JP2018524347A - 血液がん及び固形腫瘍の治療のための併用療法 - Google Patents
血液がん及び固形腫瘍の治療のための併用療法 Download PDFInfo
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Abstract
Description
3−(5−アミノ−2−メチル−4−オキソ−4H−キナゾリン−3−イル)−ピペリジン−2,6−ジオン及び少なくとも1つのチェックポイント阻害剤を含む併用療法を使用する、血液がん及び固形腫瘍を治療、予防、及び/または管理するための方法が本明細書で提供される。
がんは、免疫系の著しい抑制を誘発し、宿主の免疫監視機構から逃れることができる。宿主免疫系の調節不全は、現在、がんの重要な特徴の1つであると考えられている(Hanahan et al.,Cell,2011,144,646−674)。がんと宿主免疫系との相互作用については幅広く研究されており、がん治療のための数多くの種類の免疫療法が探究されている。
治療上有効な量の次式の3−(5−アミノ−2−メチル−4−オキソ−4H−キナゾリン−3−イル)−ピペリジン−2,6−ジオン(「化合物A」)またはその薬学的に許容される塩、溶媒和物、立体異性体、もしくはアイソトポログを、1つ以上のチェックポイント阻害剤(複数可)と組み合わせて、それを必要とする患者に投与することを含む、血液がん及び固形腫瘍を治療、予防、及び/または管理する方法が本明細書で提供される。
4.1 図面の簡単な説明
特許、出願、出願公報、及び他の公開物の全ては、その全体が参照により本明細書に援用される。本明細書で使用される略語は、化学分野及び生物学分野における通常の意味を有する。本明細書に記載される化学構造及び式は、化学分野において周知の化学上の原子価に関する標準規則に従って構築される。本明細書中において用語に関する定義が複数ある場合、別段の指示がない限り、本セクションの定義が優先される。本明細書で使用される見出しは、構造上の目的のために付するものであり、本明細書に記載される発明を限定するものでは一切ない。
4.3.1 化合物A
いくつかの実施形態において、本明細書で提供される方法における使用に好適な化合物は、次式:
いくつかの実施形態において、本明細書で提供される方法に関連して、1つ以上のチェックポイント阻害剤(複数可)が化合物Aと組み合わせて使用される。一実施形態において、本明細書で提供される方法に関連して、1つのチェックポイント阻害剤が化合物Aと組み合わせて使用される。別の実施形態において、本明細書で提供される方法に関連して、2つのチェックポイント阻害剤が化合物Aと組み合わせて使用される。更に別の実施形態において、本明細書で提供される方法に関連して、3つ以上のチェックポイント阻害剤が化合物Aと組み合わせて使用される。
本明細書に記載される併用療法を、それを必要とする対象に施すことを含む、血液がんまたは固形腫瘍を治療、予防、及び/または管理する方法が本明細書で提供される。一態様において、本明細書に記載される併用療法を、それを必要とする対象に施すことを含む、血液がんまたは固形腫瘍を治療する方法である。別の態様において、本明細書に記載される併用療法を、それを必要とする対象に施すことを含む、血液がんまたは固形腫瘍を予防する方法である。更に別の態様において、本明細書に記載される併用療法を、それを必要とする対象に施すことを含む、血液がんまたは固形腫瘍を管理する方法である。
本明細書に記載される併用療法は、本明細書に記載される疾患または障害を有する患者に療法を適用する順序についての制限なく、適用される。したがって、一実施形態において、第1の療法(例えば、化合物A)は、対象に対して、第2の療法(例えば、本明細書に記載されるチェックポイント阻害剤)を適用する前(例えば、5分、15分、30分、45分、1時間、2時間、4時間、6時間、12時間、24時間、48時間、72時間、96時間、1週間、2週間、3週間、4週間、5週間、6週間、8週間、または12週間前)、それと同時、またはその後(例えば、5分、15分、30分、45分、1時間、2時間、4時間、6時間、12時間、24時間、48時間、72時間、96時間、1週間、2週間、3週間、4週間、5週間、6週間、8週間、または12週間後)に適用することができる。このような適用は、本明細書に記載されるサイクル投与を使用して実施することができる。三剤療法もまた本明細書で意図される(例えば、本明細書に記載される第2の化合物もしくはチェックポイント阻害剤の追加、本明細書に記載される第2の治療薬の追加または本明細書に記載される別の併用療法の追加)。
