CN117425495A - 用于治疗癌症的组合 - Google Patents
用于治疗癌症的组合 Download PDFInfo
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- CN117425495A CN117425495A CN202280034693.9A CN202280034693A CN117425495A CN 117425495 A CN117425495 A CN 117425495A CN 202280034693 A CN202280034693 A CN 202280034693A CN 117425495 A CN117425495 A CN 117425495A
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本公开涉及用于治疗癌症的menin抑制剂和Bcl‑2抑制剂的组合,任选地进一步与低甲基化药物和/或FLT3抑制剂组合。具体来说,menin抑制剂联合维奈妥拉在治疗具有HOX基因标记的癌症(如急性髓性白血病)中具有协同作用。
Description
相关申请的交叉引用
本申请要求2021年5月12日提交的美国临时申请63/187,753的优先权,其全部内容通过引用并入本文。
技术领域
本公开涉及用包括menin抑制剂和Bcl-2抑制剂的组合治疗癌症的方法。
背景技术
核磷蛋白(NPM1),编码一种主要为核仁定位的多功能蛋白,是成人急性髓性白血病(AML)中最常见的突变基因(约30%)。NPM1突变导致其胞质定位异常(NPM1c)。在NPM1突变的AML中,混合谱系白血病(MLL1)与menin的相互作用与menin的MLL重排(MLL1-r)具有共同的HOX基因特征和依赖性。对menin的抑制作用已在NPM1c和MLL-rAML中显示出抗白血病活性。AML中的NPM1突变常发生于伴有其他突变的患者,如FLT3-ITD和FLT3酪氨酸激酶结构域(TKD)突变。在MLL-r/FLT3-和NPM1c/FLT3-突变AML中,menin和FLT 3联合抑制显示出增强的抗白血病活性。
靶向B细胞淋巴瘤2(Bcl-2)是AML细胞和AML干/祖细胞存活的关键因素,已成为AML患者有前途的治疗选择。然而,尽管将Bcl-2抑制剂维奈妥拉(venetoclax)与低甲基化药物联用有了显著改善,但大多数患者仍产生耐药性并最终复发。本公开解决了这些未满足的临床需求。
发明内容
在一些方面,本公开涉及在有此需要的受试者中用HOX基因标记治疗癌症的方法,该方法包括向受试者施用menin抑制剂和Bcl-2抑制剂的协同组合。在一些方面,本公开涉及在有此需要的受试者中用HOX基因标记治疗癌症的方法,该方法包括向受试者施用有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的协同组合。该方法任选地还包括施用CYP3A抑制剂、FLT3抑制剂、低甲基化药物或其组合。
在一些方面,本公开涉及包含menin抑制剂和Bcl-2抑制剂的治疗组合。所述组合任选包含CYP3A抑制剂、FLT3抑制剂、低甲基化药物或其组合。
在一些方面,本公开涉及包含有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的治疗组合。所述组合任选包含CYP3A抑制剂、FLT3抑制剂、低甲基化药物或其组合。
附图说明
图1A-1H:图1A为小鼠模型及治疗实验方案;图1B-E:2周(图1B)和4周(图1C)以及治疗结束时外周血中通过流式细胞术测定的骨髓(BM)(图1D)和脾(图1E)中hucd 45+百分比;图1F:治疗结束时脾脏重量和大小;图1G:存活曲线;图1H:治疗结束时各治疗组小鼠BM、脾脏的H&E染色(放大40×)。SNDX(SNDX-50469),一种menin抑制剂,为化合物(I);VEN是维奈妥拉。
图2A-2F:图2A:各治疗组中的HuCD45+细胞;2B:白血病细胞和白血病干/祖细胞簇;图2C:各治疗组中存活的白血病细胞及白血病干/祖细胞百分比;图2D:各治疗组huCD45+细胞中的蛋白表达;图2E:各治疗组HuCD11b+CD45+细胞百分比;图2F:各治疗组CD34+CD38+和CD34+CD38-白血病干/祖细胞的蛋白水平。在治疗结束时从小鼠BM中收集细胞,并通过CyTOF分析测定蛋白水平。SNDX为化合物(I);VEN是维奈妥拉。
图3示出了治疗2周后小鼠血浆中的化合物(I)水平。SNDX为化合物(I);VEN是维奈妥拉。
图4示出了小鼠的体重。SNDX为化合物(I);VEN是维奈妥拉。
图5示出了用于通过飞行时间(CyTOF)分析进行细胞计数的金属标记抗体。
图6A-G显示,在NPM1c/FLT3-ITD/TKD PDX模型中,menin、BCL-2和FLT 3的组合抑制具有很强的抗白血病活性并延长了生存期。(6A)实验计划。(B-E)通过流式细胞术测定的第2周(6B)和第4周(6C)外周血以及治疗结束时脾脏(6D)和BM(6E)中的HuCD45+细胞百分比。治疗结束时得到的脾脏也显示在(6D)中。(6F)按治疗类型分类的生存期。使用Kaplan-Meier法估计小鼠生存期,并使用对数秩检验分析生存期数据。(6G)HuCD45免疫组织化学染色。左图,携带PDX的NSG小鼠(阳性对照)和未携带PDX的NSG小鼠(阴性对照)的BM细胞中HuCD45的免疫组织化学染色。右图,在接受4-药物组合治疗的小鼠的肺、肝和心脏组织中对HuCD45进行免疫组织化学染色(在[F]中标记为*)。使用学生t检验确定组间差异。p值≤0.05被视为具有统计学意义。*P≤0.05;**P≤0.01;***P≤0.001;****P≤0.0001。d,天;wk,周;PB,外周血;SNDX,SNDX-50469;Gil,吉瑞替尼(gilteritinib);VEN,维奈妥拉;5-AZA,5-氮杂胞苷。
图7A-D显示menin、FLT3和/或BCL-2抑制作用靶向白血病细胞和干/祖细胞,并调节BM中的HOX靶点和BCL-2蛋白水平。PhenoGraph用于根据细胞表面标记表达对细胞群进行聚类。使用FlowJo软件(版本10.7,FlowJo LLC)对顺铂-低活度单细胞进行门控,并作为流式细胞术标准(FCS)数据导出,用于后续的Cytofkit分析。在FlowJo中对“Cytofkit_analyzedFCS”文件中通过PhenoGraph鉴定并嵌入的细胞群进行门控,以量化标记表达。使用热图对所需细胞群中每种蛋白表达的ArcSinh转化计数进行可视化。(7A)白血病细胞、白血病干/祖细胞簇。(7B)各治疗组中存活的白血病细胞和白血病干/祖细胞的百分比。(7C)各治疗组HuCD45细胞。(7D)各治疗组huCD45+细胞的蛋白表达。CON,对照;SNDX,SNDX-50469;Gil,吉瑞替尼;VEN,维奈妥拉。
具体实施方式
本文提供了治疗组合和组合物,包含menin抑制剂和Bcl-2抑制剂,任选地还包含FLT3抑制剂、低甲基化药物或其组合。还提供了施用这种组合和组合物的方法,用于治疗癌症,特别是具有HOX基因标记的癌症。
在一个方面,包含menin抑制剂和Bcl-2抑制剂的治疗组合和组合物还包含低甲基化药物。如本文所示,在menin抑制剂和Bcl-2抑制剂中加入低甲基化药物5-氮杂胞苷延长了生存期,这种组合在现有技术中接受的小鼠模型中潜在地消除了白血病。
在另一个方面,在组合和组合物中进一步添加FLT3抑制剂如吉瑞替尼,进一步延长了在现有技术中接受的AML小鼠模型中的存活时间。
除非另有定义,本文使用的所有技术和科学术语具有与所要求保护的主题所属领域的技术人员通常理解的相同的含义。应当理解,以下详细描述仅是示例性和解释性的,并不限制任何要求保护的主题。在本申请中,除非另有特别说明,单数的使用包括复数。必须注意的是,如在说明书和所附权利要求书中所使用的,单数形式“一个”、“一个”和“该”包括复数指代物,除非上下文另有明确说明。在本申请中,“或”的使用表示“和/或”,除非另有说明。
此外,术语“包括(including)”以及诸如“包括(include)”、“包括(includes)”和“包括(included)”之类的其他形式的使用不具有限制性。
此处使用的章节标题仅用于组织加构目的,不应理解为对所述主题的限制。本申请中引用的所有文件或文件的一部分,包括但不限于专利、专利申请、文章、书籍、手册和论文,均在此明确全文引入作为参考,以用于任何目的。
治疗组合
在一个方面,本文提供了包含menin抑制剂和Bcl-2抑制剂的治疗组合,任选地还包含FLT3抑制剂、低甲基化药物或其组合。menin抑制剂、Bcl-2抑制剂、FLT3抑制剂和低甲基化药物可存在于一种或多种药物组合物中。
Menin抑制剂包括5-氟-N,N-二异丙基-2-((4-(7-((反式-4-(甲基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)苯甲酰胺、N-乙基-2-((4-(7-((反式-4-(乙基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)-5-氟-N-异丙基苯甲酰胺、JNJ-75276617、KO-539、DS-1594b、DSP-5336,及其药学上可接受的盐,或其组合。
一种示例性的menin抑制剂是5-氟-N,N-二异丙基-2-((4-(7-((1r,4r)-4-(甲磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)苯甲酰胺(化合物I;SNDX-50469)或其药学上可接受的盐、立体异构体、几何异构体或互变异构体。另一种示例性的menin抑制剂是N-乙基-2-((4-(7-((1r,4r)-4-(乙基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬-2-基)嘧啶-5-基)氧基)-5-氟-N-异丙基苯甲酰胺(化合物II;SNDX-5613)或其药学上可接受的盐、立体异构体、几何异构体或互变异构体。在一些实施方案中,化合物(I)或化合物(II)的menin抑制剂包括立体异构体、几何异构体和/或互变异构体。在一些实施方案中,本文提供的治疗组合中使用的menin抑制剂选自化合物(I)和化合物(II):
或其药学上可接受的盐、立体异构体、几何异构体或互变异构体。
在一些实施方案中,化合物(I)或化合物(II)的药学上可接受的盐是双甲磺酸盐。在一些实施方案中,药物可接受的盐是双盐酸盐。在一些实施方案中,药学上可接受的盐是倍半富马酸盐。
在一些实施方案中,化合物(I)或化合物(II)的menin抑制剂可以以276mg/天(不含强CYP3A4抑制剂)和163mg/天(含强CYP3A4抑制剂)的剂量给药。化合物(I)或化合物(II)的menin抑制剂可以每天给药一次或两次。
本领域已知的其他menin抑制剂包括JNJ-75276617、KO-539、BMF-219、DSP-5336、ISC-30、抗体A300-105A(可从Bethyl Laboratories购得)、MI-0202、MI-503、MI-463、MI-136、ML-227和DS-1594。美国专利11,220,517、10,174,041、10,752,639和11,236,106;美国专利申请公开号US2021/0115018、US 2019/0307750、US2016/0339035,以及PCT申请公开号WO 2017/112768、WO 2017/214367、WO 2018/053267、WO 2020/069027、WO 2021/207335中描述了menin抑制剂,其通过引用并入本文以公开menin抑制剂。
多种药学上可接受的盐可由menin抑制剂形成,包括:通过menin抑制剂与有机酸反应形成的酸加成盐,所述有机酸包括脂族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳族酸、脂族和芳族磺酸、氨基酸等,并且包括例如乙酸、三氟乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等;通过使menin抑制剂与无机酸反应形成的酸加成盐,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、磷酸、氢碘酸、氢氟酸、亚磷酸等。
涉及menin抑制剂的术语“药学上可接受的盐”是指menin抑制剂的盐,其不会对施用它的哺乳动物造成显著的刺激,并且基本上不会消除该化合物的生物活性和性质。
本文还包括化合物(I)和化合物(II)的溶剂化物。溶剂化物包含化学计量或非化学计量的溶剂,并且在产物形成或用药学上可接受的溶剂分离的过程中形成,所述溶剂例如水、乙醇、甲醇、甲基叔丁基醚(MTBE)、二异丙基醚(DIPE)、乙酸乙酯、乙酸异丙酯、异丙醇、甲基异丁基酮(MIBK)、甲基乙基酮(MEK)、丙酮、硝基甲烷、四氢呋喃(THF)、二氯甲烷(DCM)、二恶烷、庚烷、甲苯、茴香醚、乙腈等。当溶剂为水时会形成水合物,或当溶剂为醇时会形成醇盐。
在其它实施方案中,所述menin抑制剂或其药学上可接受的盐以各种形式制备,包括但不限于无定形相、结晶形式、研磨形式和纳米颗粒形式。在一些实施方案中,menin抑制剂或其药学可接受的盐是无定形的。在一些实施方案中,menin抑制剂或其药学上可接受的盐是无定形且无水的。在一些实施方案中,menin抑制剂或其药学上可接受的盐是结晶的。在一些实施方案中,menin抑制剂或其药学上可接受的盐是结晶且无水的。
本文所述的协同组合包括menin抑制剂和Bcl-2抑制剂。示例性的Bcl-2抑制剂包括维奈妥拉、纳维托克(navitoclax)、奥巴克拉(obatoclax)、亚托曲塞(subatoclax)、马利曲塞(maritoclax)、S64315、奥利默森(oblimersen),或靶向抗凋亡Bcl-2家族蛋白的其他药物,及其组合。在一些实施方案中,Bcl-2抑制剂为维奈妥拉。
在一些实施方案中,menin抑制剂和Bcl-2抑制剂的组合协同作用于癌症,特别是具有HOX基因标记的癌症。例如,与单独使用menin抑制剂或Bcl-2抑制剂相比,联合使用menin抑制剂和Bcl-2抑制剂可能会在更大程度上减少受试者血液、脾脏和/或骨髓中的白血病细胞数量。在一些实施方案中,单独的menin抑制剂或Bcl-2抑制剂并不会显著减少受试者的血液、脾和/或骨髓中白血病细胞的量,但是menin抑制剂和Bcl-2抑制剂的组合确实显著减少受试者的血液、脾和/或骨髓中白血病细胞的数量。在临床终点(例如,血液中白血病细胞的数目,或蛋白质的表达)的改变(例如,增加或减少)的情况下,“显著”是指临床相关的或统计上显著的改变(例如,至少5%的改变)。组织(例如,血液、脾脏或骨髓)中白血病细胞的数量可以通过例如使用流式细胞术测量所述组织中人CD45+细胞的数量来确定。在一些实施方案中,受试者是根据本文所述方法治疗的人类受试者。在一些实施方案中,受试者具有一种或多种AML突变(例如,NPM1c、FLT3-ITD和/或FLT3-TKD突变)。
menin抑制剂和Bcl-2抑制剂的组合还可以协同延长患有癌症,特别是具有HOX基因标记的癌症(例如,所述癌症具有一种或多种AML突变、NPM1c、FLT3-ITD和/或FLT3-TKD)的受试者的生存期。例如,与单独使用menin抑制剂或Bcl-2抑制剂相比,联合使用menin抑制剂和Bcl-2抑制剂可以更大程度地延长癌症患者(例如NPM1c、FLT3-ITD和/或FLT3-TKD)的生存期。在一些实施方案中,menin抑制剂或Bcl-2抑制剂单独使用不会显著延长具有一种或多种AML突变(例如NPM1c、FLT3-ITD和/或FLT3-TKD)的受试者的生存期,但是menin抑制剂和Bcl-2抑制剂的组合确实显著延长具有一种或多种AML突变(例如NPM1c、FLT3-ITD和/或FLT3-TKD)的受试者的生存期。
