JP2022545661A - 新規なクレノラニブの使用 - Google Patents
新規なクレノラニブの使用 Download PDFInfo
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- JP2022545661A JP2022545661A JP2022510920A JP2022510920A JP2022545661A JP 2022545661 A JP2022545661 A JP 2022545661A JP 2022510920 A JP2022510920 A JP 2022510920A JP 2022510920 A JP2022510920 A JP 2022510920A JP 2022545661 A JP2022545661 A JP 2022545661A
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- Prior art keywords
- flt3
- mutations
- cell
- mutation
- crenolanib
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Abstract
Description
本発明は、最初にクローンの不均一性を検出し、次いでクレノラニブを用いてFLT3に関連する細胞増殖性障害を予防し、または治療することによって、細胞または対象における正常および変異FLT3のキナーゼ活性を減少させ、または阻害するための方法に関する。
適用できない。
適用できない。
本発明の範囲を限定することなく、この背景技術では、癌治療と組み合わせて、治療期間中の測定可能な残存病変をモニターし、再発性の遺伝子変異の存在または不存在を決定し、次いでクレノラニブまたはその医薬的に許容される塩を、適切な再発性遺伝子変異を保有する患者に投与して、測定可能な残存病変を除去し、および/または疾患の寛解を維持するための遺伝学的アッセイの新規な使用について説明する。
本発明の特徴および利点をより完全に理解するために、ここでは、添付の図面とともに本発明の詳細な説明を参照する。
本明細書で用いられるように、用語「測定可能な残存病変」、「微小残存病変」、および「MRD」は、従来の方法(細胞遺伝学、組織学を含むがこれらに限定されない)によって対象において検出可能な癌の証拠がない状況または状態を意味する。体内に腫瘍細胞が残っている可能性があるが、これらは従来の方法の検出限界以下の量で見出される。しかしながら、これらの残存する腫瘍細胞は、前記増殖性障害を完全に再現することができる。MRDは、典型的に、化学療法、放射線療法、および/または同種異系幹細胞移植後の完全奏効または完全寛解後に生じる。当該技術分野で公知のMRD検出方法には、事前に特定された細胞発現マーカーおよび分子の存在をモニターするフローサイトメトリーに基づく方法が含まれる。MRD検出のための分子に基づく方法には、例えば、NPM1、DNMT3A、NRAS、KRAS、JAK2、PTPN11、TET2、IDH1、IDH2、WT1、RUNX1、CEBPA、ASXL1、BCOR、SF3B1、U2AF1、STAG2、SETBP1、ZRSR2、GRB7、SRSF2、MLL、NUP98、ETV6、TCL1A、TUSC3、BRP1、CD36、TYK2、TP53、EZH2、GATA2、KIT、PHF6、MYC、ERG、MYD88、RAD21、STAT3、NF1、BRAF、KDM6A、SETBP1、CALR、CBL、KMT2A、PHF6、SMC1A、CHEK2、GNAS、PPM1D、SMC3、ZRSR2、CSF3R、HRAS、MPL、PTEN、ATM、またはMUTYHなどの変異の存在に関するPCRに基づく試験が含まれる。PCRに基づく方法は、これらの遺伝子の異常のうちの1つまたはそれ以上を有する患者について用いることができる。