特定の実施形態において、化合物Aまたはその薬学的に許容される塩、溶媒和物、立体異性体、もしくはアイソトポログ、及びチェックポイント阻害剤、またはその薬学的に許容される塩もしくは溶媒和物は、1つ以上の第2の活性薬剤と組み合わせて投与され得る。このような療法は、本明細書中、「三剤療法」と呼ばれる。
いくつかの実施形態において、本明細書に記載される併用療法の成分(例えば、化合物A及び本明細書に記載されるCPI)は、患者に対して、周期的に投与される。別の実施形態において、第2の活性薬剤は、本明細書で提供される併用療法とともにサイクル投与で共投与される。サイクル療法は、一定期間にわたる活性薬剤の投与と、それに続く一定期間の休薬、またこの一連の投与を繰り返すことを含む。サイクル療法は、所定の継続期間にわたって、各活性薬剤(例えば、化合物A、本明細書に記載されるCPI、及び/または本明細書に記載される第2の薬剤)について、独立して実施することができる。特定の実施形態において、各活性薬剤のサイクル投与は、対象に投与される1つ以上の活性薬剤に応じて決定される。一実施形態において、化合物Aまたは本明細書に記載されるチェックポイント阻害剤の投与は、各薬剤の投与日(複数可)または継続期間を固定する。別の実施形態において、化合物Aまたは本明細書に記載されるチェックポイント阻害剤の投与は、第2の活性薬剤の投与日(複数可)または継続期間を固定する。
一実施形態において、医薬組成物及び製剤が本明細書で提供され、これらは、(1)化合物A、またはそのエナンチオマーもしくはエナンチオマーの混合物、またはその薬学的に許容される塩、溶媒和物、水和物、共結晶、包接化合物、もしくは多形体、(2)チェックポイント阻害剤、またはその薬学的に許容される塩もしくは溶媒和物、あるいは(3)これらの混合物を含む。別の実施形態において、医薬組成物及び製剤は、1つ以上の賦形剤を更に含む。
特定の実施形態において、本明細書で提供される経口投与に適した医薬組成物は、個別の剤形として製剤化され、その剤形の例としては、錠剤(例えば、チュアブル錠)、キャプレット、カプセル剤、及び液剤(例えば、風味をつけたシロップ剤)が挙げられるが、これらに限定されない。かかる製剤は、所定の量の活性成分を含有し、いくつかの周知の薬学的方法によって調製することができる。一般に、Remington’s Pharmaceutical Sciences,18th ed.,Mack Publishing,Easton PA(1990)を参照されたい。
特定の実施形態において、本明細書で提供される活性成分は、制御放出手段または送達デバイスによって投与される。例としては、限定するものではないが、米国特許第3,845,770号、同第3,916,899号、同第3,536,809号、同第3,598,123号、同第4,008,719号、同第5,674,533号、同第5,059,595号、同第5,591,767号、同第5,120,548号、同第5,073,543号、同第5,639,476号、同第5,354,556号、及び同第5,733,566号に記載のものが挙げられ、これらの各特許は、その全体が参照により本明細書に援用される。特定の実施形態において、かかる製剤は、1つ以上の活性成分の徐放または制御放出を提供するために使用され、例えば、ヒドロキシプロピルメチルセルロース、他のポリマーマトリックス、ゲル、透過性膜、浸透圧系、多層コーティング、微小粒子、リポソーム、ミクロスフェア、またはこれらの組み合わせを使用して、様々な比率の所望の放出プロファイルを提供する。経口投与に好適な単一単位製剤が本明細書に包含され、限定するものではないが、制御放出に適合させた錠剤、カプセル剤、ジェルキャップ、及びキャプレットが含まれる。
非経口製剤は、限定するものではないが、皮下、静脈内(ボーラス注射を含む)、筋肉内、及び動脈内を含む、種々の経路によって患者に投与することができる。当該投与では、典型的に、汚染物質に対する患者の自然防御能を回避するために、好ましくは、非経口製剤を無菌にするか、患者への投与前に非経口製剤を滅菌することができる。非経口製剤の例には、容易に注射可能な溶液、薬学的に許容される注射用ビヒクル中に容易に溶解または懸濁可能な乾燥製品、容易に注射可能な懸濁液、及び乳濁液が挙げられるが、これらに限定されない。