在一些实施方案中,menin抑制剂和Bcl-2抑制剂的组合协同增加受试者(例如受试者的CD34+CD38+细胞)中促凋亡蛋白(例如Bim)的表达。在一些实施方案中,menin抑制剂和Bcl-2抑制剂的组合协同降低受试者(例如,受试者的CD34+CD38+细胞)中抗凋亡蛋白(例如,Bcl-2和/或Bcl-xL)的表达。在一些实施方案中,menin抑制剂和Bcl-2抑制剂的组合协同降低受试者(例如,人CD45+细胞)中与对Bcl-2抑制剂治疗的抗性(例如,Bcl-2A1)相关的蛋白的表达。可使用本领域已知或本文所述的任何合适的方法测定蛋白质的表达,包括例如流式细胞术、免疫组织化学或蛋白质印迹(Western Blotting)。可分析蛋白质表达的合适样品包括但不限于血液、骨髓和脾脏。在一些实施方案中,受试者是根据本文所述方法治疗的人类受试者。在一些实施方案中,受试者患有具有一种或多种AML突变的癌症(例如,NPM1c,具有或不具有FLT3-ITD和/或TKD)。在一些实施方案中,在CD34+CD38+受试者中测量促凋亡蛋白的协同增加、抗凋亡蛋白的协同减少和/或与对Bcl-2抑制剂治疗的抗性相关的蛋白的协同减少。在一些实施方案中,与受试者的CD34+CD38-细胞相比,促凋亡蛋白的协同增加、抗凋亡蛋白的协同减少和/或与对Bcl-2抑制剂治疗的抗性相关的蛋白的协同减少在受试者的CD34+CD38+细胞中更明显。
在一些实施方案中,menin抑制剂和Bcl-2抑制剂的组合增强、增加或延长了menin抑制剂的治疗效果的效力或持续时间。
在一个方面,所述menin抑制剂和Bcl-2抑制剂的组合还包含低甲基化药物。示例性的低甲基化药物包括氮杂胞苷、地西他滨、瓜地西他滨(Guadecitabine)及其组合。低甲基化药物可与menin抑制剂和Bcl-2抑制剂同时或依次给药。
在一个方面,所述menin抑制剂和BCL-2抑制剂的组合还包含FLT3抑制剂。另一方面,所述menin抑制剂、Bcl-2抑制剂和低甲基化药物的组合还包含FLT3抑制剂。示例性FLT3抑制剂包括米哚妥林(midostaurin)、索拉非尼、舒尼替尼、来他替尼、坦度替尼、吉瑞替尼、奎扎替尼(quizartinib)、克雷诺拉尼(crenolanib)及其组合。
FLT3抑制剂可与menin抑制剂和BCL-2抑制剂同时或依次给药。
在一些实施方案中,向用本文提供的治疗组合治疗的受试者进一步施用细胞色素P4503A(CYP3A)抑制剂,例如CYP3A4抑制剂。细胞色素P450酶修饰多种底物。这些修饰包括羟基化、环氧化、芳香族氧化、杂原子氧化、N-和O-脱烷基化、醛氧化和脱氢。在一些实施方案中,menin抑制剂、Bcl-2抑制剂和CYP3A4抑制剂的组合协同作用以治疗癌症。
不希望受理论的束缚,据信CYP3A抑制剂(例如CYP3A4抑制剂)的给药会减慢menin抑制剂和/或Bcl-2抑制剂的代谢。因此,在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增加了menin抑制剂和/或Bcl-2抑制剂的血浆水平。在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增加了menin抑制剂和/或Bcl-2抑制剂的口服生物利用度。在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增加了menin抑制剂和/或Bcl-2抑制剂的Cmax。在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增加了menin抑制剂和/或Bcl-2抑制剂的AUC。在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增加了menin抑制剂和/或Bcl-2抑制剂的T1/2。
在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增强了menin抑制剂和/或Bcl-2抑制剂治疗多种疾病的功效。在一些实施方案中,CYP3A抑制剂(例如CYP3A4抑制剂)的给药增强、增加和/或延长了menin抑制剂的治疗效果和/或Bcl-2抑制剂的治疗效果的功效或持续时间。
在一些实施方案中,CYP3A抑制剂是CYP3A4抑制剂。在一些实施方案中,CYP3A抑制剂是CYP3A5抑制剂。在一些实施方案中,CYP3A抑制剂是CYP3A7抑制剂。
在一些实施方案中,当与CYP3A抑制剂(例如CYP3A4抑制剂)组合时,包含menin抑制剂和Bcl-2抑制剂的治疗组合在较低剂量下是治疗有效的。在一些实施方案中,包含menin抑制剂和Bcl-2抑制剂的治疗组合与CYP3A抑制剂(例如CYP3A4抑制剂)组合更有效。
在一些实施方案中,CYP3A4抑制剂是:抗心律失常药、抗组胺药、唑类抗真菌药、苯二氮卓类药物、钙通道阻滞剂、艾滋病毒抗病毒药物、HMG CoA还原酶抑制剂、大环内酯类抗生素、动力促进剂、蛋白酶抑制剂、或它们的任意组合。在一些实施方案中,CYP3A4抑制剂是:阿普唑仑、胺碘酮、氨氯地平、阿瑞吡坦、阿立哌唑、阿司咪唑、阿托伐他汀、博塞匹韦、丁螺环酮、氯霉素、氯苯那敏、西咪替丁、环丙沙星、西沙必利、克拉霉素、考比司他(cobicistat)(GS-9350)、考比司他(GS-9350)的类似物或衍生物、环孢霉素、地拉韦林、地西泮→3-OH、二乙基二硫代氨基甲酸酯、地尔硫卓、红霉素、非洛地平、氟康唑、氟伏沙明、孕二烯酮、格列卫、葡萄柚汁、氟哌啶醇、伊马替尼、茚地那韦、伊曲康唑、酮康唑、洛伐他汀、美沙酮、米贝拉地尔、咪达唑仑、米非司酮、奈法唑酮、奈非那韦、硝苯地平、尼索地平、尼群地平、诺氟沙星、诺氟西汀、匹莫齐特、奎宁、奎尼丁→3-OH、利托那韦、沙奎那韦、西地那非、辛伐他汀、杨桃、他克莫司(FK 506)、他莫昔芬、特拉匹韦、泰利霉素、曲唑酮、三唑仑、曲林霉素、维拉帕米、特拉匹韦、长春新碱、伏立康唑、或它们的任意组合。在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或考比司他的类似物或衍生物(GS-9350)。在一些实施方案中,CYP3A4抑制剂是酮康唑。在一些实施方案中,CYP3A4抑制剂是利托那韦。
在一些实施方案中,menin抑制剂是化合物(I),CYP3A4抑制剂是唑类抗真菌剂。在一些实施方案中,menin抑制剂是化合物(II),CYP3A4抑制剂是唑类抗真菌剂。
在一些实施方案中,menin抑制剂是化合物(I),CYP3A4抑制剂是泊沙康唑。在一些实施方案中,menin抑制剂是化合物(II),CYP3A4抑制剂是泊沙康唑。
在一些实施方案中,menin抑制剂与CYP3A4诱导剂联合给药。在一些实施方案中,CYP3A4诱导剂包括但不限于阿瓦西米贝、苯妥英、卡马西平、利福平、恩扎鲁胺和贯叶连翘(St John’s wort)中的一种或多种。
剂量和给药
本文提供的治疗组合的menin抑制剂和Bcl-2抑制剂可以以相同的组合物或以单独的组合物给药。
menin抑制剂和Bcl-2抑制剂可同时或依次给药。在一些实施方案中,menin抑制剂和Bcl-2抑制剂以时间上接近的方式给药。
menin抑制剂和Bcl-2抑制剂的给药频率可以相同,也可以不同。在一些实施方案中,第一次给予menin抑制剂和第一次给予Bcl-2抑制剂在时间上接近。
在一些实施方案中,“时间上接近”是指一种治疗剂的给药发生在另一种治疗剂给药之前或之后的时间段内,使得在一种治疗剂和另一种治疗剂之间(例如,在menin抑制剂和Bcl-2抑制剂之间)存在协同作用。“时间上接近”可根据各种因素而变化,包括但不限于施用治疗剂的受试者的年龄、性别、体重、遗传背景、医学状况、病史和治疗史;要治疗或改善的疾病或状况;要达到的治疗结果;治疗剂的剂量、给药频率和给药持续时间;治疗药物的药代动力学和药效学;和施用治疗剂的途径。在一些实施方案中,“时间上接近”表示在15分钟内、30分钟内、1小时内、2小时内、4小时内、6小时内、8小时内、12小时内、18小时内、24小时内、36小时内、2天内、3天内、4天内、5天内、6天内、1周内、2周内、3周内、4周内、6周内或8周内。在一些实施方案中,一种治疗剂的多次给药可以与另一种治疗剂的单次给药在时间上接近。在一些实施方案中,时间上接近可在治疗周期期间或在给药方案内改变。
在一些实施方案中,每天、每2天、每3天、每4天、每5天、每6天或每周施用所述menin抑制剂。在一些实施方案中,Bcl-2抑制剂每天、每2天、每3天、每4天、每5天、每6天或每周给药。在一些实施方案中,menin抑制剂每天施用一次以上,例如每4小时、每6小时或每12小时施用一次。
在一些实施方案中,menin抑制剂和Bcl-2抑制剂同时给药。在一些实施方案中,menin抑制剂和Bcl-2抑制剂同时给药、基本上同时给药或在相同的治疗方案内给药。
在一些实施方案中,menin抑制剂的日剂量为约150毫克至约200毫克、约200毫克至约250毫克、约250毫克至约300毫克、约300毫克至约350毫克、约350毫克至约400毫克、约400毫克至约450毫克之间、约450毫克至约500毫克之间、约500毫克至约550毫克、约550毫克至约600毫克、约600毫克至约650毫克、或约650毫克至约700毫克。
在一些实施方案中,menin抑制剂的日剂量为约226mg、452mg、113mg、326mg或552mg。
在一些实施方案中,一个剂量每天给药一次、每天给药两次、每天给药三次、每天给药四次以等于日剂量。在一些实施方案中,每12小时给予一次menin抑制剂。在一些实施方案中,menin抑制剂以113mg的单位剂量给药。在一些实施方案中,单位剂量每天给药一次、每天给药两次、每天给药三次、每天给药四次。在一些实施方案中,每天给予一个单位剂量、每天给予两个单位剂量、每天给予三个单位剂量、每天给予四个单位剂量。在一些实施方案中,每天给予两次两个单位剂量。
在一些实施方案中,给予的menin抑制剂的量为约150、160、170、180、190、200、210、220、230、240250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520530、540、550、560、570、580、590、600、610、620、630、640、650、670、680、690或700mg/天。在一些实施方案中,日剂量分为多次给药,并且每天给药一次、每天给药两次、每天给药三次、每天给药四次。在一些实施方案中,menin抑制剂每天一次、每天两次、每天三次给药。在一些实施方案中,menin抑制剂每天给药一次。在一些实施方案中,menin抑制剂每天给药两次。
在一些实施方案中,menin抑制剂以50mg QD、113mg QD、113mg q12h、163mg q12h、226mg q12h、276mg q12h、339mg q12h、452mg q12h或565mg q12h的剂量给药。在一些实施方案中,menin抑制剂为化合物I,以50mg QD、113mg QD、113mg q12h、163q12h、226mg q12h、276mg q12h、339mg q12h、452mg q12h或565mg q12h的剂量给药。在一些实施方案中,menin抑制剂是化合物II的化合物,以50mg QD、113mg QD、113mg q12h、163mg q12h、226mg q12h、276mg q12h、339mg q12h、452mg q12h或565mg q12h的剂量给药。在一些实施方案中,menin抑制剂是包含化合物II的药物制剂,并以50mg QD、113mg QD、113mg q12h、163mg q12h、226mg q12h、276mg q212h、339mg q12h、452mg q12h或565mg q12h的剂量给药。在一些实施方案中,menin抑制剂是包含化合物II的胶囊,并以50mg QD、113mg QD、113mg q12h、163mgq12h、226mg q12h、276mg q12h、339mg q12h、452mg q12h或565mg q12h的剂量给药。在具体的实施方案中,每12小时(q12h)给予一次menin抑制剂,剂量为113mg。在具体的实施方案中,每12小时(q12h)给予一次menin抑制剂,剂量为163mg。在具体的实施方案中,每12小时(q12h)给予一次menin抑制剂,剂量为276mg。
在一些实施方案中,Bcl-2抑制剂的日剂量为约10毫克至约20毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约20毫克至约30毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约30毫克至约40毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约40毫克至约50毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约50毫克至约60毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约60毫克至约70毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约70毫克至约80毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约80毫克至约90毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约90毫克至约100毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约100毫克至约150毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约150毫克至约200毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约200毫克至约250毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约250毫克至约300毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约300毫克至约350毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约350毫克至约400毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约400毫克至约450毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约450毫克至约500毫克。
在一些实施方案中,Bcl-2抑制剂的日剂量为约20mg。在一些实施方案中,Bcl-2抑制剂的日剂量为约50mg。在一些实施方案中,Bcl-2抑制剂的日剂量为约100毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约200毫克。在一些实施方案中,Bcl-2抑制剂的日剂量为约400毫克。
在一些实施方案中,Bcl-2抑制剂的日剂量为第一周20mg,第二周50mg,第三周100mg,第四周200mg,第五周及随后数周400mg。
