CN115698013A - Menin抑制剂和cyp3a4抑制剂的组合及其使用方法 - Google Patents
Menin抑制剂和cyp3a4抑制剂的组合及其使用方法 Download PDFInfo
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- CN115698013A CN115698013A CN202180040679.5A CN202180040679A CN115698013A CN 115698013 A CN115698013 A CN 115698013A CN 202180040679 A CN202180040679 A CN 202180040679A CN 115698013 A CN115698013 A CN 115698013A
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- inhibitor
- menin
- cyp3a4
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- cyp3a4 inhibitor
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Abstract
本发明涉及menin抑制剂与一种或多种CYP3A4抑制剂的组合、其药物组合物以及治疗由menin‑MLL相互作用介导的癌症和其他疾病的方法。
Description
相关申请的交叉引用
本申请要求于2020年4月7日提交的美国临时申请号63/006,574的优先权和权益,该申请的内容通过引用整体并入本文。
发明领域
本发明涉及与一种或多种CYP3A4抑制剂组合的、menin与MLL和MLL融合蛋白相互作用的抑制剂,含有其的药物组合物,及其在治疗由menin-MLL相互作用介导的癌症和其他疾病中的用途。
发明背景
混合谱系白血病(MLL)蛋白是一种组蛋白甲基转移酶,在急性白血病的临床和生物学特征亚群中发生突变。重组混合谱系白血病(MLL-r)涉及11q23染色体位点的反复易位,导致急性白血病的侵袭性形式,治疗选择有限。这些易位靶向MLL基因,产生包含与60多种不同融合蛋白伴侣在框架中融合的MLL的氨基末端的致癌融合蛋白。menin是一种由多内分泌肿瘤1型(MEN1)肿瘤抑制基因编码的广泛表达的核蛋白,与MLL融合蛋白具有高亲和力结合相互作用,是致癌MLL-r融合蛋白的重要辅因子(Yokoyama et al.,2005,Cell,123:207-18;Cierpicki&Grembecka,2014,Future Med.Chem.,6:447-462)。这种相互作用的破坏导致MLL-r白血病细胞在体外(Grembecka et al.,2012,Nat.Chem.Biol.,8:277-284)和体内(Yokoyama et al.,2005,op.cit.;Borkin et al.,2015,Cancer Cell,27:589-602)的选择性生长抑制和凋亡。
Menin-MLL复合物在去势耐受性/晚期前列腺癌中起作用,并且已显示menin-MLL抑制剂减少体内肿瘤生长(Malik et al.,2015,Nat.Med.,21:344-352)。此外,已显示menin-MLL抑制剂增强人β细胞增殖(Chamberlain et al.,2014,J.Clin.Invest.,124:4093-4101),支持menin-MLL相互作用的抑制剂在糖尿病治疗中的作用(Yang et al.,2010,Proc Natl Acad Sci U S A.,107∶20358-20363)。menin与MLL或MLL融合蛋白之间的相互作用是治疗干预的一个有吸引力的靶点,并且需要抑制menin-MLL相互作用的新型组合疗法,用于治疗各种疾病和病症,包括白血病、其他癌症和糖尿病。
发明概述
本发明提供了一种组合疗法,其包括menin抑制剂和CYP3A抑制剂。在某些实施方案中,本发明提供了一种药物组合物,包含:(a)menin抑制剂,和(b)CYP3A抑制剂。在一些实施方案中,本发明涉及一种治疗患者的方法,包括(a)施用menin抑制剂,和(b)施用CYP3A抑制剂。
本发明的一些实施方案涉及设计用于治疗或管理受试者的癌症的组合疗法,其中组合疗法包括施用menin抑制剂与CYP3A抑制剂组合。特别地,本发明的一些实施方案涉及治疗或管理受试者的癌症的方法,包括同时、分开或顺序地施用menin抑制剂与治疗有效量的CYP3A抑制剂组合。
在一些实施方案中,本发明提供了一种组合疗法,包括menin抑制剂和CYP3A4抑制剂。在某些实施方案中,本发明提供了一种药物组合物,包含:(a)menin抑制剂,和(b)CYP3A4抑制剂。在一些实施方案中,本发明涉及一种治疗患者的方法,包括(a)施用menin抑制剂,和(b)施用CYP3A4抑制剂。
本发明的一些实施方案涉及设计用于治疗或管理受试者的癌症的组合疗法,其中组合疗法包括施用menin抑制剂与CYP3A4抑制剂组合。特别地,本发明的一些实施方案涉及治疗或管理受试者的癌症的方法,包括同时、分开或顺序地施用menin抑制剂与治疗有效量的CYP3A4抑制剂组合。
在一些实施方案中,CYP3A抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A抑制剂是:泊沙康唑、阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁(grapefruitjuice);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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(starfruit);他克莫司(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;维拉帕米;特拉匹韦;长春新碱;伏立康唑;或其任何组合。
在一些实施方案中,CYP3A4抑制剂是泊沙康唑、考比司他(GS-9350)或者考比司他(GS-9350)的类似物或衍生物。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抑制剂和CYP3A4抑制剂是分开的剂型。在一些实施方案中,药物组合物为组合剂型。在一些实施方案中,CYP3A4抑制剂为泊沙康唑。
在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地增加menin抑制剂的口服生物利用度。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的Cmax。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的AUC。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC为增加为没有CYP3A4抑制剂施用menin抑制剂的AUC约2X至约30X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。
在一些实施方案中,药物组合物还包括氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,药物组合物还包括环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括苯达莫司汀和利妥昔单抗。在一些实施方案中,药物组合物还包括氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,药物组合物还包括环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括依托泊苷、多柔比星、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,药物组合物还包括地塞米松和来那度胺。
在某些实施方案中,本文公开了一种药物组合,包含治疗有效量的menin抑制剂和CYP3A4抑制剂。在一些实施方案中,组合为组合剂型。在一些实施方案中,组合为分开的剂型。在一些实施方案中,并行地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,同时、基本上同时或在相同的治疗方案内施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,顺序地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,CYP3A4抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A4抑制剂是:阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;维拉帕米;troleandromycin;长春新碱;伏立康唑;或其任何组合。
在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或者考比司他(GS-9350)的类似物或衍生物。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,药物组合物包含一定量的CYP3A4抑制剂,其有效地增加menin抑制剂的口服生物利用度。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的Cmax。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的AUC。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,药物组合物包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。
在一些实施方案中,药物组合物还包括氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,药物组合物还包括环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括苯达莫司汀和利妥昔单抗。在一些实施方案中,药物组合物还包括氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,药物组合物还包括环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括依托泊苷、多柔比星、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,药物组合物还包括地塞米松和来那度胺。
在一些实施方案中,CYP3A4抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A4抑制剂是:阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;troleandromycin;维拉帕米;特拉匹韦;长春新碱;伏立康唑;或其任何组合。
在一些实施方案中,CYP3A4抑制剂是泊沙康唑。在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或者考比司他(GS-9350)的类似物或衍生物。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抑制剂的每日剂量在约10mg至约500mg之间。在一些实施方案中,menin抑制剂的每日剂量在约200mg和约500mg之间。在一些实施方案中,menin抑制剂的每日剂量在约250mg和约460mg之间。在一些实施方案中,menin抑制剂的每日剂量为约226mg。在一些实施方案中,menin抑制剂的每日剂量为452mg。
在一些实施方案中,方法包括一定量的CYP3A4抑制剂,其有效地增加menin抑制剂的口服生物利用度。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的Cmax。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效增加menin抑制剂的AUC。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,方法包含一定量的CYP3A4抑制剂,其有效地将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。在一些实施方案中,方法包括与没有CYP3A4抑制剂施用menin抑制剂的Tmax和T1/2相比,不显著影响menin抑制剂的Tmax和T1/2的药物组合。在一些实施方案中,menin抑制剂和CYP3A4抑制剂为组合剂型。在一些实施方案中,menin抑制剂和CYP3A4抑制剂为分开的剂型。在一些实施方案中,并行地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,同时、基本上同时或在同一治疗方案内施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,顺序地施用menin抑制剂和CYP3A4抑制剂。
附图的简单说明
图1显示了口服施用使用和不使用CYP3A4抑制剂泊沙康唑时的式II的menin抑制剂后稳态AUC的变化。
发明详述
与CYP3A4抑制剂组合施用的小分子menin抑制剂一起作用于治疗受多种细胞类型影响或影响多种细胞类型的多种疾病。
在一些实施方案中,本发明提供了一种组合疗法,包括menin抑制剂和CYP3A4抑制剂。在一些实施方案中,本发明提供了一种药物组合物,包含:(a)menin抑制剂,和(b)CYP3A4抑制剂。在一些实施方案中,本发明涉及一种治疗患者的方法,包括(a)施用menin抑制剂,和(b)施用CYP3A4抑制剂。在一些实施方案中,本发明涉及一种治疗患者的方法,包括(a)施用包含menin抑制剂的药物组合物,和(b)施用包含CYP3A4抑制剂的药物组合物。
本发明的一些实施方案涉及设计用于治疗或管理受试者的癌症的组合疗法,其中组合疗法包括施用menin抑制剂与CYP3A4抑制剂组合。特别地,本发明的一些实施方案涉及治疗或管理受试者的癌症的方法,包括同时、分开或顺序地施用menin抑制剂与治疗有效量的CYP3A4抑制剂组合。
在一些实施方案中,组合疗法增加menin抑制剂的血浆水平。在一些实施方案中,组合疗法增强抑制剂治疗多种疾病的功效。在一些实施方案中,组合疗法协同作用以治疗癌症。在一些实施方案中,组合治疗增强、增加或延长治疗效果的效力或持续时间。在一些实施方案中,CYP3A4抑制剂增强、增加和/或延长menin抑制剂的治疗效果的效力或持续时间。