本明細書で提供される局所及び粘膜用製剤には、スプレー剤、エアゾール剤、液剤、乳剤、懸濁剤、点眼薬もしくは他の点眼剤、または当業者に知られている他の形態が含まれるが、これらに限定されない。例えば、Remington’s Pharmaceutical Sciences,16th and 18th eds.,Mack Publishing,Easton PA(1980&1990);及びIntroduction to Pharmaceutical Dosage Forms,4th ed.,Lea&Febiger,Philadelphia(1985)を参照されたい。口腔内の粘膜組織を治療するのに好適な製剤は、含嗽剤または経口ゲル剤として製剤化することができる。
特定の実施形態において、本明細書で提供される化合物は、患者に対して、同時に、または同じ投与経路によって投与されない。したがって、医師が使用する場合に、患者に対する適切な量の活性成分の投与を容易にし得るキットが本明細書に包含される。
チェックポイント阻害剤と組み合わせた化合物Aの効果を同所性HCCモデルで調べた。6〜7週齢の雄のBALB/cまたはSCIDマウスの左肝葉の被膜下領域に、マウス肝臓がん細胞株(BNL−1MEA)の細胞を約2×105個注入することによって、同所性HCCモデルを確立した。
薬物処置の72時間後に、MTT(3−(4,5−ジメチルチアゾール−2−イル)−2,5ジフェニルテトラゾリウムブロミド)アッセイにより細胞生存率を測定し、フローサイトメトリー(sub−G1フラクション分析)によりアポトーシスの程度を測定する。
腫瘍移植から6日後、マウスを異なる処置群に無作為化した。化合物A単独、チェックポイント阻害剤単独、及びチェックポイント阻害剤と組み合わせた化合物Aによる処置から22日後に、次式:体積[mm3]=[幅]2×長さ×0.5を使用して、腫瘍体積を測定した。
薬物処置終了時に、ホルマリン固定パラフィン包理腫瘍試料を採取する。腫瘍アポトーシス(TUNELアッセイ、DeadEnd Fluorometric TUNEL System)及び腫瘍血管新生(CD31免疫組織化学染色)の分析のために、5μm厚の切片スライドを準備する。
腫瘍組織を小片に切断した後、これを、コラゲナーゼI型(0.05mg/ml)、コラゲナーゼIV型(0.05mg/ml)、ヒアルロニダーゼ(0.025mg/ml)、DNase(0.01mg/ml)及び大豆トリプシン阻害剤(1mg/ml)(全てSigma−Aldrich製)を含有するHBSSとともに15分間インキュベーションした。TILについては、Ficoll−Paque密度勾配を使用して回収し、フローサイトメトリーによるリンパ球サブ集団分析を行った(FACScan Caliber(Becton Dickinson);データはCELLQest Pro Software(BD Biosciences Pharmingen)を使用して処理した)。マウスCD3(クローン145−2C11)、CD4(クローンGK1.5)、CD8(クローン53−6.7)、またはPan−NK(クローンDX5)(BD Biosciences Pharmingen)を認識する特異的抗体での二重染色によって、CD4+T細胞、CD8+T細胞、NK細胞、またはNKT細胞を決定した。
乳酸脱水素酵素(LDH)アッセイ(Promega)が使用される。2x104個のYAC−1細胞をエフェクター細胞とともに、0.1、1及び10のエフェクター細胞/標的細胞比で、37℃、5%CO2で、195分間インキュベートする。溶解された標的細胞が放出するLDHを比色計によって定量する(OD値490nm)。培地単独または2% Triton X−100との混合物のいずれか中で標的細胞をインキュベートして、LDHの自発的放出及び最大放出のそれぞれを決定する。次式:細胞傷害性率=[(実験によるLDH放出−エフェクター及び標的による自発的LDH放出)/(最大LDH放出−自発的LDH放出)]×100を用いて特異的溶解のパーセンテージを算出する。