在一些实施方案中,向用本文提供的治疗组合治疗的受试者进一步施用CYP3A抑制剂(例如,CYP3A4抑制剂)。任何合适的CYP3A4抑制剂日剂量均可用于本文公开的组合物、剂型和方法。例如,CYP3A4抑制剂的日剂量取决于CYP3A4抑制剂的浓度。较弱的CYP3A4抑制剂(如西咪替丁)比中等的CYP3A4抑制剂(如红霉素、葡萄柚汁、维拉帕米、地尔硫卓)需要更高的日剂量,中等的CYP3A4抑制剂比较强的CYP3A4抑制剂(如茚地那韦、奈夫马韦、利托那韦、克拉霉素、伊曲康唑、酮康唑、奈法唑酮)需要更高的日剂量。
menin抑制剂、Bcl-2抑制剂和CYP3A抑制剂(例如CYP3A4抑制剂)可以在相同的组合物中、在单独的组合物中、同时、依次、时间上接近、以相同的频率或以不同的频率给药。
在一些实施方案中,与包含menin抑制剂和Bcl-2抑制剂的治疗组合联合给药的CYP3A4抑制剂的日剂量为50mg/天至高达并包括1000mg/天。在一些实施方案中,每个剂量每天给药一次、每天给药两次、每天给药三次、每天给药四次。在一些实施方案中,CYP3A4的剂量取决于特定的CYP3A4抑制剂。在一些实施方案中,每种CYP3A4抑制剂的日剂量根据其他适应症的批准标签给药。在一些实施方案中,CYP3A4抑制剂的施用量为约40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、670、680、690或700mg/天。在一些实施方案中,每日剂量被分开并每日给予一次、每日给予两次、每日给予三次或每日给予四次。
在一些实施方案中,向用本文提供的治疗组合治疗的受试者进一步施用FLT3抑制剂。任何合适的FLT3抑制剂日剂量均可用于本文公开的组合物、剂型和方法。
menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(如CYP3A4抑制剂)和FLT3抑制剂可以在相同组合物或单独组合物中给药。
menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(如CYP3A4抑制剂)和FLT3抑制剂可同时或依次给药。在一些实施方案中,menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和FLT3抑制剂以时间上接近的方式给药。
menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(如CYP3A4抑制剂)和FLT3抑制剂的给药频率可以相同也可以不同。在一些实施方案中,第一次给予menin抑制剂、第一次给予Bcl-2抑制剂、第一次给予CYP3A抑制剂(例如CYP3A4抑制剂)和第一次给予FLT3抑制剂在时间上接近。
在一些实施方案中,与包含menin抑制剂、Bcl-2抑制剂和任选的CYP3A抑制剂(例如CYP3A4抑制剂)的治疗组合联合施用的FLT3抑制剂或低甲基化药物的日剂量为50mg/天至至多且包括1000mg/天。在一些实施方案中,每个剂量每天给药一次、每天给药两次、每天给药三次、每天给药四次。在一些实施方案中,FLT3抑制剂的剂量取决于具体的FLT3抑制剂。在一些实施方案中,低甲基化药物的剂量取决于特定的低甲基化药物。在一些实施方案中,每种FLT3抑制剂的日剂量根据其他适应症的批准标签进行给药。在一些实施方案中,FLT3抑制剂的施用量为约0、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390或400mg/天。在一些实施方案中,FLT3抑制剂和/或低甲基化药物每天给药一次、每天给药两次、每天给药三次、每天给药四次。
在一些实施方案中,menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和/或低甲基化药物和/或FLT3抑制剂每天一次(例如以单一剂型或以单独剂型)联合给药。在一些实施方案中,menin抑制剂每天给药两次,Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和/或低甲基化药物和/或FLT3抑制剂每天给药四次(例如以单一剂型或以单独剂型)。在一些实施方案中,menin抑制剂每天给药两次,Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和/或低甲基化药物和/或FLT3抑制剂每天给药两次(例如以单一剂型或以单独剂型)。在一些实施方案中,menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和/或低甲基化药物和/或FLT3抑制剂是维持治疗。在一些实施方案中,menin抑制剂是维持治疗。
在一些实施方案中,施用本文公开的组合物用于预防、治疗或维持治疗。在一些实施方案中,本文公开的组合物用于治疗应用。在一些实施方案中,本文公开的组合物作为维持治疗施用,例如对缓解期患者施用。
在患者状态没有改善的情况下,可以连续给予所述化合物;可选择地,给药的药物剂量可以增加一定的时间长度。药物增加的长度可以在2天和1年之间变化,仅作为示例包括2天、3天、4天、5天、6天、7天、10天、12天、15天、20天、28天、35天、50天、70天、100天、120天、150天、180天、200天、250天、280天、300天、320天、350天或365天。剂量增加可以为10%-200%,仅作为示例,包括10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、100%、105%、110%、115%、120%、125%、130%、135%、140%、145%、150%、155%、160%、165%、170%、175%、180%、185%、190%、195%或200%。
如果未发生患者症状的改善,则可根据症状增加剂量或给药频率或两者,使其达到疾病、病症或症状改善的水平。
在患者状态确实改善的情况下,可以暂时减少给药的药物剂量或暂时暂停一定的时间(即“药物假期”)。药物假期的长度可以在2天和1年之间变化,仅作为示例包括2天、3天、4天、5天、6天、7天、10天、12天、15天、20天、28天、35天、50天、70天、100天、120天、150天、180天、200天、250天、280天、300天、320天、350天或365天。在药物假期期间的剂量减少可以为10%-100%,仅作为示例,包括10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%。
一旦患者病情有所改善,如有必要,可给予维持剂量。随后,作为症状的函数,可以将给药的剂量或频率或两者都降低到保留疾病、病症或症状改善的水平。然而,一旦症状复发,患者可能需要长期间歇性治疗。
对应于这种量的给定药剂的量将根据诸如特定化合物、疾病的严重程度、需要治疗的受试者或宿主的身份(例如,体重)等因素而变化,但是仍然可以根据病例周围的特定情况以本领域已知的方式常规地确定,所述情况包括例如所施用的特定药剂、施用途径和所治疗的受试者或宿主。然而,通常用于成人治疗的剂量通常在0.02-5000毫克/天的范围内,或约1-1500毫克/天。所需剂量可以方便地以单个剂量或同时(或在短时间内)或以适当间隔施用的分开的剂量存在,例如以每天两个、三个、四个或更多子剂量。
上述范围仅是提示性的,因为与个体治疗方案相关的变量数量很大,偏离这些推荐值相当大的偏差并不少见。这种剂量可以根据许多变量改变,包括但不限于所用化合物的活性、待治疗的疾病或病症、给药方式、个体受试者的要求、待治疗的疾病或病症的严重程度以及从业者的判断。
本文所述的此类治疗方案的毒性和治疗效果可通过细胞培养物或实验动物中的标准药学方法测定,包括但不限于测定LD50(对50%的群体致死的剂量)和ED50(对50%的群体治疗有效的剂量)。毒性和治疗效果之间的剂量比即为治疗指数,可表示为LD50与ED50的比值。表现出高治疗指数的化合物是优选的。从细胞培养测定和动物研究中获得的数据可用于配制人类使用的剂量范围。此类化合物的剂量优选在包括ED50且毒性最小的循环浓度范围内。剂量可以在该范围内变化,这取决于所用的剂型和所用的给药途径。
药物组合物
在一个实施方案中,本文提供了一种药物组合物,包含menin抑制剂、Bcl-2抑制剂、任选的FLT3抑制剂、任选的低甲基化药物和任选的药学上可接受的载体。在一个实施方案中,本文提供了一种药物组合物,包含menin抑制剂和CYPR3A4抑制剂以及任选的药学上可接受的载体。在另一个实施方案中,本文提供了药物组合物,包含menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)、任选的FLT3抑制剂、任选的低甲基化药物和任选的药学上可接受的载体。本申请的药物组合物包含与一种或多种药学上可接受的载体一起配制的有效治疗量的本申请的化合物(例如,menin抑制剂、Bcl-2抑制剂、和/或CYP3A4抑制剂、和/或FLT3抑制剂、和/或低甲基化药物)。
可以通过混合、制粒或包衣方法以常规方式制备药物组合物,所述药物组合物包括游离形式或药学上可接受的盐形式的本文所述治疗组合的单独化合物以及至少一种药学上可接受的载体或稀释剂。
本文所述的药物组合物可以是适于精确剂量单次给药的单位剂型。在单位剂型中,制剂分为单位剂量,含有适量的一种或多种化合物。单位剂量可以是包含离散量的制剂的包装形式。非限制性实例为包装的片剂或胶囊,以及小瓶或安瓿中的粉剂。水性悬浮液组合物可以包装在单剂量的不可再封闭的容器中。
或者,可以使用多剂量的可重新封闭的容器,在这种情况下,通常在组合物中包括防腐剂。仅作为示例,用于肠外注射的制剂可以以单位剂量形式存在,所述单位剂量形式包括但不限于安瓿或多剂量容器,其中添加有防腐剂。
本申请的治疗组合可以作为药物组合物通过任何常规途径给药,特别是肠道给药,例如口服,例如以片剂或胶囊的形式,或非肠道给药,例如以可注射溶液或悬浮液的形式,或局部给药,例如以洗剂、凝胶、软膏或乳膏的形式,或以鼻或栓剂的形式。
例如,口服组合物可以是片剂或明胶胶囊,其包含活性成分以及a)稀释剂,例如乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁盐或钙盐和/或聚乙二醇;对于片剂还包含c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要,包含d)崩解剂,例如淀粉、琼脂、藻酸或其钠盐,或泡腾混合物;和/或e)吸收剂、着色剂、调味剂和甜味剂。注射用组合物可以是等渗水溶液或悬浮液,栓剂可以由脂肪乳剂或悬浮液制备。所述组合物可以是灭菌的和/或含有佐剂,例如防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、用于调节渗透压的盐和/或缓冲剂。此外,它们还可能含有其他有治疗价值的物质。
本申请的药物组合物可以口服、直肠、胃肠外、脑内、阴道内、腹膜内、局部(如通过粉剂、软膏或滴剂)、经颊或作为口服或鼻喷雾剂施用于人和其它动物。
如本文所用,术语“药学上可接受的载体”是指无毒的、惰性固体、半固体或液体填料、稀释剂、包封材料或任何类型的制剂助剂。可用作为药学上可接受的载体的材料的一些实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸或山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯聚氧丙烯嵌段聚合物、羊毛脂肪、糖如乳糖、葡萄糖和蔗糖;淀粉如玉米淀粉和马铃薯淀粉;纤维素及其衍生物如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉状黄蓍胶;麦芽;明胶;滑石;赋形剂如可可脂和栓剂蜡,油如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,例如丙二醇或聚乙二醇;酯如油酸乙酯和月桂酸乙酯,琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水、等渗盐水;林格氏溶液;乙醇和磷酸盐缓冲溶液,以及其它无毒的相容润滑剂如十二烷基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和加香剂、防腐剂和抗氧化剂也可以存在于组合物中,根据配制者的判断。
口服液体剂型可包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物之外,液体剂型可以含有本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯,以及它们的混合物。除惰性稀释剂外,口服组合物还可包括佐剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和加香剂。
可注射的制剂,例如无菌可注射的含水或含油悬浮液,可以根据已知技术使用合适的分散剂或润湿剂和悬浮剂来配制。无菌注射制剂也可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌注射溶液、悬浮液或乳液,例如作为在1,3-丁二醇中的溶液。可使用的可接受载体和溶剂包括水、林格氏溶液、U.S.P.和等张氯化钠溶液。此外,无菌固定油通常用作溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成甘油一酯或甘油二酯。此外,脂肪酸如油酸用于制备注射剂。
为了延长药物的作用,通常需要减慢皮下或肌内注射的药物的吸收。这可以通过使用水溶性差的结晶或无定形材料的液体悬浮液来实现。药物的吸收速率取决于其溶出速率,而溶出速率又可能取决于晶体大小和晶型。或者,通过将药物溶解或悬浮在油载体中来实现胃肠外给药药物形式的延迟吸收。
在一些实施方案中,本文进一步公开了包含所述menin抑制剂、Bcl-2抑制剂和/或CYP3A4抑制剂的剂型。在一些实施方案中,剂型是组合剂型。在一些实施方案中,剂型是固体口服剂型。在一些实施方案中,剂型是片剂、丸剂或胶囊。在一些实施方案中,剂型是控制释放剂型、延迟释放剂型、延长释放剂型、脉冲释放剂型、多颗粒剂型或混合的立即释放和控制释放制剂。在一些实施方案中,剂型包含控释包衣。在一些实施方案中,剂型包含控制menin抑制剂释放的第一控释包衣和控制CYP3A4抑制剂释放的第二控释包衣。
活性化合物也可以是具有一种或多种如上所述的赋形剂的微囊形式。片剂、糖衣丸、胶囊、丸剂和颗粒剂的固体剂型可以用包衣和壳如肠溶衣、控释包衣和药物配制领域熟知的其它包衣制备。在这种固体剂型中,活性化合物可以与至少一种惰性稀释剂如蔗糖、乳糖或淀粉混合。这种剂型还可以包括,如通常的实践,除惰性稀释剂之外的其它物质,例如压片润滑剂和其它压片助剂,如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,剂型还可以包含缓冲剂。
治疗方法
另一方面,本文提供了治疗受试者癌症的方法,所述方法包括施用本文所述的治疗组合。
如本文所用,术语“受试者”包括人和非人动物,以及细胞系、细胞培养物、组织和器官。在一些实施方案中,受试者是哺乳动物。哺乳动物可以是例如人或适当的非人哺乳动物,例如灵长类动物、小鼠、大鼠、狗、猫、牛、马、山羊、骆驼、绵羊或猪。受试者也可以是鸟或家禽。在一些实施方案中,受试者是人。