在一些实施方案中,menin抑制剂是5-氟-N,N-二异丙基-2-((4-(7-(((1r,4r)-4-(甲基磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬-2-基)嘧啶-5-基)氧基)苯甲酰胺(式I),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,menin抑制剂是N-乙基-2-((4-(7-(((1r,4r)-4-(乙基磺酰胺基)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(式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,menin抑制剂包含任何立体异构体、几何异构体和/或互变异构体。根据本文所公开的本发明,menin抑制剂选自式(I)和式(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。
式I也描述为化学名称:5-氟-N,N-二异丙基-2-((4-(7-((反式-4-(甲基磺酰胺基)环己基)甲基)-2,7-二氮杂螺[3.5]壬-2-基)嘧啶-5-基)氧基)苯甲酰胺。式II也描述为化学名称:N-乙基-2-((4-(7-((反式-4-(乙基磺酰胺基)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。
在一些实施方案中,药学上可接受的盐是双甲磺酸盐。在一些实施方案中,药学上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,当与CYP3A4抑制剂组合时,menin抑制剂以较低剂量是治疗有效的。在一些实施方案中,menin抑制剂与CYP3A4抑制剂组合是更有效的。
在一些实施方案中,与CYP3A4诱导剂组合施用menin抑制剂。在一些实施方案中,CYP3A4诱导剂包括但不限于阿伐麦布、苯妥英、卡马西平、利福平、恩杂鲁胺和圣约翰麦芽汁中的一种或多种。
在一些实施方案中,menin抑制剂是式I并且CYP3A4抑制剂是唑类抗真菌剂。在一些实施方案中,menin抑制剂是式II并且CYP3A4抑制剂是唑类抗真菌剂。
在一些实施方案中,menin抑制剂是式I并且CYP3A4抑制剂是泊沙康唑。在一些实施方案中,menin抑制剂是式II并且CYP3A4抑制剂是泊沙康唑。
术语
除非另有定义,否则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,前述一般描述和以下详细描述仅是示例性的和说明性的,并不限制所要求保护的任何主题。在本申请中,除非另有特别说明,否则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使用的,除非上下文另有明确规定,否则单数形式“一个”、“一种”和“该”包括复数指称。在本申请中,除非另有说明,否则“或”的使用是指“和/或”。
此外,术语“包括”以及其他形式,如“包含”、“含有”和“含”的使用不受限制。
此处使用的章节标题仅用于组织目的,不得解释为限制所述主题。本申请中引用的所有文件或部分文件,包括但不限于专利、专利申请、文章、书籍、手册和论文,出于任何目的,特此通过引用将其全文明确并入本文。
术语“可接受”或“药学上可接受”,就本文所用的制剂、组合物或成分而言,是指对治疗对象的总体健康没有持续的有害影响,或不会消除化合物的生物活性或性质,且相对无毒。
“生物利用度”是指被递送至研究动物或人类全身循环中的所给药的menin抑制剂的百分比。静脉注射给药时,药物的总暴露量(AUC(0-∞))通常定义为100%生物利用度(F%)。“口服生物利用度”是指与静脉注射相比,口服药物组合物时,menin抑制剂被吸收到全身循环中的程度。
“血浆浓度”是指受试者血液中血浆组分中menin抑制剂的浓度。据了解,由于代谢和/或与其他治疗剂的可能相互作用的可变性,受试者之间的menin抑制剂的血浆浓度可以显著不同。根据本文所公开的一些实施方案,menin抑制剂的血液或血浆浓度可因受试者而异。同样,最大血浆浓度(Cmax)或达到最大血浆浓度的时间(Tmax),或血浆浓度-时间曲线下的总面积(AUC(0-∞))可能因受试者而异。由于这种可变性,构成“治疗有效量”的menin抑制剂所需的量可以因受试者而异。
本文中使用的术语“共施用”等意指包括对单个患者施用所选治疗剂,并意在包括通过相同或不同的施用途径或在相同或不同时间施用试剂的治疗方案。
本文中使用的术语“有效量”或“治疗有效量”是指施用的足量的试剂或化合物,其将在一定程度上缓解正在治疗的疾病或病况的一种或多种症状。结果可以是减少和/或减轻疾病的体征、症状或原因,或生物系统的任何其他期望的改变。例如,用于治疗用途的“有效量”是包括本文所公开的化合物的组合物的量,其是提供疾病症状的临床显著减少而无不当不良副作用所需要的。任何个别情况下的适当“有效量”可使用技术确定,如剂量递增研究。术语“治疗有效量”包括例如预防有效量。本文公开的化合物的“有效量”是指有效达到预期药理作用或治疗改善并且效果无不良副作用的量。据了解,“有效量”或“治疗有效量”因受试者而异,原因在于menin抑制剂的代谢,受试者的年龄、体重、一般情况,正在治疗的情况、正在接受治疗的病况的严重程度以及处方医生的判断。仅作为示例,治疗有效量可通过常规实验确定,包括但不限于剂量递增临床试验。
术语“增强”或“增强了”是指在效力或持续时间上增加或延长预期效果。例如,“增强”治疗剂的效果是指在治疗疾病、病症或病况期间,增加或延长治疗剂效力或持续时间的能力。本文所用的“增强有效量”是指足以增强治疗剂在治疗疾病、病症或病况中的效果的量。当用于患者时,对该用途有效的量将取决于疾病、病症或病况的严重程度和病程,既往治疗,患者的健康状况和对药物的应答,以及治疗医生的判断。术语“受试者”、“患者”和“个体”可以互换使用。如本文所用,它们指的是动物。仅作为示例,受试者可以是但不限于哺乳动物,包括但不限于人类。这些术语不需要医疗专业人员的监督(无论是连续的还是间歇的)。
如本文所用的术语“治疗”、“在治疗”或“进行治疗”包括减轻、减弱或缓解疾病或病况症状,预防额外症状,缓解或预防症状的潜在代谢原因,抑制疾病或病况,例如,阻止疾病或病况的发展,缓和疾病或病况,引起疾病或病况的消退,缓和由疾病或病况引起的状况,或者停止疾病或病况的症状。术语“治疗”、“在治疗”或“进行治疗”包括但不限于预防性和/或治疗性处理。
如本文所用,IC50是指在测量所述应答的测定法中实现最大应答的50%抑制(例如menin的抑制)的特定测试化合物的量、浓度或剂量。
如本文所用,EC50是指在特定测试化合物诱导、激发或增强的特定应答的最大表达的50%时引发剂量依赖性应答的特定测试化合物的量、浓度或剂量。
多种药学上可接受的盐由menin抑制剂形成,并且包括:通过menin与有机酸反应而形成的酸加成盐,有机酸包括脂肪族单羧酸和二羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香酸、脂肪族和芳香族磺酸、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、柠檬酸、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menin抑制剂与无机酸反应而形成的酸加成盐,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。
术语“药学上可接受的盐”指的是menin抑制剂的盐,其不会对所施用的哺乳动物造成显著刺激,也不会基本上消除该化合物的生物活性和性质。
应当理解,提及药学上可接受的盐包括溶剂加成形式(溶剂化物)。溶剂化物含有化学计量或非化学计量的量的溶剂,并且在产品形成或与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)、二噁烷、庚烷、甲苯、苯甲醚、乙腈等。在一个方面,溶剂化物使用但不限于3类溶剂形成。溶剂的类别定义于,例如,International Conference onHarmonization of Technical Requirements for Registration of Pharmaceuticalsfor Human Use(ICH),″Impurities:Guidelines for Residual Solvents,Q3C(R3),(November 2005)。当溶剂是水时,形成水合物,或当溶剂是醇时,形成醇酸盐。在一些实施方案中,在本文所述的过程中,可以方便地制备或形成menin抑制剂的溶剂化物或其药学上可接受的盐。在一些实施方案中,menin抑制剂的溶剂化物是无水的。在一些实施方案中,menin抑制剂或其药学上可接受的盐以非溶剂化形式存在。在一些实施方案中,menin抑制剂或其药学上可接受的盐以非溶剂化形式存在并且是无水的。
在另一些实施方案中,以各种形式制备menin抑制剂或其药学上可接受的盐,包括但不限于非晶相、结晶形式、研磨形式和纳米颗粒形式。在一些实施方案中,menin抑制剂或其药学上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和无水的。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的和无水的。
一般CYP3A抑制剂
在某些实施方案中,本文公开了包括menin抑制剂和CYP3A抑制剂的药物组合。在某些实施方案中,本文进一步公开了包括menin抑制剂的药物组合物和药物组合物CYP3A抑制剂的组合。
细胞色素P4503A(缩写为CYP3A)是细胞色素P450混合功能氧化酶系统的成员。CYP3A基因座包括细胞色素P450基因超家族3A亚家族的所有已知成员。这些基因编码单加氧酶,其催化药物代谢和胆固醇、类固醇和其他脂质合成中的许多反应。CYP3A簇由四个基因组成;CYP3A4、CYP3A5、CYP3A7和CYP3A43。
细胞色素P450酶修饰多种底物,包括羟基化、环氧化、芳香族氧化、杂原子氧化、N-和O-脱烷基、醛氧化和脱氢。
在一些实施方案中,并行地(例如,同时、基本上同时或在同一治疗方案内)或顺序地共施用menin抑制剂和CYP3A抑制剂。
在一些实施方案中,以分开的剂型共施用menin抑制剂和CYP3A抑制剂。在一些实施方案中,以组合剂型共施用menin抑制剂和CYP3A抑制剂。
在一些实施方案中,menin抑制剂抑制剂和CYP3A抑制剂的共施用增加menin抑制剂的口服生物利用度。在一些实施方案中,menin抑制剂抑制剂和CYP3A抑制剂的共施用增加menin抑制剂的Cmax。在一些实施方案中,menin抑制剂和CYP3A抑制剂的共施用增加menin抑制剂的AUC。在一些实施方案中,menin抑制剂和CYP3A抑制剂的共施用增加menin抑制剂的T1/2。
本文公开的组合物或疗法可以单独施用给患者或可以组合施用(例如同时、顺序或分开)。在一些实施方案中,CYP3A4抑制剂在menin蛋白抑制剂之前施用。在一些实施方案中,CYP3A4抑制剂在menin蛋白抑制剂之前施用。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,并且在式II的menin抑制剂之前施用。
在一些实施方案中,在时间上接近地施用menin抑制剂和CYP3A抑制剂(例如,menin抑制剂和CYP3A抑制剂最初可以同时施用)。因此,本公开提供了一种治疗或预防癌症的方法,包括在时间上接近地施用menin抑制剂和CYP3A抑制剂。在一些实施方案中,“时间上接近”是指在施用另一种治疗剂之前或之后的一段时间内施用一种治疗剂物,使得一种治疗剂的治疗效果与另一种药物的治疗效果重叠。在一些实施方案中,一种治疗剂的治疗效果与另一种治疗剂的治疗效果完全重叠。
在一些实施方案中,“时间上接近”是指在施用另一种治疗剂之前或之后的一段时间内施用一种治疗剂物,使得在一种治疗剂和另一种治疗剂之间存在协同效应。“时间上接近”可能会因各种因素而不同,包括但不限于将对其施用治疗剂的受试者的年龄、性别、体重、遗传背景、医疗状况、病史和治疗史;待治疗或缓解的疾病或状况;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;治疗剂的药代动力学和药效学;以及施用治疗剂的途径。在一些实施方案中,“时间上接近”是指在15分钟内、30分钟内、一小时内、两小时内、四小时内、六小时内、八小时内、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、一周内、2周内、3周内、4周内、6周内或8周内。在一些实施方案中,一种治疗剂的多次施用可以在时间上接近另一种治疗剂的单次施用。在一些实施方案中,在治疗周期期间或在给药方案内,时间上接近可以改变。
“组合疗法”旨在包括以顺序或同时的方式施用本文公开的治疗剂,其中每种治疗剂在不同的时间施用,以及并行地或以基本同时的方式施用这些治疗剂或至少两种治疗剂。例如,可以通过向受试者施用具有每种治疗剂的固定或可变比例的单个胶囊或每种治疗剂物的多个单个胶囊来实现同时施用。每种治疗剂的顺序或基本同时施用可受任何适当途径的影响,包括但不限于口服途径、静脉途径、肌肉内途径和通过粘膜组织的直接吸收。治疗剂可以通过相同途径或不同途径施用。例如,所选组合的第一治疗剂可以通过静脉注射而施用,而组合的其他治疗剂可以口服施用。可替代地,例如,所有治疗剂可以口服施用,或者所有治疗剂都可以通过静脉注射而施用。治疗剂的施用顺序可以变化。治疗剂也可以交替施用。
在一些实施方案中,本公开提供了menin抑制剂和CYP3A抑制剂的协同组合,其中menin抑制剂和CYP3A抑制剂在人体内(例如,仅在人体内)相互接触。在一些实施方案中,本公开提供了一种通过使menin抑制剂和CYP3A抑制剂在位点处彼此接触来制备组合疗法的方法。在一些实施方案中,通过使menin抑制剂和CYP3A抑制剂在位点处相互接触来制备组合疗法的方法发生在人体中(例如,仅在人体中)。
本文公开的,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。
与CYP3A4抑制剂的组合
在某些实施方案中,本文公开了包含menin抑制剂和CYP3A4抑制剂的组合。
在某些实施方案中,本文进一步公开了包含menin抑制剂和CYP3A4抑制剂的药物组合。
细胞色素P4503A4(缩写为CYP3A4)(EC 1.14.13.97)是细胞色素P450混合功能氧化酶系统的成员。细胞色素P450蛋白是单加氧酶,其催化药物代谢中的许多反应。CYP3A4由CYP3A4基因编码。该基因是染色体7q21.1上细胞色素P450基因簇的部分。CYP3A4参与大量底物的氧化,例如menin抑制剂。
细胞色素P450酶修饰多种底物,包括羟基化、环氧化、芳香族氧化、杂原子氧化、N-和O-脱烷基、醛氧化和脱氢。
在一些实施方案中,并行地(例如,同时、基本上同时或在同一治疗方案内)或顺序地共施用menin蛋白抑制剂和CYP3A4抑制剂。