54歳の女性は、2016年に単球分化を伴うAMLと診断された。この患者は63%の骨髄芽球を呈した。診断時に、バルクDNA配列決定法を用いた分子検査により、前記患者がFLT3-ITD、FLT3-N814K、FLT3-A680V、DNMT3A、およびNPM1変異を有することが明らかになった。これは、予後不良に関連する複数のFLT3変異を有する特にリスクの高い患者の症例であり、NPM1-FLT3ITD-DNMT3A変異の同時発生もまた予後不良に関連している(Papaemmanuil et al., 2016)。さらに、単球分化はCD163の過剰発現を伴っており、これはこの患者の診断用骨髄試料で遡及的に見られ、予後不良とも関連している(van Galen et al., 2019)。この患者の病気を治療し、FLT3変異を克服するために、この患者に、FLT3変異が活性化した新たに診断されたAML患者を対象とした臨床試験において、標準的な化学療法と組み合わせてベシル酸クレノラニブを経口投与した。前記患者を、7日間のシタラビンと3日間のダウノルビシン、続いて治療の10日目から1日3回100mgのベシル酸クレノラニブからなる導入化学療法で治療した。
68歳の男性は2016年にAMLと診断された。診断時に、バルクDNA配列決定を用いた分子検査により、前記患者が野生型FLT3を有し、病理学的変化と見なされるBCOR、NRAS、およびU2AF1遺伝子における変異を有することが明らかになった。最初に、前記患者を標準的なシタラビン/アントラサイクリンに基づく化学療法レジメンで治療した。前記患者は最初の治療に反応せず、難治性であると考えられた。この患者の疾患を治療し、FLT3野生型患者においてさえ、化学療法の連続ラウンド後に発生することが報告されているFLT3リガンドの上昇を克服するために、この患者に、再発/難治性患者のためのサルベージ化学療法と組み合わせて経口ベシル酸クレノラニブを供した。ベースライン時に、この患者は17%の骨髄芽球を示した。前記患者を、5日間のフルダラビン、5日間のシタラビン、3日間のイダルビシン、およびG-CSFからなるサルベージ化学療法、続いて治療7日目から1日3回100mgのベシル酸クレノラニブで治療した。
36歳の男性は2016年にAMLと診断された。診断時に、バルクDNA配列決定を用いた分子検査により、前記患者がFLT3-ITD、NRAS、およびNPM1変異を有することが明らかになった。この患者の病気を治療し、FLT3変異を克服するために、この患者に、FLT3変異を活性化する新たに診断されたAML患者を対象とした臨床試験において、標準的な化学療法と組み合わせてベシル酸クレノラニブを経口投与した。ベースライン時に、この患者は8%の骨髄芽球を示した。前記患者を、7日間のシタラビンと3日間のダウノルビシンからなる導入化学療法、続いて治療10日目から1日3回100mgのベシル酸クレノラニブで治療した。
59歳の男性は2017年にAMLと診断された。診断時に、バルクDNA配列決定を用いた分子検査により、前記患者はFLT3-D835V、FLT3-D835E、DNMT3A、NRAS、RUNX1、BCOR、およびU2AF1変異を有することが明らかになった。この患者の病気を治療し、FLT3変異を克服するために、この患者に、FLT3変異を活性化する新たに診断されたAML患者を対象とした臨床試験において、標準的な化学療法と組み合わせてベシル酸クレノラニブを経口投与した。ベースライン時に、この患者は70%の骨髄芽球を示した。前記患者を、7日間のシタラビンと3日間のイダルビシンからなる2サイクルの導入化学療法、続いて治療10日目から1日3回100mgのベシル酸クレノラニブで治療した。