如本文所用,术语“有需要的受试者”是指患有疾病或具有增加的发展为该疾病风险的受试者。有需要的受试者可以是先前已被诊断或鉴定为患有本文所公开的疾病或病症的受试者。有需要的受试者也可以是患有本文公开的疾病或病症的受试者。或者,有需要的受试者可以是相对于一般人群而言发展为这种疾病或病症的风险增加的受试者(即,相对于一般人群而言倾向于发展为这种病症的受试者)。有需要的受试者可患有本文公开的难治性或抗性疾病或病症(即本文公开的对治疗无应答或尚未应答的疾病或病症)。受试者可能在治疗开始时出现耐药性,或在治疗过程中出现耐药性。在一些实施方案中,有需要的受试者接受了本文公开的用于疾病或病症的所有已知有效疗法并且失败。在一些实施方案中,有需要的受试者接受了至少一种先前的治疗。
如本文所用,术语“治疗(treating)”或“治疗(treat)”描述了为了对抗疾病、病症或症状而对患者的管理和护理,并且包括施用本公开的化合物或其药学上可接受的盐、多晶型物或溶剂化物,以减轻疾病、病症或症状的症候或并发症,或消除疾病、病症或症状。术语“治疗”还可以包括体外细胞或动物模型的治疗。应当理解,提及“治疗(treating)”或“治疗(treatment)”包括减轻病症的既定症状。
如本文所用,术语“预防(preventing)”、“预防(prevent)”或“保护免受”描述减少或消除此类疾病、病症或症状的症候或并发症的发作。
如本文所用,术语“有效治疗量”是指治疗、改善或预防所鉴定的疾病或病症,或表现出可检测的治疗或抑制作用的药剂的量。这种作用可以通过本领域已知的任何测定方法检测。受试者的精确有效量将取决于受试者的体重、体型和健康状况;病情的性质和程度;和选择用于给药的治疗剂或治疗剂的组合。对于给定情况的有效治疗量可以通过常规实验来确定,这在临床医生的技能和判断范围内。
如本文所用,术语“有效治疗量”是指治疗或改善所鉴定的疾病或病症,或表现出可检测的治疗或抑制作用的药剂的量。这种作用可以通过本领域已知的任何测定方法检测。受试者的精确有效量将取决于受试者的体重、体型和健康状况;病情的性质和程度;和选择用于给药的治疗剂或治疗剂的组合。对于给定情况的有效治疗量可以通过常规实验来确定,这在临床医生的技能和判断范围内。
应当理解,对于任何化合物,有效治疗量最初可以在细胞培养测定中估计,例如肿瘤细胞,或在动物模型中,通常是大鼠、小鼠、兔子、狗或猪。动物模型也可用于确定合适的浓度范围和给药途径。然后,此类信息可用于确定对人类给药有效的剂量和途径。治疗/预防功效和毒性可通过细胞培养物或实验动物中的标准药物程序测定,例如ED50(在50%人群中治疗有效的剂量)和LD50(对50%人群致死的剂量)。毒性和治疗效果的剂量比是治疗指标,可表示为比值LD50/ED50。优选表现出较大治疗指数的药物组合物。剂量可在该范围内变化,取决于所用剂型、患者的敏感性和给药途径。
调整剂量和给药以提供足够水平的活性药物或维持所需效果。可考虑的因素包括疾病状态的严重程度、受试者的一般健康状况、受试者的年龄、体重和性别、饮食、给药时间和频率、药物组合、反应敏感性以及对治疗的耐受性/应答。长效药物组合物可以每3-4天、每周或每两周给药一次,这取决于特定制剂的半衰期和清除率。
一种在有需要的受试者中用HOX基因标记治疗癌症的方法,包括向受试者施用有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的协同组合,以及任选地有效治疗量的低甲基化药物和/或FLT3抑制剂。如本文所用,HOX基因标记是其表达被改变的一组基因——由改变的HOX基因表达驱动,影响癌症的发生、发展、进展或其组合。HOX基因标记在本领域是众所周知的。在一些实施方案中,所述组合包含menin抑制剂、Bcl-2抑制剂、CYP3A抑制剂(例如CYP3A4抑制剂)和任选的有效治疗量的低甲基化药物和/或FLT3抑制剂。menin抑制剂和Bcl-2抑制剂以及任选的CYP3A4抑制剂的组合任选地还包含有效治疗量的低甲基化药物、有效治疗量的FLT3抑制剂或其组合。两种、三种、四种或五种药物组合可以同时或依次给药,并通过相同或不同的给药方式,例如口服、肠胃外等。
同源盒(HOX)转录因子是一个保守的转录因子家族。HOX基因的突变或激活会导致癌症风险增加,并影响癌症的发展和/或进展。HOX基因的改变在血管生成、自噬、分化、凋亡、增殖、侵袭、转移和代谢中起作用。HOX基因标记的癌症包括乳腺癌、多发性骨髓瘤、卵巢癌、肾癌、结肠癌、结肠直肠癌、前列腺癌、胃癌、非小细胞肺癌、胶质母细胞瘤、宫颈癌、软骨肉瘤、骨肉瘤、神经母细胞瘤和白血病等血液恶性肿瘤。
术语血液恶性肿瘤包括淋巴瘤(如非霍奇金淋巴瘤)、白血病(如AML)和多发性骨髓瘤。白血病包括AML、骨髓增生异常综合征(MDS)、骨髓增生性疾病、急性淋巴细胞白血病(ALL)、慢性粒细胞性白血病(CML)和慢性淋巴细胞白血病(CLL)。本文所述的组合和组合物特别适用于治疗血液恶性肿瘤。
可通过本文所述的组合治疗的示例性白血病和淋巴瘤包括与MLL重排或MLL基因重排相关的白血病、急性白血病、慢性白血病、惰性白血病、成淋巴细胞白血病、淋巴细胞白血病、髓细胞白血病、粒细胞性白血病、儿童白血病、ALL(也称为急性成淋巴细胞白血病或急性淋巴细胞白血病)、AML(也称为急性髓细胞白血病或急性成髓细胞白血病)、急性粒细胞白血病、急性非淋巴细胞白血病、CLL(也称为慢性成淋巴细胞白血病)、CML(也称为慢性粒细胞白血病)、治疗相关白血病、MDS病、骨髓增生性疾病(MPD)(如原发性骨髓纤维化(PMF))、骨髓增生性肿瘤(MPN)、浆细胞性肿瘤、多发性骨髓瘤、骨髓发育不良、皮肤T细胞淋巴瘤、核磷蛋白(NPM1)AML、淋巴肿瘤、艾滋病相关淋巴瘤、胸腺瘤、胸腺癌(thymiccarcinoma)、蕈样霉菌病、Alibert-Bazin综合征、蕈样肉芽肿、Sézary综合征、毛细胞白血病、T细胞前淋巴细胞白血病(T-PLL)、大颗粒淋巴细胞白血病、脑膜白血病、白血病性软脑膜炎、白血病性脑膜炎、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(恶性淋巴瘤)和Waldenstrom巨球蛋白血症,或由多个基因融合、重排或突变驱动的恶性肿瘤(Issam,G.C.等人,Therapeutic implications ofmenin inhibitors in acute leukemias,Leukemia2021,35,pp.2482-2495))。在一些实施方案中,AML是理论核磷蛋白(NPM 1)-突变AML(即NPM1mut急性髓性白血病)。
在特定实施方案中,本文所述的组合用于治疗与MLL重排相关的白血病、与MLL重排相关的急性淋巴细胞性白血病、与MLL重排相关的急性成淋巴细胞性白血病、与MLL重排相关的急性淋巴性白血病、与MLL重排相关的急性髓性白血病、与MLL重排相关的急性骨髓性白血病或与MLL重排相关的急性成髓性白血病。如本文所用,“MLL重排”是指MLL基因的重排。
急性白血病通常由造血干/祖细胞的获得性突变引起。染色体异常通常是白血病的离散突变特征。其中许多染色体异常是由于特定的易位导致形成融合基因,从而成为肿瘤发生和肿瘤发展的驱动力。一个具体的例子涉及MLL1基因。MLL1基因座(11q23)的易位可导致形成致癌基因融合,这是MLL-r急性白血病的特征。MLL1蛋白是发育的关键调节因子,是果蝇的哺乳动物同源物。是HOX基因表达的重要表观遗传调节因子。MLL1基因座的易位产生嵌合蛋白,该蛋白将MLL1的N末端与来自不同易位配偶体的可变C-末端结构域融合。目前,已知有90多种不同的融合配偶体。这些融合体的表达能够实现以HOX和其他发育基因的过表达为特征的异常转录程序。该转录程序可抑制分化并增强增殖,从而导致MLL-r型急性白血病。使用荧光原位杂交(FISH)常规诊断涉及MLL1基因座(11q23)的易位。根据祖细胞来源,MLL-r可在表型上表现为ALL、AML或混合表型急性白血病(MPAL)。这些易位很罕见,在美国(US)、欧洲和日本,MLL-r的合并年发病率约为4000例。约10%的白血病存在MLL1易位。
本组合还可用于治疗MLL/KMT2A基因重排的白血病患者。
常规化疗和干细胞移植后,MLL-r患者的复发风险较高,总体5年生存率仅为约35%。目前尚无专门针对MLL-r白血病的疗法。menin抑制剂(如化合物I或化合物II)与CYP3A4抑制剂联合用药可能为MLL-r急性白血病提供一种新的靶向治疗方法。
MLL1融合蛋白与menin的相互作用是MLL-r急性白血病的关键驱动因素。MLL1和MLL-r融合体均与染色质相关蛋白menin上一个特征明确的高亲和力位点结合。MLL1融合体与menin的结合由在MLL 1的N-末端发现的氨基酸残基9-13(FPARP)介导。与menin的结合使这些融合体定位于染色质,从而启动白血病转录程序,包括HOXA位点和MEIS1基因的上调。需要融合蛋白和menin之间的相互作用来维持该转录程序。
menin抑制剂化合物(I)和化合物(II)以高亲和力与menin上的MLL1结合囊结合,并在含有MLL-r融合体的一系列细胞中表现出活性。Menin抑制剂化合物(I)和化合物(II)破坏了menin与MLL1融合蛋白之间的相互作用(这是产生白血病活性所必需的),从而削弱关键癌基因的表达,引起生长停滞和抑制细胞增殖。已有关于menin-MLL相互作用的小分子抑制剂的报道。这些抑制剂已显示出对MLL-r细胞系的抗增殖活性,并在MLL-r白血病小鼠模型中显示出单剂存活益处。
同样,将menin抑制剂(如化合物(I)或化合物(II))II与CYP3A4抑制剂联合用药可提高疗效,并已在多种白血病异种移植模型中表现出稳健的活性,并在非临床模型中口服给药后提供了显著的存活益处。总体而言,这些数据表明,对menin-MLL相互作用的药理学抑制代表了治疗MLL-r急性白血病的潜在靶向策略。
在一个方面,白血病是突变的核磷蛋白1(NPM1)。
在一些实施方案中,本发明的组合涉及治疗NPM1突变的白血病,例如AML。NPM1基因编码一种主要为核仁定位的多功能蛋白,是成人AML中最常见的突变基因(约占病例的30%)。突变(NPM1c)导致其胞质定位异常。有趣的是,在NPM1cAML中,MLL1与menin的相互作用与MLL1-r与menin的相互作用具有共同的HOX基因特征和依赖性。事实上,抑制menin已在NPM1c和MLL-rAML中显示出抗白血病活性。AML中的NPM1突变常发生于携带其他突变(如FLT3)的患者。NPM1c与FLT3-ITD以及酪氨酸激酶结构域(TKD)突变共同促进AML的发生。在MLL-r/FLT3-和NPM1c/FLT3-突变AML中,menin和FLT 3联合抑制的抗白血病活性增强。
在一些实施方案中,本发明涉及在有需要的患者中治疗NPM1 AML,包括施用menin抑制剂和CYP3A4抑制剂。在一些进一步的实施方案中,本发明涉及在有需要的患者中治疗NPM1 AML,包括施用包含menin抑制剂的药物组合物和包含CYP3A4抑制剂的药物组合物。在一些进一步的实施方案中,本发明涉及在有需要的患者中治疗NPM1 AML,包括施用包含menin抑制剂(例如,化合物(I)或化合物(II))的药物组合物和包含唑类抗真菌CYP3A4抑制剂的药物组合物。
在另一个方面,具有或不具有MLL-r和具有或不具有NPM1突变的癌症也可以具有FLT3突变。例如,约三分之一的新诊断AML患者被诊断出FLT3突变。FLT3内部串联重复与复发增加和总体生存率差相关。
靶向Bcl-2(AML的一个关键生存因子)已成为AML患者一种有前途的治疗选择。然而,尽管通过联合使用Bcl-2抑制剂维奈妥拉与低甲基化药物,CR/CRi显著增加,但大多数患者产生耐药性,最终复发。由于Bcl-2是一种pan抗凋亡蛋白,其抑制作用降低了凋亡阈值,维奈妥拉已成为组合疗法的主流。
在一些实施方案中,根据本文所述方法治疗的受试者先前已用Bcl-2抑制剂治疗。在一些实施方案中,根据本文所述方法治疗的受试者先前已用Bcl-2抑制剂治疗并已产生对Bcl-2抑制剂的耐药性。在一些实施方案中,根据本文所述方法治疗的受试者先前已用Bcl-2抑制剂治疗癌症,且所述癌症在先前的Bcl-2抑制剂治疗中继续发展。
在一些实施方案中,根据本文所述方法治疗的受试者先前已经用维奈妥拉治疗。在一些实施方案中,根据本文所述方法治疗的受试者先前已用维奈妥拉治疗并已产生对维奈妥拉的抗性。在一些实施方案中,根据本文所述方法治疗的受试者先前已经用维奈妥拉治疗癌症,并且所述癌症在先前的维奈妥拉治疗中继续发展。
本文所述的治疗方法的疗效可以使用本领域已知的或本文所述的任何合适的方法来评价。在一些实施方案中,通过使用流式细胞术测量受试者的血液、脾脏或骨髓中的白血病细胞(例如,人CD45+细胞)的数目来评价本文所述的治疗方法的疗效。在一些实施方案中,本文所述的治疗方法的疗效通过确定受试者的脾的大小来评价。许多接受维奈妥拉/低甲基化药物治疗的患者最终进展或对基于维奈妥拉的治疗产生耐药性。然而,本发明人已经发现,具有获得性耐维奈妥拉抗性的MV4-11细胞(具有MLL-r和FLT3-ITD)对诸如化合物I的menin抑制剂敏感。
在一些实施方案中,本公开的组合表现出强的抗白血病活性和显著延长的生存期,而单独使用维奈妥拉具有最小的疗效。在一些实施方案中,menin抑制优先靶向CD34+CD38+细胞。在一些实施方案中,维奈妥拉靶向CD34+CD38-细胞。在一些实施方案中,menin和Bcl-2的联合抑制有效地消除了扩展和CD34+CD38+/CD34+CD38-干细胞/祖细胞。在一些实施方案中,联合给药增加了CD11b+髓系细胞群。在一些实施方案中,给予menin抑制剂和维奈妥拉的组合协同增加了CDb1111+髓系细胞群。在一个方面,有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的组合协同降低骨髓中的白血病CD34+CD38+/CD34+CD38-干细胞/祖细胞。
在一些实施方案中,通过测量受试者(例如受试者的CD34+CD38+细胞)中促凋亡蛋白(例如Bim)的表达来确定本文所述治疗方法的疗效。在一些实施方案中,本文所述治疗方法的疗效通过测量受试者(例如受试者的CD34+CD38+细胞)中抗凋亡蛋白(例如Bcl-2和/或Bcl-xL)的表达来确定。在一些实施方案中,本文所述的治疗方法的疗效通过测量受试者(例如,受试者的人CD45细胞)中与用Bcl-2抑制剂(例如,Bcl-2A1)治疗的抗性相关的蛋白的表达来确定。可使用本领域已知或本文所述的任何合适的方法测定蛋白质的表达,包括例如流式细胞术、免疫组织化学或Western Blotting。可分析蛋白质表达的合适样品包括但不限于血液、骨髓和脾脏。
在一些实施方案中,本文所述治疗方法的疗效通过在治疗后的合适时间点(例如,1个月、2个月、3个月、6个月、9个月、12个月、18个月、2年、3年、4年、5年、10年或15年)测量受试者的总生存期和/或无进展生存期来评估。
治疗癌症可以缩小肿瘤。肿瘤大小的减小也可称为“肿瘤消退”。优选地,在治疗后,肿瘤大小相对于治疗前的大小减小5%、10%、20%、30%、40%、50%或75%或更多。肿瘤大小可通过任何可重复的测量方法进行测量。肿瘤的大小可以测量为肿瘤的直径。
根据本文所述的方法治疗癌症可导致肿瘤体积减小。优选地,在治疗后,肿瘤体积减小5%、10%、20%、30%、40%、50%或75%或更多。肿瘤体积可通过任何可重复的测量方法进行测量。
根据本文所述的方法治疗癌症可导致肿瘤数量的减少。优选地,在治疗后,肿瘤数量减少5%、10%、20%、30%、40%、50%或75%或更多。肿瘤数量可通过任何可重复的测量方法进行测量。肿瘤的数量可以通过计数肉眼可见或在指定放大率下可见的肿瘤来测量。优选地,指定的放大率为2×、3×、4×、5×、10×或50×。