化合物A及びチェックポイント阻害剤の抗腫瘍有効性における、細胞内の免疫エフェクター及びサイトカインの役割を評価するために、それぞれ抗CD8(クローン53−6.72)またはアイソタイプコントロール(クローン2A3またはHRPN)(全てBioXCell製(West Lebanon,NH))の腹腔内注射によって、CD8+T細胞の細胞を枯渇させる。抗体処置量は、腫瘍移植後、5日目に0.5mg、次いで、8、11、14、及び17日目に0.25mgとする。CD8+細胞の枯渇は、フローサイトメトリーにより確認する。
試験薬による処置から22日後のマウスから得たTIL及び血清試料由来の6つのサイトカイン(IL−2、IL−4、IL−10、IL−17、IFN−γ及びTNF−α)について、Procarta(登録商標)サイトカインアッセイPlexキット(Affymetrix,Inc.(Santa Clara,CA,USA))を製造者の説明書に従って使用して定量する。採取した試料は全て直ちに−70℃で保存し、試験まで保管しておく。その後、プレートをLuminex機器LABScan100(Luminex Corporation(Austin,USA))を使用して分析する。
化合物Aで処置した動物からの血液試料を、特定の時点(例えば、ベースライン、処置後0.5、2、4、8、及び24時間;1時点につきマウス2匹)で、直接心臓穿刺により採取する。試料を2〜8℃の温度、3,000rpmで、5分間遠心分離し、次いで、直ちに氷上に置く。等量のSorensen緩衝液を入れたラベル付きチューブに血漿のアリコート150μLを移し、よく混合する。
安定トランスフェクションのために、BNL−MEA1細胞にpCMV6−mPDL1−Myc−DDKベクター(MR203953;Origene Technologies(Rockville,MD))、pCMV6−mPDL2−Myc−DDKベクター(MR222499;Origene Technologies)または空ベクター(pCMV6ベクター;Origene Technologies(Rockville,MD))を、製造者の説明書に従って最適化したリポフェクタミン2000トランスフェクション試薬(Invitrogen(Carlsbad,CA,USA))を使用して、トランスフェクトした。
化合物Aと抗CTLA−4抗体(Bristol−Myers Squibb)との組み合わせによる抗腫瘍効果を同所性肝臓がんモデルで試験した。その結果を図1に示す。化合物Aは、腫瘍体積の点で、抗CTLA−4処置との有意性のある相乗的な抗腫瘍有効性を示した。
例示的な一試験において、化合物AでPBMC細胞を1時間前処理し、次いで、SEB/CPIを5日間添加し、5日目にIL−2のELISAを行った。その結果について、図2A(ニボルマブと組み合わせた化合物A)、図2B(BioLegendから市販されている代用の抗PD−1抗体と組み合わせた化合物A)、及び図2C(BioLegendから市販されている代用の抗PD−L1抗体と組み合わせた化合物A)に示す。チェックポイント阻害剤と組み合わせた化合物Aは、in vitroで、IL−2分泌を相乗的に高め、T細胞を活性化する。
例示的な一試験において、Easy Sepキット(StemCell Technologies)を使用して軟膜から単球を単離し、10%FBS、IL−4、及びGM−CSFを添加したRPMI中で7日間培養した。7日目に、Easy Sepキット(StemCell Technologies)を使用してロイコパックからCD4+T細胞を単離し、単球由来DC(MDC)と10:1の比を用いて共培養した。分泌されたIL−2を48時間の時点でELISAにより定量し、IFNγを5日目に測定した。実験全体を通して、表面マーカー発現は、フローサイトメトリーで決定した。結果を図3A(IL−2、10nMの化合物A)、図3B(IL−2、100nMの化合物A)、及び図4A(IFNγ、100nM)に示す。ニボルマブと組み合わせた化合物Aは、混合リンパ球反応において、IL−2及びIFNγ分泌を増大させた。
化合物Aとニボルマブの組み合わせから生じる免疫活性化について更に調査するために、NK、NKT、CD4+及びCD8+T細胞を含む免疫細胞サブセットの増殖を調べた。健康な志願者から得たPBMCをCellTrace Violet(Thermo Fisher)標識し、これを化合物A及びニボルマブの組み合わせまたは単剤で処理し、可溶性抗CD3/CD28(Stem Cell Technologies)により6日間刺激した。細胞を回収し、フローサイトメトリーを実施してCD3、CD4、CD8、及びCD56(BD Biosciences)の表面発現についてアッセイした。死細胞は、生/死固定可能染色(ThermoFisher Scientific)により除外した。フローサイトメトリーの前に、CountBrightビーズ(Thermo Fisher Scientific)を添加して、細胞絶対数の変化を調べた。