36歳の女性は2012年にAMLと診断された。診断時に、バルクDNA配列決定を用いた分子検査により、前記患者がFLT3-D835変異を有することが明らかになった。最初に、前記患者を標準的な導入化学療法と骨髄移植で治療した。残念ながら、前記患者はその後再発し、サルベージ化学療法で治療し、再度再発する前に短時間の寛解を達成した。2回目の再発時に、前記患者は、FLT3-D835変異、ならびにNPM1、NOTCH1、CEBPA、およびWT1遺伝子における変異をいまだ有することがわかった。この患者の疾患を治療し、FLT3-D835変異を克服するために、この患者に、FLT3変異を活性化する再発/難治性AML患者を対象とした臨床試験において、ベシル酸クレノラニブを経口投与した。ベースライン時に、この患者は90%の骨髄芽球を示した。前記患者を、200mg/m2の用量の単剤ベシル酸クレノラニブで1日3回治療した。
87歳の女性は2014年にAMLと診断された。診断時に、バルクDNA配列決定を用いた分子検査により、前記患者がFLT3-ITD変異を有することが明らかになった。最初に、前記患者を、低用量の標準的な導入化学療法、続いてソラフェニブの維持療法で治療したが、前記患者は完全な形態学的寛解を達成せず、5ヶ月以内に前記患者は進行性疾患を示すと考えられた。ソラフェニブ治療後に行った分子検査により、前記患者はFLT3-D835変異と第2のFLT3-ITD変異を獲得したことが明らかになった。さらに、バルクDNA配列決定により、NRASおよびRUNX1遺伝子に変異が見つかった。この患者の疾患を治療し、FLT3-ITDおよびFLT3-D835変異を克服するために、この患者に、FLT3変異を活性化する再発/難治性AML患者の臨床試験において、ベシル酸クレノラニブを経口投与した。ベースライン時に、この患者は68%の骨髄芽球を示した。前記患者を、200mg/m2の用量の単剤ベシル酸クレノラニブで1日3回治療した。
54歳の女性は2016年にAMLと診断された。彼女の診断用骨髄穿刺液は、癌関連遺伝子のNGSに回した。彼女は、FLT3-ITD、FLT3-I836del、FLT3-N841I、FLT3-V491L、FLT3-V592A、IDH2、NMP1、およびSRSF2変異を有することが見出された。この患者の病気を治療し、前記FLT3変異を克服するために、この患者に、FLT3変異を活性化する新たに診断されたAML患者を対象とした臨床試験において、標準的な化学療法と組み合わせてベシル酸クレノラニブを経口投与した。ベースライン時に、この患者は95%の骨髄芽球を示した。前記患者を、7日間のシタラビンと3日間のイダルビシンからなる導入化学療法、続いて治療10日目から1日3回100mgのベシル酸クレノラニブで治療した。
1歳の少年は2016年4月にt(9;11)+AMLと診断された。彼は、2サイクルのシタラビン、ダウノルビシン、エトポシド(ADE)、続いてシタラビン、エトポシド(AE)およびミトキサントロン、シタラビン(MA)を各1サイクル受け、2年間寛解した。2018年後半に前記患者は白血病を再発し、洞、眼窩、および蝶形骨における骨髄外疾患に罹った。そして、前記患者は、フルダラビン、シタラビン、およびG-CSF(FLAG)の1サイクルを受けたが、反応しなかった。前記患者は、ゲムツズマブ、オゾガマイシンおよびアザシチジンを追加してFLAGを再度受け、測定可能な残存病変のためのフローサイトメトリーによりネガティブである寛解を達成することができ、同種幹細胞移植を臍帯幹細胞とともに受けた。その後、前記患者は2019年に2回目の再発を経験し、その時点でバルクDNA配列決定によってFLT3-A848P変異を有することが判明した。続いて、この患者は臨床試験に登録し、ベネトクラクスを高用量のシタラビンとイダルビシンとの1サイクルを受けたが、治療に反応しなかった。続いて、リポソーム化学療法(ダウノルビシンおよびシタラビン(VYXEOS(登録商標))ならびにゲムツズマブ、オゾガマイシン)を3回受け、5日後に66.7mg/m2のベシル酸クレノラニブを経口投与し始めた。1ヶ月後、彼は、数が戻ることなく完全な形態学的寛解状態にあることがわかった。前記患者は、さらなる同種幹細胞移植の1週間前までクレノラニブを継続した。前記患者は現在移植後100日以上経過し、いまだ寛解状態である。