在一些实施方案中,以分开的剂型共施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,以组合剂型共施用menin抑制剂和CYP3A4抑制剂。
在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的口服生物利用度。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的Cmax。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC。
在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的Cmax为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的Cmax约25X至约35X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约20X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约21X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约22X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约23X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约24X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约25X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约26X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约27X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约28X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约29X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约30X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约30X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约32X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约33X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约34X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约35X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约36X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约37X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约38X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约39X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin蛋白的Cmax约40X。
在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约20X至约30X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增制menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约15X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约2X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约3X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约4X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施加增加menin抑制剂的AUC约5X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约6X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约7X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约8X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约9X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约10X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约11X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约12X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约13X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约14X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约15X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约16X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约17X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约18X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约19X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约20X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约21X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约22X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约23X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约24X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约25X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约26X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约27X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约28X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约29X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约30X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约31X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约32X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约33X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约34X。在一些实施方案中,menin抑制剂和CYP3A4抑制剂的共施用增加menin抑制剂的AUC约35X。
任何合适的每日剂量的CYP3A4抑制剂都可以与本文公开的组合物、剂型和方法一起使用。例如,CYP3A4抑制剂的每日剂量取决于CYP3A4抑制剂的强度。弱CYP3A4抑制剂(如西咪替丁)将需要比中等CYP3A4抑制剂(如红霉素、葡萄柚汁、维拉帕米、地尔硫卓)更高的每日剂量,而中等CYP3A4抑制剂需要比强CYP3A4抑制剂更高的每日剂量(如茚地那韦、奈非那韦、利托那韦、克拉霉素、伊曲康唑、酮康唑、奈法唑酮)。
示例性CYP3A4抑制剂
在一些实施方案中,将menin抑制剂与选自以下的CYP3A4抑制剂共施用:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。
在一些实施方案中,至少一种CYP3A4抑制剂选自分配给SequoiaPharmaceuticals,Inc.的以下一项或多项专利申请中公开的化合物,其中每项专利申请的公开均通过引用并入本文:美国专利公布号US 2005/0209301和美国专利公布号US2005/0267074。在一些实施方案中,至少一种CYP3A4抑制剂选自分配给BioavailabilitySystems,LLC的以下一项或多项专利和专利申请中公开的化合物,其中每项专利申请的公开均通过引用并入本文:US 2004058982,U.S.Pat.No.6,248,776,U.S.Pat.No.6,063,809,U.S.Pat.No.6,054,477,U.S.Pat.No.6,162,479,WO 2000054768,U.S.Pat.No.6,309,687,U.S.Pat.No.6,476,066,U.S.Pat.No.6,660,766,WO 2004037827,U.S.Pat.No.6,124,477,U.S.Pat.No.5,820,915,U.S.Pat.No.5,993,887,U.S.Pat.No.5,990,154,U.S.Pat.No.6,255,337。
在一些实施方案中,menin抑制剂与以下共施用:泊沙康唑、考尼伐坦、洛匹那韦、阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS→9350);考比司他(GS→9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3→OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;维拉帕米;特拉匹韦;troleandromycin;长春新碱;伏立康唑;或其任何组合。在一些实施方案中,menin抑制剂与考比司他(GS-9350)或考比司他(GS-9350)的类似物或衍生物共施用。在一些实施方案中,menin抑制剂与酮康唑共施用。在一些实施方案中,menin抑制剂与利托那韦共施用。安定→3-OH指3-羟基地西泮和奎尼丁→3-OH是指3-羟基奎尼丁。在一些实施方案中,CYP3A4抑制剂是上面或下面列出的一种或多种的药学上可接受的盐。
预期任何合适的CYP3A4抑制剂与本文公开的组合物、剂型和方法一起使用。CYP3A4抑制剂的选择取决于多种因素。例如,需要考虑的因素包括menin抑制剂每日剂量的期望减少、CYP3A4抑制剂的任何其他药物相互作用以及CYP3A4抑制剂的服用时间。在某些情况下,CYP3A4抑制剂是可以长期服用(例如慢性地)的CYP3A4抑制剂。在一些实施方案中,CYP3A4抑制剂服用有限的时间,并且menin抑制剂慢性地服用。
在某些实施方案中,本文公开了增加menin抑制剂的Cmax的方法,包括共施用menin蛋白和CYP3A4抑制剂的组合。在一些实施方案中,menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案种,方法增加menin抑制剂的AUC。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。
在某些实施方案中,本文公开了增加menin抑制剂的AUC的方法,包括施用menin蛋白和CYP3A4抑制剂的组合。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,方法增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。在一些实施方案种,方法增加menin抑制剂的Cmax。在一些实施方案中,menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,与没有CYP3A4抑制剂施用menin抑制剂的Tmax或T1/2相比,方法不显著影响menin抑制剂的Tmax或T1/2。
使用的方法
在一些实施方案中,是治疗有此需要的个体的癌症的方法,包括施用menin抑制剂和CYP3A4抑制剂的组合。因此,本发明的组合和方法被认为对广泛的癌症有效,包括但不限于血液学癌症(例如,白血病和淋巴瘤)、膀胱癌、脑癌(例如,胶质瘤、弥漫性固有脑桥胶质瘤(DIPG))、乳腺癌(例如,三阴性乳腺癌、雌激素受体阳性乳腺癌(即ER+乳腺癌))、结直肠癌、宫颈癌、胃肠道癌(例如结直肠癌,胃癌)、泌尿生殖系统癌、头颈癌、肝癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌(例如去势抗性前列腺癌)、肾癌(例如肾细胞癌)、皮肤癌、甲状腺癌(例如甲状腺乳头状癌)、睾丸癌、肉瘤(例如尤因肉瘤)和AIDS相关癌症。在一些实施方案中,癌症与重排的MLL基因相关。在一些实施方案中,癌症的病理生理学依赖于MLL基因。在一些实施方案中,MLL基因是MLL1。在一些实施方案中,癌症与突变的p53功能获得相关。