HCC腫瘍細胞の免疫媒介性殺傷に対する化合物A+チェックポイント遮断の効果を本試験で評価する。健康な志願者から得たPBMCを10pg/mlのSEBで5日間刺激した。標的細胞(JHH4、PD−L1陽性HCC細胞株)をCFSE(ThermoFisher Scientific)で標識した後、化合物A単独または免疫チェックポイント分子との併用で処理したSEB刺激PBMCと共培養した。共培養から4時間後、細胞を洗浄し、アネキシンV/ToPro−3(ThermoFisher Scientific)で染色した後、フローサイトメトリーでHCC細胞のアポトーシスを解析した。
免疫シナプスバイオアッセイを使用して、化合物A処理後のT細胞と標的CLL腫瘍細胞との相互作用を調べた(腫瘍微小環境(TME)における抗腫瘍T細胞応答モデリング)。免疫シナプスにおける共シグナル伝達複合体の発現を測定した。
再発性/難治性リンパ腫または白血病の被験者における、化合物A及びチェックポイント阻害剤を含む併用療法の有効性、安全性、及び忍容性を評価するための第1/2相オープンラベル多施設試験を実施する。
・有害事象アセスメント/特に関心のある有害事象(SPMを含む)
・併用薬/併用処置の評価
・リンパ節、脾臓及び肝臓の評価を含む身体検査を行う。リンパ節、脾臓及び/または肝臓の肥大に関する記録は、原資料及びCRFに記載されるものとする。
・体重を測定する。
・体表面積(リツキシマブまたはベンダムスチンの施設での実施につき必要に応じて)
・バイタルサインには、血圧、脈拍、及び体温が含まれる。
・ECOGパフォーマンスステータスのスコアを付ける。
・有害事象アセスメント/特に関心のある有害事象(SPMを含む)
・併用薬/併用処置の評価
・リンパ節、脾臓及び肝臓の評価を含む身体検査を行う。リンパ節、脾臓及び/または肝臓の肥大に関する記録は、原資料及びCRFに記載されるものとする。
・体重を測定する。
・バイタルサインには、血圧、脈拍、及び体温が含まれる。
・ECOGパフォーマンスステータスのスコアを付ける。
・12誘導心電図を記録する。
・サイクル1〜13(すなわち、12ヶ月)の1日目におけるデュルバルマブ(IV)注入;
・低悪性度NHL(すなわち、FLまたはMZL)の場合、サイクル1〜13、または中悪性度NHL(例えば、DLBCL)の場合、増悪、容認できない毒性、もしくは何らかの他の理由による中止までにおける1日目〜21日目(21日目を含む)の1日1回の化合物A(PO);ならびに
・サイクル1の2、8、15及び22日目及びサイクル2〜5の1日目におけるリツキシマブ(IV)注入
表1:用量決定:A群の用量レベル
切除不能肝細胞癌(HCC)の被験者における、ニボルマブと組み合わせた化合物Aの安全性、忍容性、及び予備的な有効性を評価するための第1/2相多施設オープンラベル用量決定試験を実施する。
Claims (71)
- 血液がんを治療、予防、または管理する方法である、請求項1に記載の方法。
- 前記血液がんが、骨髄腫、リンパ腫、または白血病である、請求項2に記載の方法。
- 前記血液がんが多発性骨髄腫(MM)である、請求項2に記載の方法。
- 前記多発性骨髄腫が、再発性もしくは難治性多発性骨髄腫、くすぶり型多発性骨髄腫、または新たに診断された多発性骨髄腫である、請求項4に記載の方法。
- 前記血液がんが、急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、成人T細胞白血病、慢性リンパ性白血病(CLL)、毛様細胞性白血病、脊髄形成異常、骨髄増殖性疾患、慢性骨髄性白血病(CML)、骨髄異形成症候群(MDS)、ヒトリンパ好性ウイルス1型(HTLV−1)白血病、肥満細胞症、またはB細胞急性リンパ芽球性白血病である、請求項2に記載の方法。
- 前記血液がんがCLLである、請求項6に記載の方法。
- 前記血液がんがAMLである、請求項6に記載の方法。
- 前記血液がんがALLである、請求項6に記載の方法。
