骨髄性白血病である、構成1〜3のいずれか1項に記載の方法。
(構成5)
前記急性骨髄性白血病が、新たに診断される、構成4に記載の方法。
(構成6)
変異型イソクエン酸デヒドロゲナーゼ2(IDH2)阻害剤及びDNA脱メチル化剤を被験者に投与することを含む固形腫瘍の治療方法であって、前記変異型IDH2阻害剤が、以下の式:
(化2)
を有する2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくはその多形体(化合物1)であり、前記固形腫瘍が、IDH2の変異型対立遺伝子の存在を特徴とする、前記治療方法。
(構成7)
化合物1の用量が約20〜2000mg/日である、構成1〜6のいずれか1項に記載の方法。
(構成8)
化合物1の用量が約50〜500mg/日である、構成1〜7のいずれか1項に記載の方法。
(構成9)
化合物1の用量が約50mg/日である、構成1〜8のいずれか1項に記載の方法。
(構成10)
化合物1の用量が約100mg/日である、構成1〜8のいずれか1項に記載の方法。
(構成11)
化合物1の用量が約200mg/日である、構成1〜8のいずれか1項に記載の方法。
(構成12)
前記DNA脱メチル化剤がアザシチジンである、構成1〜11のいずれか1項に記載の方法。
(構成13)
前記アザシチジンの用量が約50〜約500mg/m 2 である、構成1〜12のいずれか1項に記載の方法。
(構成14)
前記アザシチジンの用量が約50〜約200mg/m 2 である、構成1〜13のいずれか1項に記載の方法。
(構成15)
前記アザシチジンの用量が約50mg/m 2 である、構成1〜13のいずれか1項に記載の方法。
(構成16)
前記アザシチジンの用量が約60mg/m 2 である、構成1〜13のいずれか1項に記載の方法。
(構成17)
前記アザシチジンの用量が約75mg/m 2 である、構成1〜13のいずれか1項に記載の方法。
(構成18)
化合物1及びアザシチジンを同時に投与する、構成1〜17のいずれか1項に記載の方法。
(構成19)
化合物1及びアザシチジンを連続的に投与する、構成1〜17のいずれか1項に記載の方法。
(構成20)
2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくはその多形体、及びアザシチジンを含む、医薬組成物。
(構成21)
前記悪性腫瘍が急性骨髄性白血病であり、前記方法が構成20に記載の組成物を患者に投与することを含む、構成4に記載の方法。
(構成22)
血液悪性腫瘍の治療方法で使用するための変異型イソクエン酸デヒドロゲナーゼ2(IDH2)阻害剤であって、前記方法が、前記変異型IDH2阻害剤及びDNA脱メチル化剤を被験者に投与することを含み、前記変異型IDH2阻害剤が、以下の式:
(化3)
を有する2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくは多形体(化合物1)であり、前記血液悪性腫瘍が、IDH2の変異型対立遺伝子の存在を特徴とする悪性腫瘍である、前記阻害剤。
(構成23)
前記IDH2変異が、IDH2 R140QまたはR172K変異である、構成22に記載の使用のための変異型IDH2阻害剤。
(構成24)
前記悪性腫瘍が、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、慢性骨髄単球性白血病(CMML)、骨髄肉腫、多発性骨髄腫、リンパ腫(例えば、T細胞リンパ腫またはB細胞リンパ腫)、血管免疫芽球性T細胞リンパ腫(AITL)または芽球性形質細胞様樹状細胞新生物である、構成22または23に記載の使用のための変異型IDH2阻害剤。
(構成25)
前記悪性腫瘍が急性骨髄性白血病である、構成22〜24に記載の使用のための変異型IDH2阻害剤。
(構成26)
前記急性骨髄性白血病が、新たに診断される、構成25に記載の使用。
(構成27)
固形腫瘍の治療方法で使用するための変異型IDH2阻害剤であって、前記方法が、前記変異型IDH2阻害剤及びDNA脱メチル化剤を被験者に投与することを含み、前記変異型IDH2阻害剤が、以下の式:
(化4)
を有する2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくはその多形体(化合物1)であり、前記固形腫瘍が、IDH2の変異型対立遺伝子の存在を特徴とする、前記阻害剤。
(構成28)