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Claims (35)
- FLT3チロシンキナーゼ変異を伴うか、または伴わない、増殖性障害を引き起こす変異を有する対象を治療するための方法であって、治療上有効な量のクレノラニブまたはその医薬的に許容される塩を、アルキル化剤、代謝拮抗剤、天然生成物、またはこれらの組み合わせのうちの少なくとも1つと組み合わせて前記対象に投与することを含む、方法。
- 前記増殖性障害の微小残存病変が、
a.腫瘍性細胞を含む前記対象から試料を取得し、
b.前記試料をシングルセル配列決定することであって、前記配列決定が、少なくとも1,000,000個の読取/試料を含むものであり、次いで
c.10%またはそれ以下の対立遺伝子ドロップアウト率である試料のみからの変異を分析することによって検出される、請求項1に記載の方法。 - 1つまたはそれ以上の変異の存在または不存在が、前記増殖性障害と相関する患者特異的な単一細胞の変異プロファイルを作成するために用いられる、請求項1に記載の方法。
- 1つまたはそれ以上の同時発生する変異が、NPM1、DNMT3A、NRAS、KRAS、JAK2、PTPN11、TET2、IDH1、IDH2、WT1、RUNX1、CEBPA、ASXL1、BCOR、SF3B1、U2AF1、STAG2、SETBP1、ZRSR2、GRB7、SRSF2、MLL、NUP98、ETV6、TCL1A、TUSC3、BRP1、CD36、TYK2、TP53、EZH2、GATA2、KIT、PHF6、MYC、ERG、MYD88、RAD21、STAT3、NF1、BRAF、KDM6A、SETBP1、CALR、CBL、KMT2A、PHF6、SMC1A、CHEK2、GNAS、PPM1D、SMC3、ZRSR2、CSF3R、HRAS、MPL、PTEN、ATM、またはMUTYHのうちの少なくとも1つである、請求項1に記載の方法。
- 前記FLT3変異が、FLT3-ITD、FLT3-TKD、または他のFLT3変異バリアントのうちの少なくとも1つである、請求項1に記載の方法。
- 前記FLT3-TKD変異が、F612、L616、M664、M665、N676、A680、F691、D835、I836、D839、N841、Y842、またはA848のうちの少なくとも1つにおける変化、欠失、または点変異である、請求項5に記載の方法。
- 前記FLT3変異が、L20、D324、L442、E444、S451、V491、Y572、E573、L576、Y572、Q580、V591、T582、D586、Y589、V592、F594、E596、E598、Y599、D600、R607、またはA848のうちの少なくとも1つにおける変化または欠失を生じる点変異を含む、請求項5に記載の方法。
- 前記対象からの1つまたはそれ以上の縦方向に連続する試料から前記工程(a)から(c)を繰り返し、
1つまたはそれ以上の縦方向の単一細胞ゲノムの変異プロファイルを組み合わせて、治療上有効な量のクレノラニブまたはその医薬的に許容される塩の投与に応答して変化する1つまたはそれ以上の同時発生する変異の存在または不存在を決定し、次いで
前記増殖性障害と相関する治療後の患者特異的な単一細胞の変異プロファイルのパーセンテージの増加または減少として測定される増殖性障害の測定可能な残存病変状態を決定する工程をさらに含む、請求項2に記載の方法。 - 前記取得される試料が、骨髄、末梢血、または腫瘍組織のうちの少なくとも1つである、請求項2に記載の方法。
- 前記シングルセル配列決定が、1個の細胞あたり1つまたはそれ以上のマーカーを用いてゲノムDNAを調製し、次いで調製されたDNAを配列決定することを含む、請求項2に記載の方法。
- 前記シングルセル配列決定が、MiSeq、HiSeq、またはNovaSeqプラットフォームを使用する、請求項2に記載の方法。