在一些实施方案中,可通过本文所述的组合、组合物和方法治疗的特定癌症包括心脏癌,例如肉瘤(例如,血管肉瘤、纤维肉瘤、横纹肌肉瘤和脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺癌,包括例如支气管原癌(例如鳞状细胞、未分化小细胞、未分化大细胞和腺癌)、肺泡癌和细支气管癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤性错构瘤、间皮瘤、非小细胞肺癌、小细胞肺癌,支气管腺瘤/类癌和胸膜肺母细胞瘤;胃肠道癌,包括例如食道的癌症(例如鳞状细胞癌、腺癌、平滑肌肉瘤和淋巴瘤)、胃的癌症(例如癌、淋巴瘤和平滑肌肉瘤)、胰腺的癌症(例如导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌和vipoma)、小肠的癌症(例如,腺癌、淋巴瘤、类癌肿瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤和纤维瘤)、大肠或结肠的癌症(例如,腺癌、管状腺瘤、绒毛腺瘤、错构瘤和平滑肌瘤),和消化道的其他癌症(例如,肛门癌、肛门直肠癌、阑尾癌、肛管的癌症、舌头的癌症、胆囊癌、胃肠道间质瘤(GIST)、结肠癌、结直肠癌、肝外胆管癌、肝内胆管癌、直肠癌和小肠癌);泌尿生殖道癌症,包括例如肾脏的癌症(例如腺癌、肾母细胞瘤(肾母细胞癌)、淋巴瘤和白血病)、膀胱和尿道的癌症(例如鳞状细胞癌、移行细胞癌和腺癌)、前列腺的癌症(例如,腺癌和肉瘤)、睾丸的癌症(例如,精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤和脂肪瘤),以及移行细胞癌、肾盂和输尿管和其他泌尿器官的移行细胞癌症、尿道癌和膀胱癌;肝癌,包括例如肝癌(例如肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤和血管瘤;骨癌,包括例如骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因肉瘤、淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨色素瘤(骨软骨外生瘤)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤;神经系统癌症,包括例如颅骨的癌症(例如骨瘤、血管瘤、肉芽肿、黄瘤和变形性骨炎);脑膜的癌症(如脑膜瘤、脑膜肉瘤和胶质瘤病);脑的癌症(例如,星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形胶质母细胞瘤,少突胶质瘤、神经鞘瘤、视网膜母细胞瘤和先天性肿瘤);脊髓的癌症(例如神经纤维瘤、脑膜瘤、胶质瘤和肉瘤)和其他神经系统癌症(例如脑干胶质瘤、弥漫性固有脑桥胶质瘤(DIPG)、脑瘤、中枢神经系统癌、小脑星形细胞瘤、脑星形细胞细胞瘤/恶性胶质瘤、儿童小脑星形胶质细胞瘤、儿童脑星形细胞癌、原发性中枢神经系统淋巴瘤、视觉通路和下丘脑胶质瘤、神经系统淋巴瘤、幕上原始神经外胚层肿瘤、成松细胞瘤和幕上原始神经外胚层瘤);妇科癌症,包括例如子宫的癌症(例如子宫内膜癌)、宫颈的癌症(例如宫颈癌和癌前宫颈异型增生),卵巢的癌症(例如卵巢癌,包括浆液性囊腺癌、粘液性囊腺癌、未分类癌、颗粒鞘细胞瘤、Sertoli Leydig细胞瘤、无性细胞瘤和恶性畸胎瘤)、外阴的癌症(例如鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤和黑色素瘤)、阴道的癌症(如透明细胞癌、鳞状细胞癌、葡萄状肉瘤和胚胎性横纹肌肉瘤)和输卵管的癌症(如癌);其他生殖道癌症,包括,例如,子宫内膜癌、子宫内膜子宫癌、生殖细胞瘤、妊娠滋养层肿瘤、妊娠滋养细胞肿瘤胶质瘤、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低恶性潜能肿瘤、阴茎癌、阴道癌、外阴癌、颅外生殖细胞肿瘤,性腺外生殖细胞瘤,子宫癌、子宫体癌、子宫肉瘤;淋巴癌和血液癌,包括例如血液的癌症(例如,急性髓系白血病(AML)、慢性髓系白血病(CML)、急性成淋巴细胞性白血病(ALL)、慢性成淋巴细胞性白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤和骨髓增生异常综合征、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)和其他淋巴癌或血液癌,包括例如儿童白血病、骨髓增生性疾病(例如原发性骨髓纤维化)、浆细胞肿瘤/多发性骨髓瘤、骨髓发育不良、骨髓增生异常综合征、皮肤T细胞淋巴瘤、淋巴肿瘤、AIDS相关淋巴瘤、胸腺瘤、胸腺瘤和胸腺癌、蕈样肉芽肿和Sézary综合征;皮肤癌,包括例如恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣增生异常痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、银屑病、默克尔细胞癌、默克尔皮肤癌、黑色素瘤和类癌;肾上腺癌,包括例如神经母细胞瘤;与内分泌系统相关的其他癌症,包括例如肾上腺皮质癌、多发性内分泌瘤(例如,I型多发性肿瘤)、多发内分泌瘤综合征、甲状旁腺癌、垂体瘤、嗜铬细胞瘤、胰岛细胞胰腺癌和胰岛细胞瘤);结缔组织癌(例如骨癌、骨和关节癌、骨肉瘤和恶性纤维组织细胞瘤);与头、颈和口腔相关的癌症(例如,头颈癌、鼻窦和鼻腔癌、转移性鳞状颈癌、口癌、喉癌、食管癌、喉咙癌、咽癌、下咽癌、唇和口腔癌、鼻咽癌、口腔癌、口咽癌和唾液腺癌);以及与眼睛相关的癌症(例如眼癌、眼内黑色素瘤)。在一些实施方案中,癌症是尤因肉瘤。
在一些实施方案中,癌症是血液学癌症,例如白血病或淋巴瘤。可由本发明化合物治疗的示例性白血病和淋巴瘤包括混合谱系白血病(MLL)、MLL相关白血病、MLL相关性白血病、MLL-阳性白血病、MLL-诱导的白血病、重排混合谱系白血病(MLL-r)、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、无痛性白血病、成淋巴细胞性白血病、淋巴细胞白血病、髓系白血病、髓细胞白血病、儿童白血病、急性淋巴细胞白血病(ALL)(也称为急性成淋巴细胞性白血病或急性淋巴细胞白血病)、急性髓系白血病(AML)(也称为急性骨髓性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、慢性淋巴细胞白血病(CLL)(也称为慢性成淋巴细胞性白血病)、慢性粒细胞白血病(CML)(也称为慢性髓系白血病)、治疗相关白血病、骨髓增生异常综合征(MDS)、骨髓增生性疾病(MPD)(如原发性骨髓纤维化(PMF))、骨髓增殖性瘤变(MPN)、浆细胞瘤、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、AIDS相关淋巴瘤、胸腺瘤、胸腺的癌、蕈样肉芽肿、Alibert-Bazin综合征、肉芽肿样肉芽炎、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、非霍奇金氏淋巴瘤(恶性淋巴瘤)和Waldenstrom巨球蛋白血症。在一些实施方案中,急性髓系白血病(AML)是抽象核磷蛋白(NPM1)突变的急性髓系(即,NPM1mut急性髓系)白血病。
在特定的实施方案中,本发明的化合物用于治疗与MLL重排相关的白血病、与MLL重排相关的急性淋巴细胞白血病、与MLL重排相关的急性成淋巴细胞性淋巴瘤、与MLL重排相关的急性淋巴细胞性白血病、与MLL重排相关的急性髓性白血病、与MLL重排相关的急性髓细胞白血病或与MLL重排相关的急性成髓细胞白血病。如本文所用,“MLL重排”是指MLL基因的重排。
在一些实施方案中,CYP3A4抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A4抑制剂是:阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;troleandromycin;维拉帕米;特拉匹韦;长春新碱;伏立康唑;或其任何组合。在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或考比司他(GS-9350)的类似物或衍生物。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,方法增加menin抑制剂的Cmax。在一些实施方案中,menin抑制剂的Cmax增加为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,方法增加menin抑制剂的AUC。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,方法将menin抑制剂的AUC增加为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。在一些实施方案中,与没有CYP3A4抑制剂施用menin抑制剂的Tmax和T1/2相比,方法不显著影响menin抑制剂的Tmax和T1/2。在一些实施方案中,menin抑制剂和CYP3A4抑制剂为组合剂型。在一些实施方案中,menin抑制剂和CYP3A4抑制剂为分开的剂型。在一些实施方案中,并行地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,同时、基本上同时或在同一治疗方案内施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,顺序地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,方法还包括共施用氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,方法还包括共施用环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,方法还包括共施用苯达莫司汀和利妥昔单抗。在一些实施方案中,方法还包括共施用氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,方法还包括共施用环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,方法还包括共施用依托泊苷、多柔比星、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,方法还包括共施用地塞米松和来那度胺。在一些实施方案种,menin抑制剂是无定形的或结晶。
恶性淋巴瘤是主要存在于淋巴组织内的细胞的肿瘤转化。两组恶性淋巴瘤是霍奇金淋巴瘤和非霍奇金恶性淋巴瘤(NHL)。这两种类型的淋巴瘤都浸润网状内皮组织。然而,它们在起源的肿瘤细胞、疾病的部位、系统症状的存在和对治疗的应答方面有所不同((Freedman et al.,″Non-Hodgkin′s Lymphomas″Chapter 134,Cancer Medicine,(anapproved publication of the American Cancer Society,B.C.Decker Inc.,Hamilton,Ontario,2003)。
本组合还可用于治疗具有MLL/KMT2A基因重排的白血病患者。
白血病
在某些实施方案中,本文公开了一种治疗有此需要的个体的白血病的方法,包括:施用menin抑制剂或CYP3A4抑制剂。在一些实施方案中,本文公开了一种治疗有此需要的个体的白血病的方法,包括:施用menin抑制剂和施用CYP3A4抑制剂。在某些实施方案中,本文进一步公开了一种治疗有此需要的个体的白血病的方法,包括:施用包含menin抑制剂和CYP3A4抑制剂的药物组合物。在本文公开的一些实施方案中,是一种治疗有此需要的个体的白血病的方法,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。
白血病是一种血液或骨髓的癌症,其特征是血细胞,通常是白细胞(白血细胞)的异常增加。白血病是一个涵盖多种疾病的广义术语。第一种是急性和慢性形式:(i)急性白血病的特征是未成熟血细胞迅速增加。这种拥挤使得骨髓无法产生健康的血细胞。急性白血病需要立即治疗,因为恶性细胞的快速发展和积累,然后外溢到血流中并扩散到身体的其他器官。白血病的急性形式是儿童种白血病的最常见形式;(ii)慢性白血病的区别是相对成熟但仍异常的白血细胞过度积聚。通常需要数月或数年的时间才能进展,这些细胞的产生速度远远高于正常细胞,导致血液中出现许多异常的白血细胞。慢性白血病主要发生在老年人,但理论上可以发生在任何年龄组。此外,疾病根据受影响的血细胞类型进行细分。这种分裂将白血病分为成淋巴细胞性或淋巴细胞白血病和髓系或骨髓性白血病:(i)成淋巴细胞性或淋巴细胞性白血病,癌性变化发生在一种通常形成淋巴细胞的骨髓细胞中,淋巴细胞是抵抗感染的免疫系统细胞;(ii)髓系或骨髓性白血病,癌变发生在一种骨髓细胞中,通常会形成红血细胞、一些其他类型的白细胞和血小板。
在这些主要类别中,有几个子类别,包括但不限于急性成淋巴细胞性白血病(ALL)、急性髓细胞白血病(AML)、慢性髓细胞白血病(CML)和毛细胞白血病(HCL)。
上述每种病况的症状、诊断测试和预后测试都是已知的。例如,见Harrison′sPrinciples of Internal″16th ed.,2004,The McGraw-Hill Companies,Inc.Dey et al.(2006),Cytojournal 3(24)和″Revised European American Lymphoma″(REAL)classification system(see,e.g.,the website maintained by the NationalCancer Institute)。
许多动物模型可用于建立一系列治疗有效剂量的抑制剂化合物,如menin抑制剂,用于治疗任何前述疾病。
在治疗过程中,可以优化menin抑制剂对上述任何一种疾病的治疗功效。例如,正在治疗的受试者可以接受诊断评估,以将疾病症状或病理的缓解与通过施用给定剂量的menin抑制剂实现的体内menin活性的抑制相关联。本领域已知的细胞测定法可用于测定体内活性。因此,可以根据需要增加或减少施用给受试者的menin抑制剂化合物的量,以保持治疗受试者疾病状态的最佳menin抑制水平。
在一些实施方案中,menin抑制剂和CYP3A4抑制剂用于制备用于治疗任何前述病况的药物。在一些实施方案中,本发明的组合涉及治疗白血病。在一些实施方案中,本发明涉及治疗有此需要的患者的白血病,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,本发明涉及治疗有此需要的患者的白血病,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,本发明涉及治疗有此需要的患者的白血病,包括施用包含式I的menin抑制剂的药物组合物和包含唑类抗真菌CYP3A4抑制剂的药物组合物。