- 前記血液がんがMDSである、請求項6に記載の方法。
- 前記血液がんが、びまん性大細胞型B細胞リンパ腫(DLBCL)、B細胞免疫芽球性リンパ腫、小非切れ込み核細胞型リンパ腫、ヒトリンパ好性ウイルス1型(HTLV−1)白血病/リンパ腫、成人T細胞リンパ腫、マントル細胞リンパ腫(MCL)、ホジキンリンパ腫(HL)、非ホジキンリンパ腫(NHL)、AIDS関連リンパ腫、濾胞性リンパ腫、小リンパ球性リンパ腫、T細胞/組織球豊富型大細胞型B細胞リンパ腫、形質転換リンパ腫、縦隔原発大細胞型B細胞リンパ腫(PMBCL)、脾辺縁帯リンパ腫、リヒター形質転換、原発性中枢神経リンパ腫(PCNSL)、皮膚T細胞リンパ腫(CTCL)、末梢性T細胞リンパ腫(PTCL)、NK/T細胞リンパ腫、ワルデンストレームマクログロブリン血症(WM)、形質細胞腫、皮膚B細胞リンパ腫(CBCL)、節性辺縁帯リンパ腫、またはALK陽性大細胞型B細胞リンパ腫である、請求項2に記載の方法。
- 前記血液がんがNHLである、請求項11に記載の方法。
- 固形腫瘍を治療、予防、または管理する方法である、請求項1に記載の方法。
- 前記固形腫瘍が肉腫である、請求項13に記載の方法。
- 前記固形腫瘍が、肝臓がん、膵臓がん、腎細胞がん、肺がん、皮膚がん、甲状腺がん、脳腫瘍、大腸がん、膀胱がん、乳がん、卵巣がん、または頭部もしくは頸部がんである、請求項13に記載の方法。
- 前記固形腫瘍が、神経膠腫、膠芽腫、原発性腺管癌、肺癌、結腸腺癌、大腸癌、肝細胞癌、結腸直腸腺癌、アミロイド症、神経内分泌腫瘍、カポジ肉腫、非小細胞肺がん、小細胞肺がん、黒色腫、軟部組織肉腫または強皮症である、請求項13に記載の方法。
- 前記固形腫瘍がHCCである、請求項13に記載の方法。
- 前記HCCが切除不能HCCである、請求項17に記載の方法。
- 前記血液がんまたは固形腫瘍が、新たに診断されたもの、再発性、難治性、または再発・難治性である、請求項1〜18のいずれか一項に記載の方法。
- 前記患者が、前記血液がんまたは固形腫瘍に対するいかなる療法も過去に受けたことがない、請求項1〜19のいずれか一項に記載の方法。
- 前記患者が、前記血液がんまたは固形腫瘍に対する療法を過去に1、2、または3つ以上受けたことがある、請求項1〜19のいずれか一項に記載の方法。
- 前記患者が、1、2、または3つ以上の過去の療法に対して進行または不耐性を示している、請求項21に記載の方法。
- 前記患者が、過去の療法を受けた後に、微少残存病変(MRD)を有している、請求項1〜22のいずれか一項に記載の方法。
- 前記患者の前記微少残存病変のレベルが、参照レベルより高い、請求項23に記載の方法。
- 前記患者の前記微少残存病変のレベルが、1000細胞中1よりも高い、請求項23に記載の方法。
- 前記患者が、同種移植を受けたことがある、請求項1〜25のいずれか一項に記載の方法。
- 前記患者が、小児または若年成人の患者である、請求項1〜26のいずれか一項に記載の方法。
- 化合物Aが、1つのチェックポイント阻害剤と組み合わせて投与される、請求項1〜27のいずれか一項に記載の方法。
- 前記チェックポイント阻害剤がCTLA−4阻害剤である、請求項1〜28のいずれか一項に記載の方法。
- 前記CTLA−4阻害剤が抗CTLA−4抗体である、請求項29に記載の方法。
- 前記抗CTLA−4抗体がトレメリムマブまたはイピリムマブである、請求項30に記載の方法。
- 前記チェックポイント阻害剤がPD−1阻害剤である、請求項1〜28のいずれか一項に記載の方法。
- 前記PD−1阻害剤が抗PD−1抗体である、請求項32に記載の方法。
- 前記抗PD−1抗体がニボルマブ、ペンブロリズマブ、またはピジリズマブである、請求項33に記載の方法。
- 前記抗PD−1抗体がニボルマブである、請求項34に記載の方法。
- 前記チェックポイント阻害剤がPD−L1阻害剤である、請求項1〜28のいずれか一項に記載の方法。
- 前記PD−L1阻害剤が抗PD−L1抗体である、請求項36に記載の方法。
- 前記抗PD−L1抗体がMEDI4736またはMPDL3280Aである、請求項37に記載の方法。
- 化合物Aが、2つのチェックポイント阻害剤と組み合わせて投与される、請求項1〜27のいずれか一項に記載の方法。
- 化合物Aが、抗CTLA−4抗体、抗PD−1抗体、及び抗PD−L1抗体から独立して選択される2つのチェックポイント阻害剤と組み合わせて投与される、請求項39に記載の方法。