- 前記アルキル化剤が、カルムスチン、クロラムブシル、シクロホスファミド、イホスファミド、ロムスチン、ストレプトゾトシン、テモゾロミド、シスプラチン、カルボプラチン、ネダプラチン、またはオキサリプラチンのうちの少なくとも1つから選択される、請求項1に記載の方法。
- 前記代謝拮抗剤が、メトトレキサート、ペメトレキセド、ラルチトレキセド、シタラビン、フルダラビン、フルオロウラシル、フロクスウリジン、カペシタビン、またはゲムシタビンのうちの少なくとも1つから選択される、請求項1に記載の方法。
- 前記天然生成物が、ビンブラスチン、ビノレルビン、ビンクリスチン、ビンデシン、ビンフルニン、パクリタキセル、ドセタキセル、カバジタキセル、エトポシド、テニポシド、トポテカン、イリノテカン、ダウノルビシン、ドキソルビシン、イダルビシン、エピルビシン、バルルビシン、ミトキサントロン、ブレオマイシン、エストラムスチン、および/またはマイトマイシンのうちの少なくとも1つから選択される、請求項1に記載の方法。
- 前記対象が、小児患者である、請求項1に記載の方法。
- 1つまたはそれ以上の同時発生するRAS変異を有する野生型FLT3を含む増殖性障害に罹っている対象を治療するための方法であって、治療上有効な量のクレノラニブまたはその医薬的に許容される塩を、アルキル化剤、代謝拮抗剤、天然生成物、またはこれらの組み合わせのうちの少なくとも1つと組み合わせて投与することを含む、方法。
- 前記増殖性障害の微小残存病変が、
a.腫瘍性細胞を含む対象から試料を取得し、
b.前記試料をシングルセル配列決定することであって、前記配列決定が少なくとも1,000,000個の読取/試料を含むものであり、次いで
c.10%またはそれ以下の対立遺伝子ドロップアウト率である試料のみからの変異を分析することによって検出される、請求項16に記載の方法。 - 1つまたはそれ以上の変異の存在または不存在が、増殖性障害と相関する患者特異的な単一細胞の変異プロファイルを作成するために用いられる、請求項16に記載の方法。
- 前記RAS変異が、NRASまたはKRAS変異のうちの少なくとも1つである、請求項16に記載の方法。
- 前記1つまたはそれ以上の同時発生する変異が、FLT3、NPM1、DNMT3A、JAK2、PTPN11、TET2、IDH1、IDH2、WT1、RUNX1、CEBPA、ASXL1、BCOR、SF3B1、U2AF1、STAG2、SETBP1、ZRSR2、GRB7、SRSF2、MLL、NUP98、ETV6、TCL1A、TUSC3、BRP1、CD36、TYK2、TP53、EZH2、GATA2、KIT、PHF6、MYC、ERG、MYD88、RAD21、STAT3、NF1、BRAF、KDM6A、SETBP1、CALR、CBL、KMT2A、PHF6、SMC1A、CHEK2、GNAS、PPM1D、SMC3、ZRSR2、CSF3R、HRAS、MPL、PTEN、ATM、またはMUTYHのうちの少なくとも1つである、請求項16に記載の方法。
- 対象からの1つまたはそれ以上の縦方向に連続する試料から工程(a)から(c)を繰り返し、
1つまたはそれ以上の縦方向の単一細胞ゲノムの変異プロファイルを組み合わせて、治療上有効な量のクレノラニブまたはその医薬的に許容される塩の投与に応答して変化する1つまたはそれ以上の同時発生する変異の存在または不存在を決定し、次いで
前記増殖性障害と相関する治療後の患者特異的な単一細胞の変異プロファイルのパーセンテージの増加または減少として測定される前記増殖性障害の測定可能な残存病変状態を決定する工程をさらに含む、請求項17に記載の方法。 - 前記取得される試料が、骨髄、末梢血、または腫瘍組織のうちの少なくとも1つである、請求項17に記載の方法。
- 前記シングルセル配列決定が、1個の細胞あたり1つまたはそれ以上のマーカーを用いてゲノムDNAを調製し、次いで調製されたDNAを配列決定することを含む、請求項17に記載の方法。
- 前記シングルセル配列決定が、MiSeq、HiSeq、またはNovaSeqプラットフォームを使用する、請求項17に記載の方法。