急性白血病通常由造血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。许多这些染色体异常是由于特定的易位导致融合基因的形成,融合基因成为肿瘤发生和肿瘤发展的驱动因素。一个具体的示例涉及MLL1基因。MLL1基因座(11q23)的易位可导致形成以MLLr急性白血病为特征的致癌基因融合。MLL1蛋白是发育的关键调节因子,是三胸果蝇的哺乳动物同源物。它是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,将MLL1的N末端融合到来自不同易位伴侣的可变C末端结构域。目前已知有90多种不同的融合伙伴。这些融合物的表达使得以HOX和其他发育基因的过度表达为特征的异常转录程序得以实现。该转录程序抑制分化并增强增殖,导致MLLr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。根据起源的祖细胞,MLLr可以表现为ALL、AML或混合表型急性白血病(MPAL)。这些易位是罕见的,在美国、欧洲和日本,MLLr每年的总发病率为~4000例。大约10%的全部白血病有MLL1易位。
本组合还可用于治疗具有MLL/KMT2A基因重排的白血病患者。
MLLr患者在常规化疗和干细胞移植后的复发风险很高,总体5年生存率仅为约35%。目前尚无特异性靶向MLLr白血病的治疗方法。式I或式II的menin抑制剂与CYP3A4抑制剂组合可为MLLr急性白血病提供新的靶向治疗。
复发性或难治性MLLr急性白血病的治疗
MLL1融合蛋白与menin的相互作用是MLLr急性白血病的关键驱动因素。MLL1和MLLr融合物两者都与染色质相关蛋白menin上的一个特征良好的高亲和力位点结合。MLL1融合物与menin的结合是由MLL1的N末端的氨基酸残基9-13(FPARP)介导的。与menin的结合将这些融合物定位于染色质,从而启动白血病转录程序,包括HOXA基因座和MEIS1基因的上调。融合蛋白和menin之间的相互作用是维持这个转录程序所必需的。
式I或式II的menin抑制剂以高亲和力结合menin上的MLL1结合袋,并在含有MLLr融合物的一系列细胞中显示活性。式I或式II的menin抑制剂破坏menin与白血病活性所需的MLL1融合蛋白之间的相互作用,从而损害了关键癌基因的表达,导致生长停滞和细胞增殖的抑制。已经报道了menin-MLL相互作用的小分子抑制剂。这些抑制剂已显示出对MLLr细胞系的抗增殖活性,并在MLLr白血病小鼠模型中显示出单剂存活益处。
类似地,将式I或式II的menin抑制剂与CYP3A4抑制剂组合增加了功效,并在多种白血病异种移植模型中显示出强大的活性,并在非临床模型中口服给药后提供了深远的生存益处。总的来说,这些数据表明,对menin-MLL相互作用的药物抑制是治疗MLLr急性白血病的潜在靶向策略。
NPM1c AML
AML是一种急性白血病,其特征是由于分化和增殖受损产生的骨髓中的髓细胞积聚。NPM1是AML中最常见的突变基因之一。NPM1基因中的点突变导致突变蛋白的异常细胞质定位,称为NPM1c。NPM1c的鉴定是AML诊断筛查的重要部分。仅在NPM1具有突变的AML患者预后良好,五年总生存率(OS)为~60%。然而,大多数(>80%)NPMlc AML患者具有多重并发突变,这可能对预后产生不利影响。在FLT3、DNMT3A、NRAS、TET2和IDH1/2基因中发现了共突变。NPM1c通常不见于ALL。
美国癌症协会估计,2019年美国将有~21450例AML新病例。在成人AML中,~30%的患者患有NPM1c。鉴于发现携带NPM1c的细胞对menin-MLL相互作用抑制剂非常敏感,式I或式II的menin抑制剂与CYP3A4抑制剂组合可为NPM1cAML提供新的靶向治疗。
NPM1c AML患者的治疗
NPM1通常作为一种核仁蛋白存在于细胞核和细胞质之间。它具有多种功能,包括核糖体蛋白质的组装和运输、中心体复制的控制和肿瘤抑制因子ARF的调节。突变体NPMlc的胞质定位导致NPM1c相关核蛋白异常分配到细胞质中,包括几种转录因子。其中包括PU.1,单核细胞谱系分化的主要驱动因素。从NPM1c AML中细胞核的PU.1损失导致>500个末端分化基因的抑制。NPM1c对分化的抑制使得白血病转录程序能够高度依赖于HOXA簇和MEIS1基因的上调表达。这些基因的表达进一步阻断分化并诱导长期增殖,导致白血病表型。
此外,NPM1c AML的HOX/MEIS标签与MLLr白血病和造血干细胞(HSC)的HOX/MEIS标签重叠。NPM1c细胞中这种转录特征的维持直接依赖于menin-MLL1相互作用。
虽然对于突变NPM1c细胞如何维持异常基因表达知之甚少,但由于MLL1与menin的结合丧失,MLL1中menin结合基序的突变已显示强烈抑制NPM1c的增殖能力。此外,小分子menin-MLL相互作用抑制剂MI-503被证明可以抑制NPM1c细胞中的HOXA/MEIS1转录程序,导致生长停滞、终末分化和细胞死亡,证实了menin-MLL1相互作用在NPM1c中的关键作用。这些发现在另一份报告中得到了验证和扩展,该报告证明口服活性的menin抑制剂KO-539在NPM1c突变AML患者衍生的异种移植模型中具有强大的抗白血病活性。总的来说,这些结果表明,携带NPM1c的细胞对menin-MLL相互作用抑制剂非常敏感。
在一些实施方案中,本发明的组合用于治疗NMP1 AML。在一些实施方案中,本发明涉及在有此需要的患者中治疗NMP1 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,本发明涉及在有此需要的患者中治疗NMP1 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,本发明涉及在有此需要的患者中治疗NMP1 AML,包括施用包含式I的menin抑制剂的药物组合物和包含唑类抗真菌CYP3A4抑制剂的药物组合物。
其他组合疗法
在某些情况下,适当的是施用menin抑制剂和CYP3A4抑制剂与其他治疗剂组合。在某些情况下,适当的是施用menin抑制剂和CYP3A4抑制剂与另外的CYP3A4抑制剂组合。另外的治疗剂是针对它们对正在治疗的病况具有特殊的用途进行选择的。通常,不需要以相同的药物组合物、同时或通过相同的途径以及menin抑制剂和/或CYP3A4抑制剂施用另外的治疗剂。在一些实施方案中,根据已建立的方案进行初始施用,然后基于观察到的效果,进一步修改剂量、施用模式和施用时间。
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,并行地(例如,同时、基本上同时或在相同的治疗方案内)或顺序地施用另外的治疗剂。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施用重复次数的确定是基于对正在治疗的疾病和患者状况的评估。
另外的治疗剂的剂量根据另外的治疗剂、正在治疗的疾病或病况等而变化。
在某些实施方案中,本文公开了治疗有此需要的个体中的自身免疫性病症、异种免疫性病症,炎症性病症和/或癌症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文进一步公开了治疗有此需要的个体的自身免疫性病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文还公开了治疗有此需要的个体中的异种免疫病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文公开了在有此需要的个体中治疗炎症性病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文进一步公开了在有此需要的个体中治疗癌症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。
在某些实施方案中,本文公开了治疗有此需要的个体中的自身免疫性病症、异种免疫性病症,炎症性病症和/或癌症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文进一步公开了治疗有此需要的个体的自身免疫性病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文还公开了治疗有此需要的个体中的异种免疫病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文公开了在有此需要的个体中治疗炎症性病症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。在某些实施方案中,本文进一步公开了在有此需要的个体中治疗癌症的方法,包括向个体施用menin抑制剂、CYP3A4抑制剂和另外的治疗剂。
在一些实施方案中,在第二癌症治疗方案之前施用menin抑制剂减少对第二癌症治疗方案的免疫介导反应。在一些实施方案中,在奥法木单抗之前施用menin抑制剂减少对奥法木单抗的免疫介导反应。
在一些实施方案中,另外的治疗剂是化疗剂、类固醇、免疫治疗剂、靶向疗法或其组合。在一些实施方案中,另外的治疗剂是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,另外的治疗剂是抗体、B细胞受体信号传导抑制剂、PI3K抑制剂、IAP抑制剂、mTOR抑制剂、放射免疫疗法、DNA损伤剂、蛋白体抑制剂、组蛋白脱乙酰酶抑制剂、蛋白激酶抑制剂、刺猬抑制剂、Hsp90抑制剂、端粒酶抑制剂、Jak1/2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,另外的治疗剂是氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,另外的治疗剂是环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,另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,另外的治疗剂是包括氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,另外的治疗剂是环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,另外的治疗剂是依托泊苷、多柔比星、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,另外的治疗剂是地塞米松和来那度胺
可以与menin抑制剂和CYP3A4抑制剂的组合结合施用的另外的治疗剂包括但不限于氮芥,例如苯达莫司汀、氯丁嘧啶、氯甲嘧啶、环磷酰胺、异环磷酰胺、美法仑、泼尼莫司汀(prednimustine)、曲磷胺;烷基磺酸盐,如白消安、甘露舒凡、曲奥舒凡;乙烯亚胺,如碳醌、硫替帕、三氮醌;亚硝基脲类,如卡莫司汀、福莫司汀、洛莫司汀、尼莫司汀、雷尼莫司丁、塞莫司汀和链脲;环氧化物,例如依托糖酸;其他烷基化剂,例如达卡巴嗪、二溴甘露醇(mitobronito1)、哌泊溴烷(pipobroman)、替莫唑胺(temozolomide);叶酸类似物,例如甲氨蝶呤、哌美曲塞、普拉曲沙(Pralatrexate)、雷替曲塞(raltitrexed);嘌呤类似物,例如克拉德宾、氯法拉宾、氟达拉宾、巯基嘌呤、奈拉宾、硫鸟嘌呤;嘧啶类似物,例如阿扎胞苷、卡培他滨、卡莫氟、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、长春花碱、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,例如去秋水仙素;紫杉醇,例如多西他赛、紫杉醇、紫杉醇聚葡萄糖;其他植物生物碱和天然产物,例如曲贝替定;放线菌素,例如达克霉素;抗环素类,例如多柔比星、柔红霉素、多柔比星、表柔比星、依达比星、米托蒽醌、吡柔比星、缬柔比星和佐红霉素;其他细胞毒性抗生素,例如博莱霉素、伊沙贝隆、丝裂霉素、褶皱霉素;铂化合物,例如卡铂、顺铂、奥沙利铂、沙特拉铂;甲基肼,例如丙卡巴嗪;敏化剂,例如氨基乙酰丙酸、依法普罗司、氨基乙酰丙酯甲酯、波菲美钠、替莫福姆;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、帕佐尼尼、索拉非尼、舒尼替尼、坦罗莫司;其他抗肿瘤剂,例如阿维酸、阿曲他明、氨扎克林、阿那格雷、三氧化二砷、天冬酰胺酶、贝沙罗汀、硼替佐米、塞来昔布、地尼白介素(denileukin diftitox)、雌霉素、羟基尿素、伊立替康、罗尼达明、马索罗酚(Masoprocol)、密尔替磷、米托瓜酮、米托坦、布洛米森(oblimersen)、培门冬酶(pegaspargase)、戊唑醇、罗美肽、sitimagene ceradenovec、噻唑呋喃、托泊替康(topotecan)、维甲酸、伏立诺他(vorinostat);雌激素,例如己烯雌酚、炔雌醇、磷雌醇、聚雌二醇磷酸酯;
孕激素,例如孕酮、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,例如富维他汀、他莫昔芬、托雷米芬;抗雄激素,例如比卡鲁胺、氟他胺、尼鲁酰胺,酶抑制剂、氨基谷氨酰亚胺、阿那曲唑、依西美坦、福美坦、来曲唑、伏罗唑;其他激素拮抗剂,例如阿巴瑞克(Abarelix)、地加瑞克(degarelix);免疫刺激剂,如组胺二氢氯化物、米法脲、匹多莫德、普利沙韦、罗奎尼美、胸腺五肽;免疫抑制剂,例如依维莫司、古斯派莫司、来氟米特、霉酚酸、西罗莫司;钙调素抑制剂,例如环孢素、他克莫司;其他免疫抑制剂,例如硫唑嘌呤、来那度胺、甲氨蝶呤、沙利度胺;以及放射性药物,例如碘苯胍。
可与menin抑制剂和CYP3A4抑制剂的组合结合施用的其他治疗剂包括但不限于干扰素、白介素、肿瘤坏死因子、生长因子等。
可以与menin抑制剂和CYP3A4抑制剂的组合结合施用的另外的治疗剂包括但不限于,免疫刺激剂,例如安西替姆、非格司亭、来格司亭(lenograstim)、莫拉司亭(molgramostim)、聚乙二醇非格司亭(pegfilgrastim)和沙格司亭(sargramostin);干扰素,例如干扰素α-天然、干扰素a-2a、干扰素α-2b、干扰素α-1、干扰素o-nl、干扰素β-天然、干扰素β-1a、干扰素β-1b、干扰素γ、聚乙二醇干扰素o-2a、聚乙二醇干扰素α-2b;白细胞介素,例如白细胞介蛋白、奥拉韦金;其他免疫刺激剂,例如BCG疫苗、醋酸格拉替拉姆、二氢组胺、免疫色素苷、香菇多糖、黑色素瘤疫苗、米法莫肽、聚乙二醇酶、匹多莫德、普利沙韦、poly I:C、poly ICLC、罗奎尼美、塔索那明、胸腺五肽;免疫抑制剂,例如阿巴他西普、阿贝替莫斯、阿莱西普、抗淋巴细胞免疫球蛋白(马)、抗胸腺细胞免疫球蛋白(兔)、埃克单抗、依法单抗、依维莫司、胍立莫司、来氟米特、muromab-CD3、霉酚酸、那他珠单抗、西罗莫司;TNFα抑制剂,例如阿达木单抗、阿非莫单抗、塞托利珠单抗、依那西普、戈利单抗、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、卡纳金单抗、达利珠单抗、美泊利珠单单抗、利罗纳西普、托利珠单克隆抗体、乌司特金单抗;钙调素抑制剂,例如环孢素、他克莫司;其他免疫抑制剂,如硫唑嘌呤、来那度胺、甲氨蝶呤、沙利度胺。