根据本文所述的方法治疗癌症可导致远离原发性肿瘤部位的其它组织或器官中的转移性病变的数目减少。优选地,治疗后,转移病灶的数量减少5%、10%、20%、30%、40%、50%或75%。可通过任何可重复的测量方法测量转移性病变的数量。可通过计数肉眼可见或在指定放大率下可见的转移病灶来测量转移病灶的数量。优选地,指定的放大率为2×、3×、4×、5×、10×或50×。
与单独接受载体的群体相比,根据本文所述的方法治疗癌症可导致治疗对象群体的平均存活时间延长。优选地,平均存活时间延长30天以上;更优选超过60天;更优选超过90天;最优选延长120天以上。可用任何可重复的方法测量群体平均存活时间的延长。群体平均存活时间的延长可以通过例如计算群体在开始用活性化合物治疗后的平均存活时间来测量。还可以测量群体平均存活时间的延长,例如,通过计算群体在用活性化合物完成第一轮治疗后的平均存活时间。
根据本文所述的方法治疗癌症可导致治疗对象群体与未治疗对象群体相比的平均存活时间延长。优选地,平均存活时间延长30天以上;更优选超过60天;更优选超过90天;最优选延长120天以上。可用任何可重复的方法测量群体平均存活时间的延长。群体平均存活时间的延长可以通过例如计算群体在开始用活性化合物治疗后的平均存活时间来测量。还可以测量群体平均存活时间的延长,例如,通过计算群体在用活性化合物完成第一轮治疗后的平均存活时间。
与接受非本发明化合物或其药学上可接受的盐、前药、代谢物、类似物或衍生物的药物的单一疗法的群体相比,根据本文所述的方法治疗癌症可导致治疗对象群体的平均存活时间延长。优选地,平均存活时间延长30天以上;更优选超过60天;更优选超过90天;最优选延长120天以上。可用任何可重复的方法测量群体平均存活时间的延长。群体平均存活时间的延长可以通过例如计算群体在开始用活性化合物治疗后的平均存活时间来测量。还可以测量群体平均存活时间的延长,例如,通过计算群体在用活性化合物完成第一轮治疗后的平均存活时间。
与单独接受载体的人群相比,根据本文所述的方法治疗癌症可导致治疗对象群体的死亡率降低。与未治疗人群相比,治疗癌症可导致治疗对象人群的死亡率降低。与接受非本发明化合物或其药学上可接受的盐、前药、代谢物、类似物或衍生物的药物的单一疗法的人群相比,根据本文所述的方法治疗癌症可导致治疗对象人群的死亡率降低。优选地,死亡率降低2%以上;更优选超过5%;更优选超过10%;最优选超过25%。可通过任何可重复的方法测量接受治疗的受试者群体的死亡率下降。例如,可以通过计算群体在开始用活性化合物治疗后每单位时间的疾病相关死亡的平均数来测量群体死亡率的降低。还可以测量群体死亡率的降低,例如,通过计算群体在用活性化合物完成第一轮治疗后每单位时间的疾病相关死亡的平均数。
根据本文所述的方法治疗癌症可导致肿瘤生长速率的降低。优选地,在治疗后,肿瘤生长速率降低至少5%、10%、20%、30%、40%、50%或75%。肿瘤生长速率可通过任何可重复的测量方法进行测量。肿瘤生长速率可以根据单位时间内肿瘤直径的变化来测量。
根据本文所述的方法治疗癌症可导致肿瘤再生长的减少。优选地,在治疗后,肿瘤再生长小于5%、10%、20%、30%、40%、50%或75%。肿瘤再生长可通过任何可重复的测量方法进行测量。例如,通过测量治疗后先前肿瘤缩小后肿瘤直径的增加来测量肿瘤再生长。肿瘤再生长的减少表现为治疗停止后肿瘤未能复发。
根据本文所述的方法治疗癌症或细胞增殖性病症可导致细胞死亡,并且优选地,细胞死亡导致群体中细胞数量减少至少10%。更优选地,细胞死亡是指减少至少10%、20%、30%、40%、50%或75%。可用任何可重复的方法测量群体中的细胞数量。通过荧光激活细胞分选(FACS)、免疫荧光显微镜和光学显微镜可以测量群体中的细胞数量。测量细胞死亡的方法见Li等人,ProcNatl AcadSci USA.100(5):2674-8,2003。在一个方面,细胞死亡是通过凋亡发生的。
本文提供的治疗组合可在疾病或癌症的治疗中产生协同效应。“协同效应”定义为治疗组合的药物组合(例如,menin抑制剂和Bcl-2抑制剂)的疗效大于单独给药的任何药物的疗效总和。协同效应也可以是以单一药剂形式给药任何药剂都无法实现的疗效。协同作用可以包括但不限于通过减小肿瘤大小、抑制肿瘤生长或增加受试者的存活率来治疗癌症的疗效。协同效应还可以包括降低癌细胞的生存力、诱导癌细胞死亡、以及抑制或延迟癌细胞生长。
如本文所提供的,用本文所提供的治疗组合的治疗导致协同抗增殖应答、协同诱导白血病细胞中的凋亡、协同诱导白血病细胞的分化和协同延长生长存期。
联合治疗
如本文所述,“联合治疗”还包括本文所述的治疗组合与其它生物活性成分和非药物治疗(例如手术或放射治疗)的进一步组合的施用。在联合治疗进一步包括非药物治疗的情况下,非药物治疗可以在任何合适的时间进行,只要获得治疗性联合治疗和非药物治疗的联合作用的有益效果即可。例如,在适当的情况下,当非药物治疗暂时从治疗组合的给药中去除时,可能通过数天或甚至数周,仍可实现有益效果。
在另一方面,本发明的治疗组合可以与放射治疗联合施用。放射治疗也可以与本发明的组合物和本文所述的另一种化疗剂联合给药,作为多药剂治疗的一部分。
在某些情况下,适当的是将本文提供的包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4抑制剂、低甲基化药物、FLT3抑制剂或其组合)的治疗组合与另外的治疗剂联合给药。
可根据其对所治疗疾病的特殊用途选择额外的治疗剂。一般而言,额外的治疗剂不需要以与本文提供的包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4抑制剂、低甲基化药物、FLT3抑制剂或两者)的治疗组合相同的药物组合、同时或经由相同的途径施用。在一些实施方案中,根据建立的方案进行额外的治疗剂的初始给药,然后基于观察到的效果,进一步改变剂量、给药方式和给药时间。
在一些实施方案中,根据疾病的性质、患者的状况和所用化合物的实际选择,同时(例如,同时,基本上同时或在相同的治疗方案内)或顺序施用额外的治疗剂。在某些实施方案中,在治疗方案期间每种治疗剂的施用顺序和重复施用次数的确定是基于对所治疗的疾病和患者状况的评估。
额外的治疗剂的剂量根据额外的治疗剂、所治疗的疾病或病症等而变化。
在一些实施方案中,额外的治疗剂是化疗剂、类固醇、免疫治疗剂、靶向治疗或其组合。在一些实施方案中,所述额外的治疗剂是CD79A抑制剂、CD79B抑制剂、CD19抑制剂、Lyn抑制剂、Syk抑制剂、PI3K抑制剂、Blnk抑制剂、PLCy抑制剂、PKCP抑制剂或其组合。在一些实施方案中,所述额外的治疗剂是抗体、B细胞受体信号传导抑制剂、PI3K抑制剂、IAP抑制剂、mTOR抑制剂、放射免疫治疗剂、DNA损伤剂、蛋白体抑制剂、组蛋白去乙酰化酶抑制剂、蛋白激酶抑制剂、hedgehog抑制剂、Hsp90抑制剂、端粒酶抑制剂、Jakl/2抑制剂、蛋白酶抑制剂、PKC抑制剂、PARP抑制剂或其组合。
在一些实施方案中,所述额外的治疗剂是苯丁酸氮芥、异环磷酰胺、阿霉素、美沙拉嗪、沙利度胺、来那度胺、替西罗莫司、依维莫司、氟达拉滨、福他沙替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、泼尼松、CAL-101、伊布妥单抗、托西莫单抗、硼替佐米、喷司他丁、内皮抑素或其组合。
在一些实施方案中,额外的治疗剂是环磷酰胺,羟基柔红霉素、长春新碱和泼尼松,以及任选的利妥昔单抗。在一些实施方案中,额外的治疗剂是苯达莫司汀和利妥昔单抗。在一些实施方案中,额外的治疗剂是氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,额外的治疗剂是环磷酰胺、长春新碱和泼尼松,以及任选的利妥昔单抗。在一些实施方案中,额外的治疗剂是依托泊苷、阿霉素、长春新碱、环磷酰胺、泼尼松龙和任选的利妥昔单抗。在一些实施方案中,额外的治疗剂是地塞米松和来那度胺。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的其它治疗剂包括但不限于氮芥,例如苯达莫司汀、苯丁酸氮芥、氯甲胺、环磷酰胺、异环磷酰胺、美法仑、泼尼莫司汀、氯乙环磷酰胺;烷基磺酸盐,例如白消安、甘露糖胺、苏消安(treosulfan);乙烯亚胺,例如碳醌、噻替派、三亚胺醌;亚硝脲,例如卡莫司汀、福莫司汀、洛莫司汀、尼莫司汀、拉莫司汀、司莫司汀、链脲佐菌素;环氧化物,例如依托葡萄糖酸;另一种烷化剂,例如达卡巴嗪、丝裂霉素、匹泊罗曼、替莫唑胺;叶酸类似物,例如甲氨蝶呤、培美曲塞、普拉曲克、雷替曲塞;嘌呤类似物,例如克拉屈滨、氯法拉滨、氟达拉滨、巯基嘌呤、奈拉滨、硫鸟嘌呤;嘧啶类似物,例如阿扎胞苷、卡培他滨、卡莫福、阿糖胞苷、地西他滨、氟尿嘧啶、吉西他滨、替加氟;长春花生物碱,例如长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨;鬼臼毒素衍生物,例如依托泊苷、替尼泊苷;秋水仙碱衍生物,例如地美可辛;紫杉烷,例如多西他赛、紫杉醇、聚谷氨酸紫杉醇;另一种植物生物碱或天然产物,例如曲贝替丁;放线菌素,例如放线菌素D;蒽环类药,例如阿柔比星、柔红霉素、阿霉素、表柔比星、伊达比星、米托蒽醌、吡柔比星、缬柔比星、佐鲁比星;另一种细胞毒性抗生素,例如博莱霉素、伊沙匹隆、丝裂霉素、普卡霉素;铂类化合物,例如卡铂、顺铂、奥沙利铂、沙曲铂;甲基肼,例如丙卡巴嗪;敏化剂,例如氨基乙酰丙酸、依非昔洛韦、甲基氨基乙酰丙酸酯、卟吩姆钠(Porfimer Sodium)、替莫泊芬;蛋白激酶抑制剂,例如达沙替尼、厄洛替尼、依维莫司、吉非替尼、伊马替尼、拉帕替尼、尼洛替尼、帕佐奈、索拉非尼、舒尼替尼、替西罗莫司;另一种抗肿瘤剂,例如阿立替林、阿替他明、安扎克林、阿那格雷、三氧化二砷、门冬酰胺酶、贝沙罗汀、硼替佐米、塞来昔布、地尼洛韦酯、雌莫司汀、羟基卡巴胺、依立替康、氯尼达明、马索前列醇、米托福辛、米托瓜酮、米托坦、奥利默森、聚乙二醇单丁醚、喷司他丁、罗米地辛、sitimagene ceradenovec、噻唑呋啉、拓扑替康、维甲酸、伏立诺他;雌激素,例如己烯雌酚、炔雌醇、磷雌酚、聚雌二醇磷酸酯;孕激素,例如孕烯醇酮、甲羟孕酮、甲地孕酮;促性腺激素释放激素类似物,例如布舍瑞林、戈舍瑞林、亮丙瑞林、曲普瑞林;抗雌激素,例如氟维司群、他莫昔芬、托瑞米芬;抗雄激素药,例如比卡鲁胺、氟他胺、尼鲁他胺;酶抑制剂,例如氨基谷氨酰胺、阿那曲唑、依西美坦、福美司坦、来曲唑、沃罗唑;另一种激素拮抗剂,例如阿倍瑞克、地加瑞克;免疫刺激剂,例如二盐酸组胺、米法莫地、匹多莫德、普利昔福、罗喹那美、胸腺五肽;免疫抑制剂,例如依维莫司、格培美司、来氟米特、霉酚酸、西罗莫司;钙调磷酸酶抑制剂,例如环孢素、他克莫司;另一种免疫抑制剂,例如硫唑嘌呤、来那度胺、甲氨蝶呤、沙利度胺;和放射性药物,例如碘苯胍。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的其它治疗剂包括但不限于干扰素、白介素、肿瘤坏死因子和生长因子。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的额外的治疗剂包括但不限于免疫刺激剂,例如,安塞司亭(ancestim)、非格司亭(filgrastim)、来格司亭(lenograstim)、莫拉司亭(molgramostim)、培非格司亭(pegfilgrastim)、沙格司亭(sargramostim)干扰素,例如天然干扰素α、干扰素α-2a、干扰素α-2b、干扰素α-1、干扰素α-n1、天然干扰素β、干扰素β-1a、干扰素β-1b、干扰素γ、聚乙二醇干扰素α-2a、聚乙二醇干扰素α-2b;白细胞介素,例如阿地白介素(aldesleukin)、奥普瑞白介素(oprelvekin);另一种免疫刺激剂,例如卡介苗、醋酸格拉默、二盐酸组胺、免疫球蛋白、香菇多糖、黑色素瘤疫苗、米法莫肽、培加酶、匹多莫德、普立沙福、聚I:C、聚ICLC、罗喹那美、他索那敏、胸腺五肽;免疫抑制剂,例如阿巴西普、阿贝莫司、阿法西普、抗淋巴细胞免疫球蛋白(马)、抗淋巴细胞免疫球蛋白(兔)、依库珠单抗、依非利珠单抗、依维莫司、古斯匹莫司、来氟米特、莫罗莫那-CD3、霉酚酸、那他利珠单抗、西罗莫司;TNFα抑制剂,例如阿达木单抗、阿非利马单抗、培塞利珠单抗、依那西普、戈利木单抗、英夫利昔单抗;白细胞介素抑制剂,例如阿那金拉、巴利昔单抗、卡那金单抗、达珠单抗、美波单抗、利那奈普、托昔单抗、乌司替卡因单抗;钙调磷酸酶抑制剂,例如环孢素、他克莫司;另一种免疫抑制剂,例如硫唑嘌呤、来那度胺、甲氨蝶呤、沙利度胺。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的其它治疗剂包括但不限于阿达木单抗、阿仑单抗、巴利昔单抗、贝伐单抗、西妥昔单抗、培生赛妥珠单抗、达珠单抗、依库珠单抗、依法利珠单抗、吉妥珠单抗、替伊莫单抗、英利昔单抗、莫罗莫那-CD3、那他珠单抗、帕尼单抗、拉尼珠单抗、利妥昔单抗、托西妥单抗、曲妥珠单抗及其组合。
可以与包含提供的menin抑制剂和Bcl-2抑制剂的治疗组合(和任选的CYP3A4、FLT3抑制剂,或两者)联合施用的额外的治疗剂在本文中包括但不限于单克隆抗体,例如阿仑单抗、贝伐单抗、卡珠单抗、西妥昔单抗、依地昔单抗、吉妥珠单抗、奥法单抗、帕尼单抗、利妥昔单抗、曲妥单抗、免疫抑制剂例如依库珠单抗、依法珠单抗、莫罗莫那-CD3、那他珠单抗;TNFα抑制剂,例如阿达木单抗、阿非利马单抗、赛妥珠单抗、戈利木单抗、英夫利昔单抗、白细胞介素抑制剂、巴利昔单抗、卡那单抗、达珠单抗、美波利珠单抗、托西珠单抗、乌司奴单抗(ustekinumab)、放射性药物、伊布替莫单抗、托西莫单抗;另一种单克隆抗体,例如阿巴戈单抗、阿替卡单抗、阿仑单抗、抗CD30单克隆抗体Xmab2513、抗MET单克隆抗体MetMab、阿泊珠单抗、阿朴珠单抗、阿西莫单抗、巴利昔单抗、双特异性抗体2B1、博纳吐单抗(Blinatumomab)、维布妥昔单抗(Brentuximab Vedotin)、抗前列腺肿瘤单抗、西妥木单抗(cixutumumab)、克劳地昔单抗(claudiximab)、康那木单抗(conatumumab)、达西妥珠单抗、地诺单抗、依库珠单抗(eculizumab)、依普妥珠单抗(epratuzumab)、尼妥珠单抗、依他珠单抗(etaracizumab)、芬妥木单抗(Figitumumab)、非苏木单抗(Fresolimumab)、加利昔单抗(Galiximab)、加尼妥单抗(ganitumab)、吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)、格巴妥木单抗(glembatumumab)、替伊莫单抗、奥英妥珠单抗(inotuzumab ozogamicin)、伊匹单抗、来沙木单抗、林妥珠单抗(lintuzumab)、林妥珠单抗(lintuzumab)、卢卡木单抗、马帕木单抗、马妥珠单抗、米拉组单抗(milatuzumab)、单克隆抗体CC49、耐昔妥珠单抗(Necitumumab)、尼妥珠单抗(Nimotuzumab)、奥法木单抗、奥戈伏单抗、帕妥珠单抗、雷莫芦单抗(Ramucirumab)、雷尼珠单抗、西利珠单抗、索奈珠单抗(sonepcizumab)、坦珠单抗、托司妥单抗、曲妥珠单抗、替西木单抗(tremelimumab)、西莫白介素单抗(tucotuzumabcelmoleukin)、维妥组单抗(veltuzumab)、维西珠单抗、伏洛昔单抗、扎芦木单抗。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合施用的其它治疗剂包括但不限于影响肿瘤微环境如细胞信号网络(例如磷脂酰肌醇3-激酶(PI3K)信号通路、来自B细胞受体和IgE受体的信号)的试剂。在某些实施方案中,第二种药物是PI3K信号抑制剂或syc激酶抑制剂。在一些实施方案中,syk抑制剂是R788。在另一个实施方案中,第二种药物是PKCy抑制剂,例如仅作为示例,恩扎妥林。