- 前記アルキル化剤が、カルムスチン、クロラムブシル、シクロホスファミド、イホスファミド、ロムスチン、ストレプトゾトシン、テモゾロミド、シスプラチン、カルボプラチン、ネダプラチン、またはオキサリプラチンのうちの少なくとも1つから選択される、請求項17に記載の方法。
- 前記代謝拮抗剤が、メトトレキサート、ペメトレキセド、ラルチトレキセド、シタラビン、フルダラビン、フルオロウラシル、フロクスウリジン、カペシタビン、またはゲムシタビンのうちの少なくとも1つから選択される、請求項17に記載の方法。
- 前記天然生成物が、ビンブラスチン、ビノレルビン、ビンクリスチン、ビンデシン、ビンフルニン、パクリタキセル、ドセタキセル、カバジタキセル、エトポシド、テニポシド、トポテカン、イリノテカン、ダウノルビシン、ドキソルビシン、イダルビシン、エピルビシン、バルルビシン、ミトキサントロン、ブレオマイシン、エストラムスチン、および/またはマイトマイシンのうちの少なくとも1つから選択される、請求項17に記載の方法。
- 前記対象が、FLT3チロシンキナーゼ変異をさらに含む、請求項17に記載の方法。
- 前記対象が、小児患者である、請求項17に記載の方法。
- 過去に治療されて増殖性障害に罹っていない対象における前記増殖性障害の再発を予防するための方法であって、治療上有効な量のクレノラニブまたはその医薬的に許容される塩を、導入化学療法、強化療法に対する応答後または造血幹細胞移植後に十分な期間投与して、前記増殖性障害の再発を予防することを含む方法。
- 前記増殖性障害が、1つまたはそれ以上の機能変化変異および少なくとも1つの再発性遺伝子変異を含むことを特徴とする、請求項30に記載の方法。
- 前記増殖性障害が、1つまたはそれ以上の同時発生する変異を伴うか、または伴わない野生型FLT3を含むことを特徴とする、請求項30に記載の方法。
- 前記対象が、
カルムスチン、クロラムブシル、シクロホスファミド、イホスファミド、ロムスチン、ストレプトゾトシン、テモゾロミド、シスプラチン、カルボプラチン、ネダプラチン、またはオキサリプラチンのうちの少なくとも1つから選択されるアルキル化剤、
メトトレキサート、ペメトレキセド、ラルチトレキセド、シタラビン、フルダラビン、フルオロウラシル、フロクスウリジン、カプシタビン、またはゲムシタビンのうちの少なくとも1つから選択される代謝拮抗剤、あるいは
ビンブラスチン、ビノレルビン、ビンクリスチン、ビンデシン、ビンフルニン、パクリタキセル、ドセタキセル、カバジタキセル、エトポシド、テニポシド、トポテカン、イリノテカン、ダウノルビシン、ドキソルビシン、イダルビシン、エピルビシン、バルルビシン、ミトキサントロン、ブレオマイシン、エストラムスチン、および/またはマイトマイシンのうちの少なくとも1つから選択される天然生成物
で過去に治療されたものである、請求項30に記載の方法。 - 前記1つまたはそれ以上の同時発生する変異が、NPM1、DNMT3A、NRAS、KRAS、JAK2、PTPN11、TET2、IDH1、IDH2、WT1、RUNX1、CEBPA、ASXL1、BCOR、SF3B1、U2AF1、STAG2、SETBP1、ZRSR2、GRB7、SRSF2、MLL、NUP98、ETV6、TCL1A、TUSC3、BRP1、CD36、TYK2、TP53、EZH2、GATA2、KIT、PHF6、MYC、ERG、MYD88、RAD21、STAT3、NF1、BRAF、KDM6A、SETBP1、CALR、CBL、KMT2A、PHF6、SMC1A、CHEK2、GNAS、PPM1D、SMC3、ZRSR2、CSF3R、HRAS、MPL、PTEN、ATM、またはMUTYHのうちの少なくとも1つである、請求項28に記載の方法。
- 前記対象が、小児患者である、請求項30に記載の方法。
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