可与menin抑制剂和CYP3A4抑制剂的组合结合施用的其他治疗剂包括但不限于阿达木单抗(Adalimumab)、阿仑单抗(Alemtuzumab)、巴西利单抗(Basiliximab)、贝伐单抗(Bevacizumab)、西妥昔单抗(Cetuximab)、塞托利单抗聚乙二醇(Certolizumab pegol)、达利珠单抗(Daclizumab)、依库珠单抗(Eculizumab)、依法珠单抗(Efalizumab)、吉妥单抗(Gemtuzumab)、替伊莫单抗(Ibritumomab tiuxetan)、英夫利昔单抗(Infliximab)、莫罗单抗-CD3(Muromonab-CD3)、纳他珠单抗(Natalizumab)、帕尼单抗(Panitumum)、雷珠单抗(Ranibizumab)、利妥昔单抗(Rituximab)、托西莫单抗(Tositumomab)、曲妥珠单抗(Trastuzumab)等或其组合。
可以与menin抑制剂和CYP3A4抑制剂的组合结合施用的另外的治疗剂包括但不限于单克隆抗体,例如阿仑单抗、贝伐单抗、卡妥索单抗(catumaxomab)、西妥昔单抗、依决罗单抗(edrecolomab)、吉妥单抗、奥法珠单抗、帕尼单抗、利妥昔单抗、曲妥珠单抗、免疫抑制剂、依库珠单抗、依法珠单抗、莫罗单抗-CD3、那他珠单抗;TNF-α抑制剂,例如阿达木单抗、阿非莫单抗(afelimomab)、塞托利珠单抗聚乙二醇(certolizumab pegol)、戈利木单抗(golimumab)、英夫利昔单抗(infliximab);白介素抑制剂、巴利昔单抗(basiliximab)、卡纳金单抗(canakinumab)、达利珠单抗(daclizumab)、美普利单抗(mepolizumab)、托西单抗(tocilizumab)、乌司特单抗(ustekinumab);放射性药物、替伊莫单抗(ibritumomabtiuxetan)、托西莫单抗(tositumomab);其他单克隆抗体,例如阿巴伏单抗(abagovomab)、阿德木单抗(adecatumumab)、阿仑单抗(alemtuzumab)、抗CD30单克隆抗体Xmab2513、抗MET单克隆抗体MetMab、阿泊珠单抗(apolizumab)、apomab、阿西莫单抗(arcitumomab)、巴利昔单抗(basiliximab)、双特异性抗体2B1、博纳吐单抗(blinatumab)、维布妥昔单抗(brentuximab vedotin)、capromab pendetide、西妥木单抗(cixutumab)、claudiximab、可那木单抗(conatumab)、达西组单抗(dacetuzumab)、地诺单抗(denosumab)、依库丽单抗(eculizumab)、依帕珠单抗(epratuzumab)、依帕珠单抗(epratuzumab)、厄妥索单抗(ertumaxomab)、埃达组单抗(etaracizumab)、芬妥木单抗(figitumumab)、fresoliumab、加利昔单抗(galiximab)、加尼妥单抗(ganitumab)、吉妥珠单抗(gemtuzumab ozogamicin)、格巴妥木单抗(glembatumumab)、替伊莫单抗(ibritumomab)、inotuzumab ozogamicin、伊匹单抗(ipiliumab)、lexatuumab、林妥珠单抗(lintuzumab)、林妥珠单抗、卢卡木单抗(lucatumab)、mapatummab、马妥珠单抗(matuzumb)、milatuzumab、单克隆抗体CC49、耐昔妥珠单抗(nectumab)、尼妥珠单抗(nimotuzumab)、奥法木单抗(ofatumab)、奥戈伏单抗(oregovomab)、帕妥珠单抗(pertuzumab)、雷莫芦单抗(ramacurimab)、雷珠单抗(ranibumab)、西利珠单抗(siplizumab)、索那普利单抗(sonepcizumab)、坦珠单抗(tanezumab),托西妥单抗(tositumomab)、曲妥珠单抗(trastuzumab)、特雷利单抗(tremelimumab)、tucotuzumab celmoleukin、维妥组单抗(veltuzumb)、维西珠单抗(visilizumab)、伏洛昔单抗(volociximab)、扎芦木单抗(zalutuumab)。
可以与menin抑制剂和CYP3A4抑制剂的组合结合施用的其他治疗剂包括但不限于影响肿瘤微环境的试剂,例如细胞信号传导网络(例如磷脂酰肌醇3-激酶(PI3K)信号传导通路、来自B细胞受体和IgE受体的信号传导)。在某些实施方案中,第二试剂是PI3K信号传导抑制剂或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,第二试剂是PKCy抑制剂,例如仅作为示例的恩扎妥林。
影响肿瘤微环境的试剂的示例包括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、尼洛替尼、帕唑帕尼、索拉非尼、舒尼替尼、坦罗莫司;其他血管生成抑制剂,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、阿西替尼、AZD1152、AZD7762、AZD28055、AZD 8931、巴菲替尼、BAY 73-4506、BGJ398、BGT226、BI 811283、BI6727、BIBF 1120、BIBW 2992、BMS-690154、BMS-777607、BMS-863233、BSK-461364、CAL-101、CEP-1981、CYC116、DCC-2036、dinaciclib、乳酸多维替尼、E7050、EMD 1214063、ENMD-2076、福坦替尼二钠、GSK2256098、GSK690693、INCB18424、INNO-406、JNJ-26483327、JX-594、KX2-391、利尼法尼(linifanib)、LY2603618、MGCD265、MK-0457、MK1496、MLN8054、MLN8237、MP470、NMS-1116354、NMS-1286937、ON01919.Na、OSI-027、OSI-930、PF-00562271、PF-02341066、PF-03814735、PF-04217903、PF-04554878、PF-04691502、PF-3758309、PHA-739358、PLC3397、祖细胞生成素、R547、R763、雷莫芦单抗(ramucirumab)、瑞戈非尼(regorafenib)、R05185426、SAR103168、SCH727965、SGI→1176、SGX523、SNS→314、TAK-593、TAK-901、TKI258、TLN-232、TTP607、XL147、XL228、XL281R05126766、XL418、x1765。
与menin抑制剂和CYP3A4抑制剂组合使用的治疗剂的其他示例包括但不限于丝裂原激活蛋白激酶信号传导抑制剂,例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素(wortmannin)或LY294002;Syk抑制剂;mTOR抑制剂;和抗体(例如利妥昔单抗)。
可与menin抑制剂和CYP3A4抑制剂组合使用的其他试剂包括但不限于多柔比星、达克霉素、博莱霉素、长春碱、顺铂、阿昔韦;阿柔比星;盐酸阿哒唑;阿克罗宁(acronine);阿多来新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波霉素(ambomycin);醋酸阿美蒽醌(ametantroneacetate);氨鲁米特(aminoglutethimide);安吖啶(amsacrine);阿那曲挫(anastrozole);蒽霉素(anthramycin);天冬酰胺酶(asparaginase);曲林菌素(asperlin);阿扎胞苷(azacitidine);阿扎替派(azetepa);阿佐霉素(azotomycin);巴马司他(batimastat);苯佐替派(benzodepa);比卡鲁胺(bicalutamide);盐酸比生群(bisantrene hydrochloride);甲横酸双萘法特(bisnafidedimesylate);比折来新(bizelesin);硫酸博来霉素;布喹那钠(brequinar sodium);溴匹立明(bropirimine);白消安;放线菌素C(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡贝替姆(carbetimer);卡钼;卡莫司汀(carmustine);盐酸卡柔比星(carubicin hydrochloride);卡折来新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西罗霉素(cirolemycin);克拉屈滨(cladribine);甲磺酸克立那托(crisnatol mesylate);环磷酰胺(cyclophosphamide);阿糖胞苷(cytarabine);达卡巴嗪(dacarbazine);盐酸柔红霉素(daunorubicin hydrochloride);地西他滨(decitabine);右奥马钼(dexormaplatin);地扎胍宁(dezaguanine);甲磺酸地扎胍宁(dezaguaninemesylate);地吖醌(diaziquone);多柔比星;盐酸多柔比星;屈洛昔芬(droloxifene);枸橡酸屈洛昔芬;丙酸屈他雄酮(dromostanolone propionate);达佐霉素(duazomycin);依达曲沙(edatrexate);盐酸依氟鸟氨酸(eflornithine hydrochloride);依沙芦星(elsamitrucin);恩洛钼(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);厄布洛挫(erbulozole);盐酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸钠;依他硝挫(etanidazole);依托泊苷(etoposide);磷酸依托泊苷;氯苯乙喃胺(etoprine);盐酸法倔挫(fadrozole hydrochloride);法扎拉滨(fazarabine);芬维A胺(fenretinide);氟脲喃啶脱氧核苷(floxuridine);磷酸氟达拉滨(fludarabine phosphate);氟脲喃啶(fluorouracil);氟西他滨(flurocitabine);磷喹酮(fosquidone);福司曲星钠(fostriecin sodium);吉西他滨(gemcitabine);盐酸吉西他滨;羟基脲;盐酸伊达比星(idarubicin hydrochloride);异环磷酰胺(ifosfamide);iimofosine;白细胞介素II(包括重组白细胞介素II或r1L2)、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;异丙钼;盐酸伊立替康(irinotecan hydrochloride);醋酸兰瑞肽(lanreotide acetate);来曲挫(letrozole);醋酸亮丙瑞林(leuprolide acetate);盐酸利阿挫(liarozole hydrochloride);洛美曲索钠(lometrexol sodium);洛莫司汀(1omustine);盐酸洛索蒽醌(losoxantrone hydrochloride);马索罗酷(masoprocol);美坦生(maytansine);盐酸双氯乙基甲胺(mechlorethamine hydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美仑孕酬(melengestrol acetate);美法仑;美诺立尔(menogaril);疏喂呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);丝裂红素(mitocromin);米托洁林(mitogillin);米托马星(mitomalcin);丝裂霉素(mitomycin);米托司培(mitosper);米托坦(mitotane);盐酸米托蒽醌(mitoxantrone hydrochloride);麦考酷酸(Mycophenolic Acid);诺考达挫(nocodazoie);诺拉霉素(nogalamycin);奥马钼(ormaplatin);奥昔舒仑(oxisuran);培门冬酶(pegaspargase);培利霉素(peliomycin);溴新斯的明(pentamustine);硫酸培洛霉素(peplomycin sulfate);培磷酰胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);盐酸吡罗蒽醌(piroxantrone hydrochloride);普卡霉素(piicamycin);普洛美坦(plomestane);卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼莫司汀(prednimustine);盐酸丙卡巴肼(procarbazine hydrochloride);嘌呤霉素(puromycin);盐酸嘌呤霉素(puromycinhydrochloride);吡挫霉素(pyrazofurin);利波腺苷(riboprine);罗谷亚胺(rogletimide);沙芬戈(safingol);盐酸沙芬戈;司莫司汀(semustine);辛曲秦(simtrazene);磷乙酰天冬氨酸钠(sparfosate sodium);司帕霉素(sparsomycin);盐酸锗螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺钼(spiroplatin);链黑菌素(streptonigrin);链佐星(streptozocin);磺氯苯脲(sulofenur);他利霉素(talisomycin);替可加兰钠(tecogalan sodium);替加氟(tegafur);盐酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替罗昔隆(teroxirone);睾内酪(testolactone);硫咪嘌呤(thiamiprine);硫鸟嘌呤(thioguanine);塞替派(thiotepa);噻唑呋林(tiazofurin);替拉扎明(tirapazamine);柠檬酸托瑞米芬(toremifene citrate);乙酸曲托龙(trestolone acetate);磷酸曲西立滨(triciribine phosphate);三甲曲沙(trimetrexate);葡酸三甲曲沙;曲普瑞林(triptorelin);盐酸妥布氯唑(tubulozole hydrochloride);乌拉莫司汀(uracilmustard);乌瑞替派(uredepa);伐普肽(vapreotide);维替泊芬(verteporfin);硫酸长春碱(vinblastine sulfate);硫酸长春新碱(vincristine sulfate);长春地辛(vindesine);硫酸长春地辛;硫酸长春匹定(vinepidine sulfate);硫酸长春甘酯(vinglycinate sulfate);硫酸长春罗新(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbine tartrate);硫酸长春罗定(vinrosidine sulfate);硫酸长春利定(vinzolidine sulfate);伏氯挫(vorozole);折尼钼(zeniplatin);净司他丁(zinostatin);盐酸佐柔比星(zorubicin hydrochloride)。