化合物1の用量が約20〜2000mg/日であり;好ましくは約50〜500mg/日;好ましくは約50mg/日;好ましくは約100mg/日;または好ましくは約200mg/日である、構成20〜27に記載の使用のための変異型IDH2阻害剤。
(構成29)
前記DNA脱メチル化剤がアザシチジンであり;好ましくは、アザシチジンの用量が約50〜約500mg/m 2 であり;好ましくは約50〜約200mg/m 2 ;好ましくは約50mg/m 2 ;好ましくは約60mg/m 2 ;または好ましくは約75mg/m 2 である、構成22〜28に記載の使用のための変異型IDH2阻害剤。
(構成30)
化合物1及びアザシチジンを同時に投与するか;または化合物1及びアザシチジンを連続的に投与する、構成22〜29に記載の使用のための変異型IDH2阻害剤。
(構成31)
2−メチル−1−[(4−[6−(トリフルオロメチル)ピリジン−2−イル]−6−{[2−(トリフルオロメチル)ピリジン−4−イル]アミノ}−1,3,5−トリアジン−2−イル)アミノ]プロパン−2−オール、またはその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、同位体置換体、プロドラッグ、代謝産物、もしくはその多形体、及びアザシチジンを含む、医薬組成物。
(構成32)
前記悪性腫瘍が急性骨髄性白血病(AML)であり、前記方法が、構成35に記載の医薬組成物を患者に投与することを含む、構成31に記載の使用のための変異型IDH2阻害剤。
Claims (15)
- 前記IDH2変異が、IDH2 R140QまたはR172K変異である、請求項1に記載の医薬組成物。
- 前記急性骨髄性白血病が、新たに診断されている、請求項1に記載の医薬組成物。
- 化合物1が約20〜2000mg/日の量で投与されるように用いられることを特徴とする、請求項1〜3のいずれか1項に記載の医薬組成物。
- 化合物1が約50〜500mg/日の量で投与されるように用いられることを特徴とする、請求項1〜4のいずれか1項に記載の医薬組成物。
- 化合物1が約50mg/日の量で投与されるように用いられることを特徴とする、請求項1〜5のいずれか1項に記載の医薬組成物。
- 化合物1が約100mg/日の量で投与されるように用いられることを特徴とする、請求項1〜5のいずれか1項に記載の医薬組成物。
- 化合物1が約200mg/日の量で投与されるように用いられることを特徴とする、請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記アザシチジンが約50〜約500mg/m2の量で投与されるように用いられることを特徴とする、請求項1に記載の医薬組成物。
- 前記アザシチジンが約50〜約200mg/m2の量で投与されるように用いられることを特徴とする、請求項1または9に記載の医薬組成物。
- 前記アザシチジンが約50mg/m2の量で投与されるように用いられることを特徴とする、請求項1または9〜10のいずれか1項に記載の医薬組成物。
- 前記アザシチジンが約60mg/m2の量で投与されるように用いられることを特徴とする、請求項1または9〜11のいずれか1項に記載の医薬組成物。
- 前記アザシチジンが約75mg/m2の量で投与されるように用いられることを特徴とする、請求項1または9〜12のいずれか1項に記載の医薬組成物。
- 化合物1及びアザシチジンが同時に投与されるように用いられることを特徴とする、請求項1または9〜13のいずれか1項に記載の医薬組成物。
- 化合物1及びアザシチジンが連続的に投与されるように用いられることを特徴とする、請求項1または9〜13のいずれか1項に記載の医薬組成物。
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US20210100805A1 (en) | 2021-04-08 |
US20180303840A1 (en) | 2018-10-25 |
EP3362070A1 (en) | 2018-08-22 |
CN108601787A (zh) | 2018-09-28 |
EP3362070B1 (en) | 2021-01-27 |
SG11201802964QA (en) | 2018-05-30 |
BR112018007447B1 (pt) | 2023-12-05 |
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