影响肿瘤微环境的药剂的示例包括PI3K信号传导抑制剂、syc激酶抑制剂、蛋白激酶抑制剂,例如达沙替尼、厄洛替尼、依维莫司、吉非替尼、伊马替尼、拉帕替尼、尼罗替尼、帕佐那尼、索拉非尼、舒尼替尼、替西罗莫司;另一种血管生成抑制剂,例如GT-111、JI-101、R1530;其他激酶抑制剂,例如AC220、AC480、ACE-041、AMG 900、AP24534、Arry-614、AT7519、AT9283、AV-951、阿昔替尼、AZD1152、AZD7762、AZD8055、AZD8931、巴氟替尼、BAY 73-4506、BGJ398、BGT226、BI 811283、BI6727、BIBF 1120、BIBW2992、BMS-690154、BMS-777607、BMS-863233、BSK-461364、CAL-101、CEP-11981、CYC116、DCC-2036、dinaciclib、多韦替尼乳酸盐、E7050、EMD 1214063、ENMD-2076、福他替尼二钠盐(fostamatinib disodium)、GSK2256098、GSK690693、INCB18424、INNO-406、JNJ-26483327、JX-594、KX2-391、利尼伐尼(linifanib)、LY2603618、MGCD265、MK-0457、MK1496、MLN8054、MLN8237、MP470、NMS-1116354、NMS-1286937、ON 01919.Na、OSI-027、OSI-930、PF-00562271、PF-02341066、PF-03814735、PF-04217903、PF-04554878、PF-04691502、PF-3758309、PHA-739358、PLC3397、促生殖生成素(progenipoietin)、R547、R763、雷莫芦单抗、瑞戈非尼、R05185426、SAR103168、SCH 727965、SGI-1176、SGX523、SNS-314、TAK-593、TAK-901、TKI258、TLN-232、TTP607、XL147、XL228、XL281R05126766、XL418、XL765。
本文提供的与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合使用的治疗剂的其它实例包括但不限于有丝分裂原活化蛋白激酶信号传导的抑制剂,例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-43、渥曼青霉素或LY294002;Syk抑制剂;mTOR抑制剂;和抗体(例如,利妥昔单抗)。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合使用的其它药剂包括但不限于阿霉素、放线菌素、博莱霉素、长春碱、顺铂、阿昔洛韦、阿柔比星、阿可达佐(Acodazole hydrochloride)、阿克罗宁、阿多来新、阿地白介素、六甲蜜胺、二霉素、乙酸阿比特龙酯(Abiraterone Acetate)、氨鲁米特(aminoglutethimide)、安丫啶、阿那曲唑、蒽霉素、天冬酰胺酶、阿斯普林、氮杂胞苷、阿替派、阿佐霉素、巴马司他(batimastat)、苯佐替派、比卡鲁胺、盐酸双蒽、二甲基水杨酸双萘酯、比折来新(bizelesin)、硫酸博莱霉素、短喹那钠、溴吡嗪(bropirimine)、白消安、放线菌素C、二甲睾酮、卡醋胺(caracemide)、卡贝替默、卡铂、卡莫司汀、盐酸卡柔比星、卡折来新、cedefmgol、苯丁酸氮芥、西罗霉素、克拉屈滨、crisnatol mesylate、环磷酰胺、阿糖胞苷、达卡巴嗪、盐酸柔红霉素、地西他滨、右奥马铂(dexormaplatin)、地扎胍宁、甲磺酸地扎胍宁、二氮喹酮、阿霉素、盐酸阿霉素、屈洛昔芬、枸橼酸屈洛昔芬、丙酸屈莫醇酮、去氮霉素、依达曲酯、盐酸依氟鸟氨酸、依沙芦星(elsamitrucin)、恩洛铂、恩普罗马特(enpromate)、表丙啶、盐酸表柔比星、厄布唑、盐酸埃索柔比星、雌莫司汀、雌莫司汀磷酸钠、依他唑、依托泊苷、磷酸依托泊苷、依托普林、盐酸法多唑、法扎拉滨(fazarabine)、芬维A胺(fenretinide)、氟尿苷、磷酸氟达拉滨(fiudarabine phosphate)、氟尿嘧啶、氟罗西他滨、磷喹酮、福司曲星钠(fostriecin sodium)、吉西他滨、盐酸吉西他滨、羟基脲、盐酸伊达比星、异环磷酰胺、艾莫福辛、白细胞介素II(包括重组白细胞介素II或rlL2)、干扰素α-2a、干扰素α-2b、干扰素α-nl、干扰素α-n3、干扰素β-1a、干扰素γ-1b、异博铂、盐酸伊立替康、醋酸兰瑞肽、来曲唑、醋酸亮丙瑞林、盐酸利亚唑、洛美沙星钠、洛莫司汀、盐酸氯蒽醌、马索罗酚(masoprocol)、美登木碱、盐酸氮芥、醋酸甲地孕酮、醋酸美仑孕酮、梅尔法仑、美诺立尔(menogaril)、巯基嘌呤、甲氨蝶呤、甲氨蝶呤钠、美托普林、美妥替哌(meturedepa)、米丁度胺(mitindomide)、丝裂霉素(mitocarcin)、丝裂红素、丝林霉素(mitogillin)、丝裂马菌素(mitomalcin)、丝裂霉素(mitomycin)、米托司培(mitosper)、米托坦、盐酸米托蒽醌、霉酚酸、诺可达唑(nocodazoie)、诺加霉素、奥马铂、奥昔舒仑(oxisuran)、培门冬酶(Pegaspargase)、培来霉素、戊霉素(pentamustine)、硫酸佩洛霉素、培磷酰胺、哌泊溴烷(pipobroman)、哌泊舒凡(piposulfan)、盐酸吡罗蒽醌、褶霉素、普洛美司坦、泊菲莫钠、泊菲霉素、尼莫司汀、盐酸普鲁卡因、嘌呤霉素、盐酸嘌呤霉素、吡唑呋啉、核糖嘌呤、罗格列胺、safmgol、盐酸safmgol、司莫司汀、simtrazene磷酸铵钠、稀疏霉素、螺锗盐酸盐、螺霉素、螺铂、链脲菌素、链脲佐菌素、辛曲秦(sulofenur)、他林霉素、替加兰钠、替吉奥胶囊(tegafur)、盐酸托蒽醌、temoporfm、替尼泊甙、泰罗昔隆、睾丸酮、硫胺素、硫代鸟嘌呤、硫替帕、硫唑嘌呤、替拉帕胺、枸橼酸托瑞米芬、醋酸曲托酮、曲西立滨磷酸酯(triciribinephosphate)、三甲曲沙、葡糖醛酸三曲沙、曲普瑞林、盐酸妥布氯唑(tubulozolehydrochloride)、尿嘧啶芥、乌瑞替派(uredepa)、伐普肽(vapreotide)、维替泊芬(Verteporfm)、硫酸长春碱、硫酸长春新碱、长春地辛、硫酸长春地辛、硫酸甘酯(vinglycinate sulfate)、硫酸长春甘氨酸酯、硫酸长春瑞滨、酒石酸长春瑞滨、硫酸长春瑞丁、硫酸长春唑胺、沃罗唑、泽尼铂、西洛他汀、盐酸佐柔比星。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的其它治疗剂包括但不限于20-epi-l,25二羟基维生素D3、5-乙酰尿嘧啶、阿比特龙、阿柔比星、酰基富烯、阿德塞酚、阿多来新、阿地白介素、ALL-TK拮抗剂、利他胺、安巴莫司汀、阿米多克、氨磷汀、氨基乙酰丙酸、氨柔比星、安丫啶、阿那格雷(anagrelide)、阿那曲唑、穿心莲内酯、血管生成抑制剂、D拮抗剂、G拮抗剂、antarelix、抗背化形态发生蛋白-1、抗雄激素、前列腺癌、抗雌激素、抗肿瘤药、反义寡核苷酸、aphidicolin glycinate、凋亡基因调节剂、细胞凋亡调节剂、嘌呤酸、ara-CDP-DL-PTBA、精氨酸脱氨酶、阿苏拉克林、阿他美坦、阿曲霉菌素、阿昔他汀1、阿昔他汀2、阿昔他汀3、阿扎司琼、氮杂毒素、氮杂酪氨酸、浆果赤霉素III衍生物、巴拉诺(balanol)、巴马司他(batimastat)、BCR/ABL拮抗剂、苯并二氢卟酚、苯甲酰星形孢菌素、β-内酰胺衍生物、β-丙氨酸、倍他霉素B、桦木酸、bFGF抑制剂、比卡鲁胺、双蒽、双氮丙啶基精胺、双奈法德(bisnafide)、bistrateneA、比折来新、breflate、溴匹立明(bropirimine)、布多坦、丁硫氨酸磺酰亚胺、钙泊三醇、钙磷蛋白C、喜树碱衍生物、金丝雀痘白介素-2、卡培他滨、羧酰胺-氨基-三唑、羧酰胺三唑、CaRest M3、CARN 700、软骨来源的抑制剂、卡折来新(carzelesin)、酪蛋白激酶抑制剂(ICOS)、栗树精胺、天蚕丝抗菌肽、曲那林(cetrorelix)、chlorlns、氯喹喔啉磺酰胺(chloroquinoxaline sulfonamide)、西前列素、顺式卟啉、克拉屈滨、氯米芬类似物、克霉唑、克林霉素A、克林霉素B、康布他汀A4、康布他汀类似物、conagenin、crambescidin 816、克立那托(crisnatol)、隐藻蛋白8、隐藻毒素A衍生物、箭毒素A、环戊烯蒽醌、环磷酰胺、cypemycin、阿糖胞苷十八碳磷酸酯钠、细胞溶解因子、细胞抑制素、达克利昔单抗、地西他滨、脱氢双苯甲素B、地洛瑞林、地塞米松、右氧磷酰胺、右旋唑烷(dexrazoxane)、右维拉帕米、二氮喹酮、膜海鞘素(didemninB)、didox、二乙基亚硝胺、二氢-5-氮杂胞苷、9-二氧霉素、二苯基螺霉素、二十二烷醇(docosanol)、多拉司琼、多西呋啶、屈洛昔芬(droloxifene)、屈大麻酚、多卡霉素SA、依布硒啉、依莫司汀、依地福辛、埃德瑞科莫单抗、依氟鸟氨酸、榄香烯、乙嘧替氟、表柔比星、爱普列特、雌莫司汀类似物、雌激素激动剂、雌激素拮抗剂、依他唑、磷酸依托泊苷、依西美坦、法屈唑(fadrozole)、法扎拉滨(fazarabine)、芬维A酸、非格司亭、非那雄胺、黄酮吡哆醇、弗莱泽拉斯汀、氟紫菀酮、氟达拉滨、盐酸氟柔红霉素、福酚美克(forfenimex)、福美斯坦、磷三烯霉素、福莫司汀、钆替沙芬、硝酸镓、伽罗他滨、加尼瑞克、明胶酶抑制剂、吉西他滨、谷胱甘肽抑制剂、hepsulfam、调蛋白(heregulin)、六亚甲基二乙酰胺、金丝桃素、伊班膦酸、伊达比星、艾多昔芬、伊德拉曼通、伊尔莫福新、伊洛司他、咪唑并吖啶酮、咪喹莫特、免疫刺激剂肽、胰岛素受体抑制剂、干扰素激动剂、干扰素、白细胞介素、碘苯甲醚、碘柔比星、4-IPO meanol、易洛普拉特;伊索拉定、异苯唑、异高盐性骨钙素B、itasetron、茉莉酮酸、kahalalide F、lamellarin-Ntriacetate、兰瑞肽、莱茵霉素、来格司亭(lenograstim)、硫酸香菇多糖、leptolstatin、来曲唑、白血病抑制因子、白细胞α干扰素、亮丙瑞林+雌激素+孕酮、亮丙瑞林、左旋咪唑、噻罗唑、线性多胺类似物、亲脂性二糖肽、亲脂性铂化合物、利索林酰胺7、洛铂、伦巴第碱、洛美沙星、氯尼达明、洛沙宗酮、洛伐他汀、洛索立滨、鲁托替康、德克萨斯镥、溶纤素、裂解肽迈坦辛、甘露糖他汀A、马里马司他、马索普罗考、马斯平、基质溶素抑制剂、基质金属蛋白酶抑制剂、menogaril、默巴隆、美特林(meterelin)、甲硫氨酸酶、甲氧氯普胺、MIF抑制剂、米非司酮、米替福辛、米莫司亭、错配的双链RNA有丝分裂愈伤组织、有丝分裂内酯、丝裂霉素类似物、米托那非、丝裂毒素成纤维细胞生长因子-皂苷、米托蒽醌、莫法罗汀、molgramostim,人绒毛膜促性腺激素、单磷酸脂A+肌细菌细胞壁sk、莫匹达莫、多重耐药基因抑制剂、基于多肿瘤抑制物1的疗法、一种芥末抗癌剂、马槟榔氧化物B、分枝杆菌细胞壁提取物、多螺孔酮、N-乙酰地那林、N-取代的苯甲酰胺、萘法瑞林、纳格雷斯蒂普、纳洛酮+喷他佐辛、纳帕文、naphterpin、nartograstim、奈达铂、奈莫比星、尼屈膦酸、中性内肽酶、尼罗替米、乳酸链球菌素、一氧化氮调节剂、氮氧化物抗氧化剂、尼特鲁林、06-苄基鸟嘌呤、奥曲肽、奥基西酮、寡核苷酸、奥那司酮(onapristone)、昂丹司琼、昂丹司琼、oracin、口服细胞因子诱导剂、奥玛铂、奥司特龙、奥沙利铂、奥沙霉素、palauamine、棕榈酰根瘤毒素、帕米膦酸、人参氧三醇、潘诺米芬、副肌动蛋白、帕泽利汀、培门冬酶、peldesine、戊聚糖聚硫酸钠、戊司他丁、喷曲唑、perflubron、环磷酰胺、紫苏醇、非那嗪霉素、苯基乙酸酯、磷酸酶抑制剂、picibanil、盐酸毛果芸香碱、吡柔比星、匹曲辛、胎盘素A、胎盘素B、纤溶酶原激活物抑制剂、铂络合物、铂化合物、铂-三胺络合物、卟啉钠、卟啉霉素、泼尼松、丙基双吖啶酮、前列腺素J2、蛋白酶体抑制剂、基于蛋白质的免疫调节剂:蛋白激酶C抑制剂、蛋白激酶C抑制剂,微藻、蛋白质酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、紫色素、吡唑并吖啶、吡啶氧基化血红蛋白聚氧乙基偶联物、raf拮抗剂、雷替曲塞、雷莫司琼、ras、法尼酰蛋白转移酶抑制剂、ras抑制剂、ras-GAP抑制剂、去甲基化的瑞替利汀、铼Re 186依替膦酸盐、根蛋白、核酶、RII视黄酰胺、罗格列胺、罗希托金、罗穆肽、罗喹尼麦、rubiginone Bl、ruboxyl、safmgol、saintopin、SarCNU肉甾醇A、萨格拉莫斯蒂姆(sarghramostim)、Sdi 1模拟物、司莫司汀、衰老衍生抑制剂1、有义寡核苷酸、信号转导抑制剂、信号转导调节剂、单链抗原结合蛋白、西索非林、sobuzoxane、硼氢化钠、苯乙酸钠、溶剂醇、生长激素结合蛋白、sonermin、天冬氨酸、骨针霉素D、螺霉素、脾开放素、海绵生长抑制素1、角鲨胺、干细胞抑制剂、干细胞分裂抑制剂、针茅酰胺、基质分解素抑制剂、硫肌苷、超活性血管活性肠肽拮抗剂、suradista、苏拉明、苦马豆素、合成的糖胺聚糖、托利莫司汀、他莫昔芬甲硫化物、牛磺莫司汀、他扎罗汀、替加兰钠、替加氟、碲吡啶、端粒酶抑制剂、temoporfm、替莫唑胺、替尼泊苷、四氯十氧化物、四唑胺、反应停、噻可拉林、血小板生成素、血小板生成素模拟物、胸腺法新、胸腺生成素受体激动剂、胸腺肽、促甲状腺激素、乙基依替普嘌呤锡、替拉帕胺、二氯化茂钛、托普森廷、托瑞米芬、全能干细胞因子、翻译抑制剂、维甲酸、三乙酰尿苷、三西他滨、三甲氧苄酯、曲普瑞林、托烷司琼、妥洛瑞特(turosteride)、酪氨酸激酶抑制剂、酪氨酸磷酸酶、UBC抑制剂、ubenimex、泌尿生殖窦源性生长抑制因子、尿激酶受体拮抗剂、伐普肽、天花素B、载体系统,红细胞基因治疗、贝拉雷索、维拉明、维丁斯、verteporfm、长春瑞滨、长春西汀、维他辛、沃罗唑、扎诺特隆、泽尼铂、zilascorb和净司他丁斯酯(zinostatinstimalamer)。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的其它治疗剂包括但不限于另一种CYP3A4抑制剂、烷化剂、抗代谢剂、天然产物或激素、氮芥(例如,甲基乙胺、环磷酰胺、苯丁酸氮芥等)、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司坦等)或三氮烯类(达卡巴嗪等)。抗代谢物的实例包括但不限于叶酸类似物(如甲氨蝶呤)或嘧啶类似物(如阿糖胞苷)、嘌呤类似物(如巯基嘌呤、硫鸟嘌呤、戊司他丁)。
烷化剂的实例包括但不限于氮芥(例如,甲氯乙胺、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺和甲基三胺(例如六亚甲基胺、硫替帕)、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、链脲佐菌素等)或三氮烯(达卡巴嗪等)。抗代谢物的实例包括但不限于叶酸类似物(如甲氨蝶呤)或嘧啶类似物(如氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(如巯基嘌呤、硫鸟嘌呤、戊司他丁)。