可与menin抑制剂和CYP3A4抑制剂的组合结合施用的其他治疗剂包括但不限于20-epi-1,25-二羟基维生素D3;5-乙基尿嘧啶;阿比特龙;阿柔比星;酰基氟烷;阿德赛酚;adozelene;醛白素;ALL-TK拮抗剂;牛磺酸;安巴西汀;酰胺氧;氨磷汀;氨基乙酰丙酸;氨柔比星(Amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安替雷利;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;甘氨酸蚜虫素;凋亡基因调节剂;凋亡调节因子;亚嘌呤酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;苦味酸;阿他美坦;阿莫司汀(atrimustine);axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼;氮杂毒素;氮杂酪氨酸;baccatin III衍生物;巴洛尔(balanol);巴马司他;BCR/ABL拮抗剂;苯并二氢卟吩;苯甲酰星孢菌素;β内酰胺衍生物;β-alethine;β-clamycin B;桦木酸;bFGF抑制剂;比卡鲁胺;比生群;双氮丙啶基精胺;双奈法德;bistratene A;比折来新;breflate;溴匹立明;布度钛;丁硫堇;卡泊三醇;卡弗他丁C;喜树碱衍生物;canarypox IL-2;卡培他滨;氨甲酰基氨基三唑;羧酰氨三唑;CaRest M3;CARN 700;软骨源性抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);栗精胺;杀菌肽B;西曲瑞克;绿素类(chlorlns);氯喹喔啉磺酰胺;西卡前列素;顺-卟啉(cis-porphyrin);克拉屈滨;氯米芬类似物;克霉唑;collismycin A;collismycin B;考布他丁A4;考布他丁类似物;conagenin;crambescidin 816;克立那托;cryptophycin 8;cryptophycin A衍生物;curacin A;环戊稀蒽醌(cyclopentanthraquinone);环铀(cycloplatam);cypemycin;阿糖胞苷十八烷基磷酸盐;溶细胞因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱水代代宁B;地洛瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌;代代宁B;didox;二乙基去甲精胺;二氢-5-氮胞苷;9-dioxamycin;二苯基螺莫司汀;多西他赛;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;倍癌毒素SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;依托泊苷磷酸盐;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺;flavopiridol;氟卓斯汀;氟阿固酮(fluasterone);氟达拉滨;fluorodaunorunicin盐酸盐;福酸美克;福美坦;福司曲星;福莫司汀;德克萨卟啉钆;硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;heregulin;六亚甲基双乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;imidazoacridone;咪喹莫特;免疫刺激剂肽;胰岛素例如生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘多柔比星;4-甘薯苦醇;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalideF;片螺素-N三醋酯盐;兰瑞肽;leinamycin;来格司亭;硫酸蘑菇多糖;leptolstatin;来曲唑;白血病抑制因子;白细胞α干扰素;亮脯利特+雌激素+黄体酮;亮丙瑞林;左旋咪唑;利阿唑;直链聚胺类似物;亲脂性二糖肽;亲脂性铀化合物;lissoclinamide 7;洛铂;胍乙基磷酸丝氨酸(lombricine);洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;德克萨卟啉镥;利索茶碱(lysofylline);裂解肽;美坦新;制甘糖酶素A;马立马司他;马索罗酸;maspin;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;麦尔巴隆(merbarone);美替瑞林;蛋氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;米托毒素(mitotoxin)成纤维细胞生长因子-皂素;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒毛膜促性腺激素;单磷酰酯A+分支杆菌细胞壁sk;莫昵达醇;多种药物耐性基因抑制剂;基于多肿瘤抑制剂1的疗法;芥末抗癌剂;印度洋海绵B(mycaperoxide B);分支杆菌细胞壁萃取;myriaporone;N-乙酰地那林;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;奈达铀;奈莫柔比星;奈立膦酸;中性肽链内切酶;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;06-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口腔细胞因子诱导剂;奥马铀;奥沙特隆;奥沙利铀;oxaunomycin;palauamine;棕榈酰根霉素;帕米磷酸;人参三醇;帕诺米芬;副球菌素;帕折普汀;培门冬酶;培得星;木聚硫钠;喷司他丁;pentrozole;全氟溴烷;培磷酰胺;紫苏子醇;苯连氮霉素;乙酸苯酯;磷酸酶抑制剂;溶链菌;盐酸毛果芸香碱;啦柔比星;啦曲克辛;帕斯婷A;帕斯婷B;纤维蛋白溶酶原活化因子抑制剂;铂络合物;铂化合物;铂-三胺络合物;扑吩姆钠;泊非霉素;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A的免疫调节剂;蛋白激酶C抑制剂;微藻蛋白激酶C抑制剂;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;紫红素;吡唑啉吖啶;吡醇羟乙酯化血红蛋白聚氧乙烯结合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基化的瑞替普汀;轻乙二磷酸铼Re 186;根霉素;核糖酶;RII视黄酰胺;罗希吐碱;罗莫肽;罗喹美克;rubiginone Bl;ruboxy1;沙芬戈;SarCNU;saintopin;sarcophytol A;沙格司亭;Sdi 1模拟物;司莫司汀;衰老源抑制剂1;正义寡核苷酸;信号转导抑制剂;信号转导调节剂;单练抗原结合蛋白;西佐喃;索布佐生;硼卡钠;苯基乙酸钠;solverol;促生长因子结合蛋白;索纳明;膦门冬酸;穗霉素D;螺莫司汀;脾脏五肽;海绵抑制素1;角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;基质降解酶抑制剂;sulfinosine;超强血管活性肠肽拮抗剂;suradista;苏拉明;苦马豆碱;合成萄糖胺多糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂;替莫泊芬(temoporfm);替莫唑胺;替尼泊苷;tetrachlorodecaoxide;tetrazomine;菌体胚素;噻可拉林;促血小板生成素;促血小板生成素模拟物;胸腺法新;促胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;tin ethyletiopurpurin;替拉扎明;二氯环戊二稀钛;topsentin;托瑞米芬;全能干细胞因子;转化抑制剂;维甲酸;酪氨酸激酶抑制剂;三乙酰基尿肝(triacetyluridine);曲西立滨;三甲曲沙;曲普瑞林;托烧司琼;妥罗雄脲;酪氨酸激酶抑制剂;tyrphostins;UBC抑制剂;乌苯美司;泌尿生殖窦源生长抑制因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统,红细胞基因疗法;维拉雷琐;藜芦明;verdins;维替泊芬;长春瑞滨;vinxaltine;整合素诘抗剂(vitaxin);伏氯唑;扎诺特隆;折尼铀;亚节维C和净司他丁斯酯。
可与menin抑制剂和CYP3A4抑制剂的组合结合施用的另外的治疗剂包括但不限于另一种CYP3A4抑制剂、烷基化剂、抗代谢剂、天然产物或激素,例如氮芥(例如,甲氯乙胺、环磷酰胺、氯丁嘧啶等)、烷基磺酸盐(例如,丁砜)、亚硝基脲(如卡莫司汀、洛莫司汀等)或三氮烯(达卡巴嗪等)。抗代谢物的示例包括但不限于叶酸类似物(例如,甲氨蝶呤)或嘧啶类似物(如,阿糖胞苷)、嘌呤类似物(比如,巯基嘌呤、硫代鸟嘌呤和喷司他丁)。
烷基化剂的示例包括但不限于氮芥(例如,甲氯乙胺、环磷酰胺、氯丁嘧啶、美法仑等)、亚乙基胺和甲基甲胺(例如,六甲基三聚氰胺、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、链霉素等)或三氮烯(达卡巴嗪等)。抗代谢物的示例包括但不限于叶酸类似物(例如,甲氨蝶呤)或嘧啶类似物(如,(e.g.,氟尿嘧啶,floxouridine,阿糖胞苷)、嘌呤类似物(比如,巯基嘌呤、硫代鸟嘌呤,喷司他丁)。
可与menin抑制剂和CYP3A4抑制剂的组合结合施用的另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)、异硫代米沃布林(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)、Altorhyrtin(例如Altorhyrtin A和Altorhyrtin C)、海绵素(例如海绵素1、海绵素2、海绵素3、海绵素4、海绵素5、海绵素6、海绵素7、海绵素8和海绵素9)、盐酸西马多丁(也称为LU-103793和NSC-D-669356)、埃博霉素(例如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素B N-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF),26-氟埃博霉素)、澳瑞他汀(Auristatin)PE(也称为NSC-654663)、Soblidotin(也称为TZT-1027)、LS-4559-P(Pharmacia,也称为LS-4577)、LS-4578(Pharma,也称为LS-477-P)、LS-4477(Pharmachia)、LS-5559(Pharmasia)、RPR-112378(Aventis)、硫酸长春新碱、Dz-3358(Daiichi)、FR-182877(Fujisawa,也称为WS-9885B)、GS-164(Takeda)、GS-198(Takeda),KAR-2(Hungarian Academy of Sciences)、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-35703)、AC-7739(Ajinomoto,也称为AVE-8063A和CS-39.HCI)、AC-7700(Ajinomoto,也称为AVE-8062、AVE-8062A、CS-39-L-SeΩγr.HCI和RPR-258062A)、Vitilevuamide、Tubulysin A、Canadensol、矢车菊黄素(Centaureidin)(也称为NSC-106969)、T-138067(Tularik,也称为T-67、TL-138067和TI-138067)、COBRA-1(Parker Hughes Institute,也称为DDE-261和WHI-261)、H10(Kansas State University)、H16(Kansas State University)、Oncocidin Al(也称为BTO-956和DIME)、DDE-313(Parker Hughes Institute)、Fijianolide B、Laulimalide、SPA→2(Parker Hughes Institute)、SPA-1(Parker Hughes InstInstitute,也称为SPIKET-P)、3-IAABU(Cytoskeleton/Mt.Sinai School of Medicine,也称为MF→569)、Narcosine(也称为NSC-5366)、Nascapine、D-24851(Asta Medica)、A-105972(Abbott)、Hemisterlin、,3-BAABU(Cytoskeleton/Mt.Sinai School of Medicine,也称为MF-191)、TMPN(Arizona State Univers的)、二茂乙酰丙酮、T-138026(Tularik)、Monsatrol、lnanocine(也称为NSC-698666)、3-1AABE(Cytoskeleton/Mt.Sinai School ofMedicine)、A-204197(Abbott)、T-607(Tuiarik,也称为T-900607)、RPR-115781(Aventis)、Eleutherobin(如Desmethyleleutherobin、Desaetyleleutheropin、IsoelseleutherobinA和Z-Eleutherobin)、Caribaeoside、Caribeiolin、Halichondrin B、D-64131(AstaMedica)、D-68144(Asta Medica)、Diazonamide A、A-293620(Abbott)、NPI-2350(Nereus)、Taccalonolide A、TUB-245(Aventis)、A-259754(Abbot)、Diozostatin、(-)-Phenylahistin(也称为NSCL-96F037)、D-68838(Asta Medica),D-68836(Asta Medica)、Myoseverin B、D-43411(Zentaris,也称为D-81862)、A-289099(Abbott)、A-318315(Abbot)、HTI-286(也称为SPA-110、三氟乙酸盐)(Wyeth)、D-82317(Zentoris)、D-81318(Zenteris)、SC-12983(NCI)、白藜芦醇磷酸酯钠、BPR-OY-007(National Health ResearchInstitutes)和SSR→250411(Sanofi)。