- 化合物Aが、抗CTLA−4抗体及び抗PD−1抗体と組み合わせて投与される、請求項39に記載の方法。
- 化合物Aが、抗CTLA−4抗体及び抗PD−L1抗体と組み合わせて投与される、請求項39に記載の方法。
- 前記抗CTLA−4抗体が、トレメリムマブまたはイピリムマブである、請求項40〜42のいずれか一項に記載の方法。
- 前記抗PD−1抗体が、ニボルマブ、ペンブロリズマブ、またはピジリズマブである、請求項40〜43のいずれか一項に記載の方法。
- 前記抗PD−L1抗体が、MEDI4736またはMPDL3280Aである、請求項40〜44のいずれか一項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、経口投与される、請求項1〜45のいずれか一項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約1mg〜約5mgの用量で投与される、請求項1〜46のいずれか一項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約1mgの用量で投与される、請求項47に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約2mgの用量で投与される、請求項47に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約3mgの用量で投与される、請求項47に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約4mgの用量で投与される、請求項47に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1日当たり約5mgの用量で投与される、請求項47に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、28日サイクルで、28日間連続して1日1回投与される、請求項1〜52のいずれか一項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、28日サイクルで、5日間連続して1日1回投与され、続く2日間は投与されない、請求項1〜52のいずれか一項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、28日サイクルで、21日間連続して1日1回投与され、続く7日間は投与されない、請求項1〜52のいずれか一項に記載の方法。
- 前記チェックポイント阻害剤がニボルマブである、請求項17または18に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1以上の7日サイクルで、5日間連続して1日1回投与され、続く2日間は投与されず、ニボルマブが、2週に1回投与される、請求項56に記載の方法。
- 化合物Aまたはその薬学的に許容される塩もしくは溶媒和物が、1以上の7日サイクルで、5日間連続して1日1回、約2mgの用量で投与され、続く2日間は投与されず、ニボルマブが、2週に1回、約3mgの用量で投与される、請求項57に記載の方法。
- 治療上または予防上有効な量の第2の薬剤を投与することを更に含み、前記第2の薬剤は、1)抗CD38抗体、2)抗CD19抗体、3)抗CD33抗体、4)抗CD20抗体、5)FLT−3阻害剤、もしくは6)メチル化抑制剤、またはこれらの組み合わせである、請求項1〜58のいずれか一項に記載の方法。
- 前記第2の薬剤が抗CD38抗体である、請求項59に記載の方法。
- 前記抗CD38抗体がイサツキシマブである、請求項60に記載の方法。
- 前記第2の薬剤が抗CD19抗体である、請求項59に記載の方法。
- 前記抗CD19抗体がブリナツモマブである、請求項62に記載の方法。
- 前記第2の薬剤が抗CD33抗体である、請求項59に記載の方法。
- 前記抗CD33抗体がSGN−CD33AまたはAMG330である、請求項64に記載の方法。
- 前記第2の薬剤が抗CD20抗体である、請求項59に記載の方法。
- 前記抗CD20抗体がリツキシマブである、請求項66に記載の方法。
- 前記第2の薬剤がFLT−3阻害剤である、請求項59に記載の方法。