本文提供的可与包含menin抑制剂和Bcl-2抑制剂(以及任选的CYP3A4、FLT3抑制剂或两者)的治疗组合联合给药的额外的治疗剂包括但不限于:厄布洛唑(Erbulozole)(也称为R-55104)、多司他丁10(也称为DLS-10和NSC-376128)、米沃布林羟乙磺酸盐(也称为CI-980)、长春新碱、NSC-639829、地可罗定(也称为CI-980),长春新碱、NSC-639829、Discodermolide(也称为NVP-XX-A-296)、ABT-751(Abbott,也称为E-7010)、Altorhyrtins(如AltorhyrtinA和Altorhyrtin C)、海绵抑制素(Spongistatin,例如海绵抑制素1、海绵抑制素2、海绵抑制素3、海绵抑制素4、海绵抑制素5、海绵抑制素6、海绵抑制素7、海绵抑制素8和海绵抑制素9)、盐酸西马定(也称为LU-103793和NSC-D-669356)、埃坡霉素(例如埃坡霉素A、埃坡霉素B、埃坡霉素C(也称为去氧埃坡霉素A或dEpoA)、埃坡霉素D(也称为21-羟基埃坡霉素D(也称为KOS-862、dEpoB和去氧埃博霉素B)、埃坡霉素E、埃坡霉素F、埃坡霉素BN-氧化物、埃坡霉素AN-氧化物、16-氮杂-埃坡霉素B、21-氨基埃坡霉素B(也称为BMS-310705)、21-羟基埃坡霉素D(也称为去氧埃坡霉素F和dEpoF)、26-氟埃坡霉素)、奥瑞他汀PE(也称为NSC-654663)、索布利多汀(也称为TZT-1027)、LS-4559-P(Pharmacia,也称为LS-4577)、LS-4578(Pharmacia,也称为LS-477-P)、LS-4477(Pharmacia)、LS-4559(Pharmacia)、RPR-112378(Aventis)、硫酸长春新碱、DZ-3358(Daiichi)、FR-182877(藤泽,也称为WS-9885B)、GS-164(Takeda)、GS-198(Takeda)、KAR-2(匈牙利科学院)、BSF-223651(BASF,也称为ILX-651和LU-223651)、SAH-49960(Lilly/Novartis)、SDZ-268970(Lilly/Novartis)、AM-97(Armad/Kyowa Hakko)、AM-132(Armad)、AM-138(Armad/Kyowa Hakko)、IDN-5005(Indena)、Cryptophycin 52(也称为LY-355703)、AC-7739(Ajinomoto,也称为AVE-8063Aand CS-39.HCI)、AC-7700(味之素,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCI和RPR-258062A)、Vitilevuamide、TubulysinA、Canadensol、Centaureidin(也称为NSC-106969)、T-138067(Tularik,也称为T-67、TL-138067和TI-138067)、COBRA-1(ParkerHughes Institute,也称为DDE-261和WHI-261)、H10(堪萨斯州立大学)、H16(堪萨斯州立大学)、OncocidinAl(也称为BTO-956和DIME)、DDE-313(Parker Hughes Institute)、Fijianolide B、Laulimalide、SPA-2(Parker Hughes Institute)、SPA-1(Parker HughesInstitute,也称为SPIKET-P)、3-IAABU(Cytoskeleton/Mt.Sinai School ofMedicine,也称为MF-569)、纳西索新(也称为NSC-5366)、那卡品、D-24851(Asta Medica)、A-105972(Abbott)、Hemiasterlin、3-BAABU(细胞骨架/西奈山医学院,也称MF-191)、TMPN(亚利桑那州立大学)、乙酰丙酮伐那多烯、T-138026(tural rik)、Monsatrol、lnanocine(也称NSC-698666)、3-1AABE(Cytoskeleton/Mt.Sinai School ofMedicine)、A-204197(Abbott)、T-607(Tuiarik,也称为T-900607)、RPR-115781(Aventis)、Eleutherobins(如Desmethyleleutherobin、Desaetyleleutherobin、lsoeleutherobin A和Z-Eleutherobin)、Caribaeoside、Caribaeolin、Halichondrin B、D-64131(Asta Medica)、D-68144(AstaMedica)、DiazonamideA、A-293620(Abbott)、NPI-2350(Nereus)、他卡洛尔A、TUB-245(Aventis)、A-259754(Abbott)、哌唑嗪、(-)-苯基组氨酸(也称为NSCL-96F037)、D-68838(AstaMedica)、D-68836(Asta Medica)、肌球蛋白B、D-43411(Zentaris,也称为D-81862)、A-289099(Abbott)、A-318315(Abbott)、HTI-286(也称为SPA-110,trifiuoroacetate salt)(Wyeth)、D-82317(Zentaris)、D-82318(Zentaris)、SC-12983(NCI)、Resverastatinphosphate sodium、BPR-OY-007(National Health ResearchInstitutes)、和SSR-250411(Sanofi)。
本文提供的包含menin抑制剂和Bcl-2抑制剂(和任选的CYP3A4、FLT3抑制剂或两者)的治疗组合可与以下物质联合使用:免疫抑制剂(例如,他克莫司、环孢霉素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯基嘌呤、霉酚酸酯或FTY720)、糖皮质激素(例如,泼尼松、醋酸可的松、泼尼松龙、甲基泼尼松龙、地塞米松、倍他米松、曲安奈德、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、奥昔康、昔布类或磺酰苯胺)、Cox-2特异性抑制剂(例如,伐地昔布、塞来昔布或罗非昔布)、来氟米特、金硫代葡萄糖、金硫代苹果酸、aurofm、柳氮磺吡啶、羟基氯奎宁、米诺环素、TNF-a结合蛋白(例如英夫利昔单抗、依那西普或阿达木单抗)、阿巴他塞、阿那金拉、干扰素-β、干扰素-γ、白细胞介素-2、变态反应疫苗、抗组胺药、抗真菌病药、β-激动剂茶碱和/或抗胆碱能药。
试剂盒和制造品
为了用于本文所述的治疗性使用方法,本文还描述了试剂盒和制品。这种试剂盒包括载体、包装或容器,其被分隔以容纳一个或多个容器,例如小瓶、管等,每个容器包括在本文所述方法中使用的单独元件之一。合适的容器包括,例如,瓶子、小瓶、注射器和试管。在一个在实施方案中,容器由多种材料形成,例如玻璃或塑料。
本文提供的制品包含包装材料。药物包装材料的实例包括但不限于泡罩包装、瓶、管、袋、容器、瓶和适于所选制剂和预期给药和治疗模式的任何包装材料。
例如,容器包括本文所公开的menin抑制剂和Bcl-2抑制剂以及任选的CYP3A4抑制剂、低甲基化药物、FLT3抑制剂或其组合。可以在一个、两个、三个或四个容器中提供menin抑制剂和Bcl-2抑制剂、CYP3A4抑制剂、低甲基化药物和/或FLT3抑制剂。此类试剂盒任选地包括与其在本文所述方法中的用途相关的鉴别描述或标签或说明书。
试剂盒通常包括列出内容物和/或使用说明的标签,以及带有使用说明的包装插页。通常还包括一组说明。
在一些实施方案中,标签在容器上或与容器相关联。在一些实施方案中,当形成标签的字母、数字或其他字符被附着、模制或蚀刻到容器本身中时,标签在容器上;当标签存在于也保持容器的容器或载体内时,例如作为包装插入物,标签与容器相关联。在一些实施方案中,标签用于指示内容物将用于特定的治疗应用。该标签还指示内容物的使用说明,例如在本文所述的方法中。
在某些实施方案中,药物组合物(例如本文提供的药物组合物)以包含一种或多种含有本文提供的化合物的单位剂型的包装或分配器装置存在。例如,该包装包含金属或塑料箔,如泡罩包装。在一些实施方案中,包装或分配器装置附有给药说明。在一些实施方案中,包装或分配器还伴随有与容器相关联的通知,该通知采用由管理药物的制造、使用或销售的政府机构规定的形式,该通知反映了该机构对用于人类或兽医给药的药物形式的批准。例如,此类通知是指美国食品药品监督管理局批准的处方药标签或批准的产品说明书。在一些实施方案中,还制备含有本文提供的化合物的组合物,所述组合物配制在相容的药物载体中,置于合适的容器中,并标记用于治疗所指示的病症。
实施例
本节中的实施例仅用于说明,并非用于限制。
实施例1.menin抑制剂(化合物(I));SNDX-50469)与维奈妥拉联合用药
在NPM1c/FLT3-ITD/TKD患者来源的异种移植物(PDX)模型中,对menin-MLL1抑制剂化合物(I)(化合物(II)的等效替代物)与维奈妥拉联用的抗白血病活性和潜在协同作用及机制进行了体内研究。
小鼠实验按照机构动物护理和使用委员会批准的方案进行。使用Kaplan-Meier法估计小鼠存活率,并使用对数秩检验分析存活数据。使用学生t-text确定组间差异;P值≤0.05被视为具有统计学意义。PDX(DFAM-16835)是从PRoXe保藏中心获得的。植入的NSG小鼠用0.05%或0.1%化合物(I)(SNDX)加标食物、维奈妥拉(VEN)或0.1%化合物(I)加维奈妥拉(图1A)处理。第2周时,化合物(I)在0.05或0.1%(P<0.0001)或维奈妥拉(P=0.0012)浓度下通过人CD45+(huCD45+)细胞的流式细胞术测量显著降低了循环原始细胞。在这方面,较高剂量更有效(P=0.05),且联合用药明显比0.1%化合物(I)或维奈妥拉更有效(P<0.0001)(图1B)。第4周时,化合物(I)及其与维奈妥拉的联合用药显著(P<0.0001)减少了循环白血病细胞,而单独使用维奈妥拉无效(图1C)。
流式细胞术分析显示,治疗结束时,化合物(I)在0.05%(P=0.05)或0.1%(P=0.02)浓度下部分减少了BM白血病细胞。尽管较高剂量往往更有效,但未达到统计学意义。单独使用维奈妥拉无活性,但与0.1%化合物I联合使用时,显著降低了BM白血病负荷(P=0.0035对比0.1%化合物I)(图1D)。除了一只0.1%化合物I治疗的小鼠表现出高原始细胞和扩大的脾脏之外,单独使用维奈妥拉在脾脏中也缺乏活性,而化合物I单独使用或与维奈妥拉联合使用极大地减少了脾脏huCD45+细胞(图1E)和脾脏重量或大小(图1F)。这一只小鼠还显示出相对较高的BM huCD45+细胞(图1D)。结果与H&E染色一致(图1H)。
如图1A-1H所示,在NPM1c/FLT3-ITD/TKD PDX模型中,menin抑制表现出抗白血病活性和延长的小鼠生存期,这通过Bcl-2抑制进一步增强。因此,0.05%或0.1%的化合物(I)显著延长了小鼠存活时间(分别为中位值125天和131天,而对照组为61天;P=0.0001),较高剂量组的获益增加(P=0.008)。与对照组相比,单用维奈妥拉最低限度地延长了生存期(中位值69天,P=0.026)。然而,与未治疗(P=0.0003)或维奈妥拉(P=0.0008)治疗的小鼠相比,用0.1%化合物(I)加维奈妥拉治疗的小鼠的生存期(中位值143天)延长了一倍以上,并进一步延长了生存期超过0.1%化合物(I)治疗小鼠的生存期(P=0.0005)。
治疗结束时,通过本领域已知方法进行的细胞因子分析,评估了对白血病原始细胞和表型定义的白血病干细胞/祖细胞的治疗效果以及BM白血病细胞的蛋白表达。图5所示为CyTOF图。
如图2A-2E所示,menin和Bcl-2抑制靶向白血病细胞和干/祖细胞,并在治疗结束时通过BM细胞中的CyTOF分析调节Bcl-2蛋白水平。基于细胞表面标记对细胞群体进行表型聚类。用FlowJo(软件v10.7,FlowJo LLC)对顺铂低存活单细胞进行门控,并作为流式细胞术标准(FCS)数据输出,用于随后在Cytofkit中的分析。在“Cytofkit_analyzedFCS”文件中由PhenoGraph鉴定和嵌入的细胞群在FlowJo中进行门控,以量化标记表达。用热图显示所需细胞群中每种蛋白表达的ArcSinh转化计数。对huCD45+细胞的分析显示,化合物I改变了细胞组成,并且维奈妥拉对白血病细胞仅具有最小的影响,而该组合有效地消除了白血病细胞(图2A)。基于细胞表面标记表达的表型聚类将huCD45+细胞分为:CD34+CD38+、CD34+CD38+CD123+、CD34+CD38+CD123+Tim3+、CD34+CD38-、CD34+CD38-CD123+和CD34+CD38-CD123+Tim3+群体(图2B)。0.05%和0.1%以上的化合物(I)部分抑制大量白血病细胞,并有效靶向CD34+CD38+/CD34+CD38+CD123+/CD34+CD38+CD123+Tim 3细胞。仅在0.1%时,化合物(I)能够减少CD34+CD38-/CD34+CD38-CD123+细胞,但不能减少CD34+CD38-CD123+Tim3+细胞。维奈妥拉对大量白血病无活性,在CD34+CD38+/CD34+CD38+CD123+/CD34+CD38+CD123+Tim 3细胞中有部分活性,但在CD34+CD38-/CD34+CD38-CD123+/CD34+CD38-CD123+Tim 3+细胞群中有活性。0.1%化合物(I)和维奈妥拉的组合在消除所有细胞类型,包括白血病干/祖细胞方面最有效(图2C)。白血病细胞的蛋白质分析(图2D)表明,化合物(I),尤其是该组合,降低了Bcl-2和Bcl-xL,并增加了Bim。此外,该组合降低了Bcl-2抑制的抵抗因子Bcl-2A1。CD34+CD38+和CD34+CD38-细胞的蛋白分析(图2F)显示化合物(I)增加了多种促凋亡蛋白。化合物(I)降低CD34+CD38+中的Bcl-2,但不特别降低CD34+CD38-细胞中的Bcl-2,这可以部分解释其在CD34+CD38+细胞群中的有效性,而不是在CD34+CD38-细胞群中的有效性。在联合治疗组中,CD34+CD38+和CD34+CD38-细胞数量极低。
与NPM1c/FLT3突变的AML中menin抑制作用靶向FLT3的报道相反,p-FLT3在化合物(I)处理的细胞中增加,特别是在组合组中。在短期menin抑制剂治疗后,在细胞系中体外观察到FLT3表达降低,而这些结果是在治疗一个月的小鼠体内获得的,并反映了存活细胞的单细胞蛋白质组学。p-FLT3的增加可能是由BM环境因素诱导,或者可能是存活细胞的抵抗机制。较高水平的pFAK和CD44可能表明间质相互作用被激活以提高存活率。此外,在化合物(I)处理的小鼠BM细胞中观察到增加的huCD11b水平(图2D)和huCD11b+群体(图2E)。
为了确保适当的药物摄入,在用添加化合物(I)的食物喂养的小鼠中采集血样,并测定血浆中的药物水平(n=5)。观察到化合物(I)的剂量依赖性血浆水平,其不受维奈妥拉治疗的影响(图3)。然而,联合治疗导致体重减轻,这可能会导致低估联合治疗的疗效。治疗结束后,小鼠体重开始增加(图4)。
总的来说,这些数据表明,menin抑制表现出强烈的抗白血病活性,并显著延长小鼠存活时间,这在NPM1c/FLT3-ITD/TKDAMLPDX模型中与维奈妥拉组合时进一步增强。Menin抑制优先靶向CD34+CD38+细胞,而维奈妥拉靶向CD34+CD38-细胞。只有menin和Bcl-2的联合抑制有效地消除了扩展和CD34+CD38+/CD34+CD38-干细胞/祖细胞。从机制上讲,menin抑制减少了多种抗凋亡Bcl-2蛋白,同时增加了促凋亡Bcl-2蛋白,这似乎增强了Bcl-2抑制剂维奈妥拉的活性。目前还不知道延长治疗是否会进一步增强这种组合的益处。这项研究进一步证实了menin作为一个治疗靶点,并证明在NPM1/FLT3突变的AML中menin抑制与维奈妥拉协同作用,这保证了进一步的临床评估。不希望被理论所束缚,考虑到治疗结束时pFLT3的高活性,以及所报道的menin和FLT3抑制的协同作用,三联药物组合可进一步增强FLT3突变体AML中menin抑制的活性。
在NPM1c/FLT3-ITD/TKD患者来源的异种移植物(PDX)模型中进行了在体内对menin-MLL1抑制剂化合物(I)和维奈妥拉的组合的抗白血病活性和潜在协同作用以及机制的研究。
用添加0.05或0.1%化合物(I)的食物、维奈妥拉(50mg/kg)或0.1%化合物(I)加维奈妥拉处理移植了PDX细胞的NSG小鼠一个月。通过流式细胞术测量小鼠外周血中的人CD45+细胞来评估移植和疾病进展。监测生存期。通过CyTOF质谱计测定对各种白血病细胞群及其蛋白质表达水平的治疗效果。
Menin抑制表现出很强的抗白血病活性和显著延长的小鼠生存期,当与维奈妥拉联合使用时进一步增强,而维奈妥拉单独使用的效果最小。该组合在延长小鼠存活方面最有效(0.1%化合物(I)加维奈妥拉为143天,P=0.0003;0.1%或0.5%化合物(I)分别为131天和125天,两者的P=0.0001;维奈妥拉69天对比对照组的61天,P=0.025)。在治疗结束时,收集骨髓细胞,CyTOF分析表明menin抑制优先靶向CD34+CD38+细胞,而维奈妥拉靶向CD34+CD38-细胞。只有menin和Bcl-2的联合抑制有效地消除了扩展和CD34+CD38+/CD34+CD38-干细胞/祖细胞。Menin抑制也增加了CD11b+髓样细胞群。从机制上讲,menin抑制减少了多种抗凋亡Bcl-2蛋白,包括Bcl-2和Bcl-xL,同时增加了促凋亡Bcl-2蛋白,如Bax,这似乎增强了维奈妥拉抑制Bcl-2的活性。然而,在治疗结束时,观察到存活的白血病细胞中的p-FLT3增加,特别是在联合治疗组中。不希望被理论所束缚,这可能有助于白血病细胞的再生。证明了化合物(I)与维奈妥拉在NPM1/FTL3介导的AML中的协同抑制作用。
实施例2:在NPM1/FLT3突变的AML中联合menin、Bcl-2和FLT3抑制和低甲基化药物的抗白血病活性
实施例1显示menin抑制剂SNDX-50469(化合物(I))与BCL-2抑制剂维奈妥拉协同作用,但是存活的白血病细胞在治疗结束时FLT3信号传导增加。不受理论约束,据信p-FLT3的这种增加了MCL-1并促成了白血病的进展。使用相同的PDX模型,我们研究了用吉瑞替尼抑制FLT3是否可以增强共同靶向menin和Bcl-2的功效。
我们使用了与实施例1中相同的PDX模型(NPM1c/FLT3-ITD/TKD,DFAM-16835)。当循环人类CD45(huCD45)阳性率达到2.6%时,用SNDX-50469(0.1%在食物中)、吉瑞替尼(35mg/kg)、SNDX-50469/吉瑞替尼、维奈妥拉(50mg/kg)/吉瑞替尼、SNDX-50469/吉瑞替尼/维奈妥拉或SNDX-50469/吉瑞替尼/维奈妥拉/5-杂胞苷治疗携带PDX的NSG小鼠。由于用3种药物组合(1只小鼠在治疗第8天死亡)和4种药物组合(2只小鼠在治疗第7天死亡)(在随后的分析中排除)治疗的小鼠体重迅速减轻(指示毒性),我们从治疗第10天开始将这两组中的吉替尼剂量从35mg/kg减少到25mg/kg,将维奈妥拉剂量从50mg/kg减少到35mg/kg。减少维奈妥拉和吉瑞替尼的剂量防止了进一步的体重减轻(数据未显示)。
通过流式细胞仪测量和/或免疫组织化学染色在治疗结束时或濒死时收集的外周血或组织中的huCD45+细胞来评估疾病进展和治疗反应。为了评估治疗对BM白血病细胞群中白血病母细胞和表型确定的白血病干/祖细胞和蛋白质的影响,使用我们之前描述的抗体组(也包括HOXA9、MEIS1和PBX3)进行了治疗后CyTOF单细胞蛋白质组学。
在2周时,与未治疗的对照组相比,所有治疗显著降低了循环huCD45+细胞,并且吉瑞替尼和吉瑞替尼/维奈妥拉极大地增强了SNDX-50469活性(图6B)。在第4周,与对照组相比,所有处理显著减少了循环成纤维细胞;没有观察到治疗组之间的显著差异(图6C)。治疗后评估显示,所有治疗组的脾脏白血病负担都显著低于对照组;SNDX-50469、SNDX-50469/吉瑞替尼和SNDX-50469/吉瑞替尼/维奈妥拉的活性明显高于吉瑞替尼;SNDX-50469/吉瑞替尼/维奈妥拉比SNDX-50469和SNDX-50469/吉瑞替尼更有效,但没有达到统计学意义(图6D)。这些结果与脾脏大小的减少一致。所有治疗组的骨髓白血病负担也明显低于对照组;在治疗组中,吉瑞替尼是最不有效的,并且它没有增强SNDX-50469的活性,其活性明显高于吉瑞替尼;SNDX-50469/吉瑞替尼/维奈妥拉组中的BM白血病细胞百分比显著低于所有其他治疗组(图6E)。
与对照组(中值62天)相比,所有治疗显著延长了生存期(图6G)。SNDX-50469(128天)明显长于吉瑞替尼(90.5天;P=0.0001)。对照组和SNDX-50469治疗组小鼠的存活时间与我们之前的研究相似。与单独的SNDX-50469相比,SNDX-50469/吉瑞替尼(119天)并没有进一步延长生存期,这可能是因为这两种药物对FLT3信号传导具有重叠效应。吉瑞替尼/维奈妥拉组(121天)和SNDX-50469组的存活时间没有显著差异。然而,即使减少了吉瑞替尼和维奈妥拉的剂量,SNDX-50469/吉瑞替尼/维奈妥拉组合延长了生存期,显著长于SNDX-50469、吉瑞替尼、SNDX-50469/吉瑞替尼或维奈妥拉/吉瑞替尼,后者在HMA治疗中得到进一步改善。用3种药物或4种药物组合获得的存活时间比用SNDX-50469/维奈妥拉获得的存活时间长得多,并且在两组中仍有几只小鼠存活超过一年。
单独使用维奈妥拉对耐药/复发AML的临床疗效有限,老年AML患者对维奈妥拉与低甲基化药物联合用药的反应率较高。因此,我们也用SNDX-50469/吉瑞替尼/维奈妥拉加5-氮杂胞苷治疗小鼠。用4种药物组合治疗的小鼠的中位存活时间(长于用3种药物组合治疗的小鼠的中位存活时间(图6F,两组中的几只小鼠在一年后仍然存活)。用4种药物组合治疗的一只小鼠存活了258天(图6F中标记为*),并且在BM(0.06%)和脾(0.15%)中具有最小的白血病负担,并且在肺、肝或心脏中没有huCD45+细胞(图6G),表明疾病治愈。3种和4种药物组合组中的几只小鼠的寿命接近正常NSG小鼠的预期寿命。
在CyTOF分析中,白血病细胞根据细胞表面标记表达进行聚类(图7A)。图7B和7C分别显示了治疗组中存活的白血病母细胞和干/祖细胞的百分比以及每组代表性小鼠中的细胞群。正如我们之前报道的,SNDX-50469对CD34+CD38+和CD34+CD38+CD123+群体(CD34+CD38+CD123+Tim3+细胞除外)的活性高于CD34+CD38-、CD34+CD38-CD123+或CD34+CD38-CD123+Tim3+群体,后者对吉瑞替尼更敏感。SNDX-50469/吉瑞替尼组合与任一单独药物相比没有表现出增强的活性,并且3种药物的组合大大减少了白血病母细胞和白血病干/祖细胞。
蛋白质表达数据如图7D所示。与显示SNDX-50469对Molm13细胞中RNA水平的影响的研究相一致,CyTOF分析揭示,在体内,SNDX-50469和SNDX-50469/吉瑞替尼都大大降低了MEIS1和PBX3蛋白水平,但对HOXA9的影响较小。SNDX-50469/吉瑞替尼/维奈妥拉也降低HOXA9,并且比单独的SNDX-50469更显著地降低MEIS1和PBX,并抑制BCL-2、BCL-2A1和BCL-XL,与3种药物组合的效果一致。不出所料,SNDX-50469增加了CD11b。
我们的研究结果表明,与NPM1c/FLT3-ITD/TKDAML PDX模型中单一或双剂治疗相比,联合抑制menin、BCL-2和FLT3对AML细胞和干细胞祖细胞具有很强的活性,并减少了HOX下游靶点和抗凋亡BCL-2蛋白,这带来了更大的生存益处,即使剂量降低。
在3种药物联合组中,尽管FLT3水平降低,但残留的白血病细胞增加了pFLT3/MCL-1。未确定在4种药物组合组中pFLT3/MCL-1是否被抑制。然而,在3种药物组合中加入5-氮杂胞苷可以显著延长生存期。我们的数据强烈支持在NPM1/FLT3突变的AML中用低甲基化药物联合抑制剂menin、BCL-2和FLT3的临床评估。
如本文所示,SNDX-50469/吉瑞替尼/维奈妥拉组合对白血病细胞和AML干/祖细胞具有优异的活性,并显著延长了生存期(图6F;我们仍在跟踪一年后的生存期),导致存活持续时间比用SNDX-50469/维奈妥拉组合获得的存活持续时间长得多(图1G)。CyTOF分析显示,除了BCL-2,SNDX-50469还降低了体内的MEIS1和PBX3蛋白,并且3种药物的组合进一步降低了这些蛋白。向3部分组合中加入低甲基化药物5-氮杂胞苷进一步延长了生存期(图6F;我们仍在跟踪一年多后的存活情况),这种组合可能消除了一些小鼠的白血病。这些数据支持在NPM1/FLT3突变的AML中用低甲基化药物联合抑制剂menin、BCL-2和FLT3的临床评估。
Claims (30)
1.一种在有需要的受试者中治疗具有HOX基因标记的癌症的方法,包括给受试者施用有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的协同组合。
2.根据权利要求1所述的方法,其中所述menin抑制剂和Bcl-2抑制剂同时或依次口服施用。
3.根据权利要求1或权利要求2所述的方法,其中所述有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂的协同组合协同减少骨髓中的白血病CD34+CD38+/CD34+CD38-干细胞/祖细胞,协同减少大量白血病细胞,协同减少抗凋亡Bcl-2蛋白,与单独的menin抑制剂或Bcl-2抑制剂相比提高疗效,协同延长受试者的生存期,或其组合。
4.根据权利要求1或权利要求2所述的方法,其中所述有效治疗量的所述menin抑制剂和所述有效治疗量的Bcl-2抑制剂的协同组合协同地延长了所述受试者的生存期,其中所述受试者患有具有一个或多个AML突变的急性髓性白血病,所述AML突变选自具有异常细胞质定位的核磷蛋白1突变(NPM1c)、FLT3内部串联重复(FLT3-ITD)和/或FLT3酪氨酸激酶结构域突变(TKD)。
5.根据前述权利要求中任一项所述的方法,其中与作为单一药剂施用的有效治疗量相比,所述menin抑制剂的有效治疗量、所述Bcl-2抑制剂的有效治疗量或两者均减少。
6.根据前述权利要求中任一项所述的方法,其中所述menin抑制剂为5-氟-N,N-二异丙基-2-((4-(7-((反式-4-(甲基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)苯甲酰胺、N-乙基-2-((4-(7-((反式-4-(乙基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)-5-氟-N-异丙基苯甲酰胺、JNJ-75276617、KO-539、DS-1594b、DSP-5336,及其药学上可接受的盐,或其组合。
7.根据权利要求6所述的方法,其中所述menin抑制剂是5-氟-N,N-二异丙基-2-((4-(7-((反式-4-(甲基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)苯甲酰胺,或N-乙基-2-((4-(7-((反式-4-(乙基磺酰氨基)环己基)甲基)-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-5-基)氧基)-5-氟-N-异丙基苯甲酰胺,每天给药一次或两次,日剂量为200mg-600mg。
8.根据前述权利要求中任一项所述的方法,其中所述Bcl-2抑制剂是维奈妥拉、纳维托克、奥巴克拉、亚托曲塞、马利曲塞、S64315、奥利默森或其组合。
9.根据前述权利要求中任一项所述的方法,其中所述Bcl-2抑制剂是维奈妥拉,在第一周以20mg的日剂量给药,在第二周以50mg的日剂量给药,在第三周以100mg的日剂量给药,在第四周以200mg的日剂量给药,在第五周及随后的周以400mg的日剂量给药。
10.根据前述权利要求中任一项所述的方法,进一步包括施用CYP3A抑制剂。
11.根据前述权利要求中任一项所述的方法,进一步包括施用FLT3抑制剂。
12.根据权利要求11所述的方法,其中所述FLT3抑制剂是米哚妥林、索拉非尼、舒尼替尼、来他替尼、坦度替尼、吉瑞替尼、奎扎替尼、克雷诺拉尼或其组合。
13.根据前述权利要求中任一项所述的方法,进一步包括施用低甲基化药物。
14.根据权利要求11所述的方法,其中所述低甲基化药物是阿扎胞苷、地西他滨、瓜地西他滨或其组合。
15.根据前述权利要求中任一项所述的方法,进一步包括施用FLT3抑制剂和低甲基化药物。
16.根据前述权利要求中任一项所述的方法,进一步包括施用额外的化疗剂。
17.根据权利要求16所述的方法,其中所述额外的化疗剂包括阿糖胞苷、5-氟尿嘧啶、6-巯基嘌呤、卡培他滨、氟尿苷、氟达拉滨、吉西他滨、羟基脲、甲氨蝶呤、培美曲塞、光曲塞或其组合。
18.根据前述权利要求中任一项所述的方法,其中所述受试者先前已接受用于癌症的维奈妥拉治疗,且所述受试者在先前维奈妥拉治疗的基础上病情进展。
19.根据前述权利要求中任一项所述的方法,其中所述受试者先前已接受过维奈妥拉治疗并已对维奈妥拉产生抗性。
20.根据前述权利要求中任一项所述的方法,其中所述癌症为血液恶性肿瘤。
21.根据权利要求20所述的方法,其中所述血液恶性肿瘤是淋巴瘤、白血病或多发性骨髓瘤。
22.根据权利要求20所述的方法,其中所述血液恶性肿瘤是白血病。
23.根据权利要求22所述的方法,其中所述白血病是急性髓细胞性白血病、急性淋巴细胞性白血病、骨髓增生异常综合征、慢性髓细胞性白血病或慢性淋巴细胞性白血病。
24.根据权利要求23所述的方法,其中所述白血病是急性髓性白血病。
25.根据权利要求22-24中任一项所述的方法,其中所述白血病的特征在于混合谱系白血病(MLL)重排。
26.根据权利要求22-25中任一项所述的方法,其中所述白血病的特征在于核磷蛋白(NPM1)突变。
27.根据权利要求22-26中任一项所述的方法,其中所述白血病的进一步特征在于FLT3突变。
28.根据权利要求1所述的方法,其中具有HOX基因标记的癌症是乳腺癌、多发性骨髓瘤、卵巢癌、肾癌、结肠癌、结肠直肠癌、前列腺癌、胃癌、非小细胞肺癌、胶质母细胞瘤、宫颈癌、软骨肉瘤、骨肉瘤或神经母细胞瘤。
29.一种治疗组合,包含有效治疗量的menin抑制剂和有效治疗量的Bcl-2抑制剂。
30.根据权利要求29所述的治疗组合,进一步包含CYP3A抑制剂、FLT3抑制剂、低甲基化药物或其组合。
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