- 前記FLT−3阻害剤がミドスタウリン、ギルテリチニブ、またはキザルチニブである、請求項68に記載の方法。
- 前記第2の薬剤がメチル化抑制剤である、請求項59に記載の方法。
- 前記メチル化抑制剤がSGI−110、アザシチジン、またはデシチビンである、請求項70に記載の方法。
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2016
- 2016-07-01 KR KR1020187002705A patent/KR20180023968A/ko unknown
- 2016-07-01 AU AU2016288246A patent/AU2016288246A1/en not_active Abandoned
- 2016-07-01 CA CA2991164A patent/CA2991164A1/en not_active Abandoned
- 2016-07-01 JP JP2017568243A patent/JP6727237B2/ja not_active Expired - Fee Related
- 2016-07-01 MX MX2018000216A patent/MX2018000216A/es unknown
- 2016-07-01 WO PCT/US2016/040718 patent/WO2017004532A1/en active Application Filing
- 2016-07-01 EP EP16739642.3A patent/EP3316888A1/en not_active Withdrawn
- 2016-07-01 BR BR112017028530A patent/BR112017028530A2/pt not_active Application Discontinuation
- 2016-07-01 EA EA201890199A patent/EA201890199A1/ru unknown
- 2016-07-01 US US15/741,130 patent/US10973822B2/en active Active
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JP2014508780A (ja) * | 2011-03-11 | 2014-04-10 | セルジーン コーポレイション | 免疫関連疾患及び炎症性疾患の治療における3−(5−アミノ−2−メチル−4−オキソキナゾリン−3(4h)−イル)ピペリジン−2,6−ジオンの使用 |
WO2014039960A1 (en) * | 2012-09-10 | 2014-03-13 | Celgene Corporation | Methods for the treatment of locally advanced breast cancer |
WO2014179661A1 (en) * | 2013-05-03 | 2014-11-06 | Celgene Corporation | Methods for treating cancer using combination therapy |
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US10973822B2 (en) | 2021-04-13 |
EP3316888A1 (en) | 2018-05-09 |
AU2016288246A1 (en) | 2018-02-01 |
JP6727237B2 (ja) | 2020-07-22 |
KR20180023968A (ko) | 2018-03-07 |
JP2020172502A (ja) | 2020-10-22 |
WO2017004532A1 (en) | 2017-01-05 |
MX2018000216A (es) | 2018-05-22 |
US20180193342A1 (en) | 2018-07-12 |
EA201890199A1 (ru) | 2018-06-29 |
CA2991164A1 (en) | 2017-01-05 |
BR112017028530A2 (pt) | 2018-08-28 |
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