menin抑制剂和CYP3A4抑制剂可与以下组合使用:免疫抑制剂(例如,他克莫司、环孢素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯基嘌呤盐、霉酚酸酯或FTY720)、糖皮质激素(例如,强的松、醋酸可的松、泼尼松龙、甲基强的松龙、地塞米松、倍他米松、曲安奈龙、倍氯米松、醋酸氟可的松,醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如,水杨酸盐、芳基烷基酸、2-芳基丙酸、N-芳基镧酸、昔康(oxicam)、coxib或磺苯胺),Cox-2特异性抑制剂(如伐地昔布、塞来昔布或罗非昔布)、来氟米特、硫代葡萄糖金、硫代苹果酸金、aurom、柳氮磺胺吡啶、羟氯喹、二甲胺四环素、TNF-a结合蛋白(如英夫利昔单抗、依那西普或阿达木单抗)、阿巴他西普、安纳金拉、干扰素-β、干扰扰素-γ、白介素-2、过敏疫苗、抗组胺、抗白三烯、β激动剂、茶碱或抗胆碱能剂。
药物组合物/制剂
在某些实施方案中,本文公开的药物组合物包括menin抑制剂和药学上可接受的赋形剂,以及药物组合物CYP3A4抑制剂和药理学上可接受赋形剂。在某些实施方案中,本文进一步公开了药物组合物,其包含(a)menin抑制剂和CYP3A4抑制剂,以及(b)药学上可接受的赋形剂。
在一些实施方案中,CYP3A4抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A4抑制剂是:泊沙康唑、考尼伐坦、洛匹那韦、阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;维拉帕米;特拉匹韦;长春新碱;伏立康唑;或其任何组合。
在一些实施方案中,CYP3A4抑制剂是泊沙康唑。在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或考比司他(GS-9350)的类似物或衍生物。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,CYP3A4抑制剂是考尼伐坦。在一些实施方案中,CYP3A4抑制剂是洛匹那韦。
在一些实施方案中,menin抑制剂是无定形的或结晶。在一些实施方案中,menin抑制剂是研磨的或是纳米颗粒。在一些实施方案中,药物组合物是组合剂型。在一些实施方案中,组合物增加menin抑制剂的口服生物利用度。在一些实施方案中,组合物增加menin抑制剂的Cmax。在一些实施方案中,组合物增加menin抑制剂的AUC。在一些实施方案中,组合物增加menin抑制剂的Cmax为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,组合物增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,组合物增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,组合物增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X的CYP3A4抑制剂的量。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X的CYP3A4抑制剂的量。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X的CYP3A4抑制剂的量。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X的CYP3A4抑制剂的量。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X的CYP3A4抑制剂的量。在一些实施方案中,组合物包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X的CYP3A4抑制剂的量。在一些实施方案中,与没有CYP3A4抑制剂施用menin抑制剂的Tmax和T1/2相比,组合物不显著影响menin抑制剂的Tmax和T1/2。
在一些实施方案中,药物组合物还包括氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,药物组合物还包括环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括苯达莫司汀和利妥昔单抗。在一些实施方案中,药物组合物还包括氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,药物组合物还包括环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,药物组合物还包括依托泊苷、多柔比星、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,药物组合物还包括地塞米松和来那度胺。
药物组合物可以使用一种或多种生理上可接受的载体包括赋形剂和助剂以常规方式配制,所述载体促进将活性化合物加工成可在药学上使用的制备物。适当的制剂取决于所选的施用途径。任何公知的技术、载体和赋形剂均可在本领域中适当和理解的情况下使用。本文所述药物组合物的概述见于在例如Remington:The Science and Practice ofPharmacy,Nineteenth Ed(Easton,Pa.:Mack Publishing Company,1995);Hoover,JohnE.,Remington′s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical DosageForms,Marcel Decker,New York,N.Y,1980;以及Pharmaceutical Dosage Forms andDrug Delivery Systems,Seventh Ed.(Lippincott Williams&Wilkins,1999),通过引用将其全文并入本文。
如本文所用的药物组合物是指menin抑制剂、CYP3A4抑制剂和/或另外的治疗剂与其他化学成分,例如载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂的混合物。
在实践本文所提供的治疗或使用方法时,施用治疗有效量的本文所公开的化合物,具有待治疗的疾病、病症或病症。在一些实施方案中,哺乳动物是人。化合物的治疗有效量可根据化合物、疾病的严重程度、受试者的年龄和相对健康以及其他因素而变化。
本文中使用的术语“组合”是指由menin抑制剂和CYP3A4抑制剂(以及任何另外的治疗剂)的混合或组合产生的产品,并且包括固定和非固定组合。术语“固定组合”指的是以单一实体或剂型施用menin抑制剂和CYP3A4抑制剂。术语“非固定组合”指的是同时、并行地或顺序地,没有特定的间隔时间限制地,以多个单独实体或剂型施用menin抑制剂和CYP3A4抑制剂,其中这种施用在患者体内提供有效水平的两种化合物。后者也适用于鸡尾酒疗法,例如施用三种或多种活性成分。
包括本文所述化合物的药物组合物可以以常规方式制造,例如仅作为示例,通过常规混合、溶解、造粒、糖锭剂制造、研磨、乳化、包封、封装或压缩工艺。
剂型
在某些实施方案中,本文公开了一种或多种剂型或药物组合物,其包含与包含CYP3A4抑制剂的一种或多种剂型或药物组合物组合施用的menin抑制剂。
本申请的药物组合物包含治疗有效量的本申请的化合物(例如,menin抑制剂、CYP3A4抑制剂或两者)与一种或多种药学上可接受的载体一起配制。本申请的化合物可通过任何常规途径作为药物组合物施用,特别是经肠,例如口服,例如以片剂或胶囊形式,或经肠胃外,例如以可注射溶液或悬浮液形式,或局部,例如以洗剂、凝胶、软膏或乳膏形式,或者以鼻或栓剂形式。
可通过混合、造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申请组合的单独化合物与至少一种药学上可以接受的载体或稀释剂相关联。例如,口服组合物可以是片剂或明胶胶囊,其包含活性成分和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,还有c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄芪、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,d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐或泡腾混合物;和/或e)吸收剂、着色剂、香料和甜味剂。可注射组合物可以是等渗水溶液或悬浮液,并且栓剂可以由脂肪乳剂或悬浮液制备。组合物可以被灭菌和/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。用于透皮应用的合适制剂包括有效量的本发明化合物和载体。载体可以包括可吸收的药理学上可接受的溶剂,以帮助通过宿主的皮肤。例如,透皮装置可以是绷带的形式,包括背衬构件、含有任选地具有载体的化合物的储库、任选地以受控和预定速率在长时间内将化合物递送至宿主皮肤的速率控制屏障,以及将装置固定至皮肤的设备。
也可以使用基质透皮制剂。用于局部应用(例如至皮肤和眼睛)的合适制剂优选为本领域已知的水溶液、软膏、乳膏或凝胶。这类制剂可含有增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。本申请的药物组合物包含治疗有效量的本申请化合物与一种或多种药学上可接受的载体一起配制。如本文所用,术语“药学上可接受的载体”是指任何类型的无毒、惰性固体、半固体或液体填料、稀释剂、封装材料或制剂助剂。可用作可药用载体的材料的一些示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,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如鱼精蛋白硫酸盐、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;黄芪粉;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;无热原水、等渗盐水;林格溶液;乙醇和磷酸盐缓冲溶液,以及其他无毒兼容润滑剂,如十二烷基硫酸钠和硬脂酸镁,以及着色剂、释放剂、涂层剂、甜味剂、调味剂和香料、防腐剂和抗氧化剂也可以根据配方师的判断,存在于组合物中。
本申请的药物组合物可以口服、经直肠、肠胃外、脑室内、阴道内、腹腔内、局部(如通过粉末、软膏或滴剂)、经面颊或作为口服或鼻喷雾剂施用给人类和其他动物。
如本文所用,术语“药学上可接受的载体”是指任何类型的无毒、惰性固体、半固体或液体填料、稀释剂、封装材料或制剂助剂。可用作可药用载体的材料的一些示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、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质、如鱼精蛋白硫酸盐、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;黄芪粉;麦芽;明胶;滑石;辅料如可可脂和栓剂蜡,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;无热原水、等渗盐水;林格溶液;乙醇和磷酸盐缓冲溶液,以及其他无毒兼容润滑剂,如十二烷基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、涂层剂、甜味剂、调味剂和香料、防腐剂和抗氧化剂根据配方师的判断,也可以存在于组合物中。
本申请的药物组合物可以口服、经直肠、肠胃外、脑室内、阴道内、腹腔内、局部(如通过粉末、软膏或滴剂)、经面颊或者作为口腔或鼻喷雾剂施用给人类和其他动物。
载体。
口服施用的液体剂型可包括药学上可接受的乳剂、微乳剂、溶液、悬浮液、糖浆和酏剂。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,例如水或其他溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、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、花生、玉米、胚芽、橄榄、蓖麻和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨醇的脂肪酸酯及其混合物。除了惰性稀释剂之外,口服组合物还可以包括佐剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和香料。
可注射制备物,例如无菌可注射含水或含油悬浮液,可根据已知技术使用合适的分散剂或润湿剂和悬浮剂配制。无菌注射制备物也可以是无菌注射溶液、悬浮液或乳剂,其在无毒肠胃外可接受的稀释剂或溶剂中,例如在1,3-丁二醇中的溶液。可使用的可接受载体和溶剂包括水、林格溶液、U.S.P.和等渗氯化钠溶液。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,包括合成的单甘油酯或二甘油酯。此外,脂肪酸如油酸也用于制备注射剂。
为了延长药物的效果,通常需要减缓皮下或肌肉注射对药物的吸收。这可以通过使用水溶性差的结晶或非定型材料的液体悬浮液来实现。然后,药物的吸收速率取决于其溶解速率,而溶解速率又取决于晶体大小和晶体形式。可替代地,通过将药物溶解或悬浮在油媒介物中来实现肠胃外施用的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menin抑制剂和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,剂型是控释剂型、延迟释放剂型、延长释放剂型、脉冲释放剂型,多颗粒剂型,或混合立即释放和控释制剂。在一些实施方案中,剂型包括控释涂层。在一些实施方案中,剂型包括控制menin抑制剂释放的第一控释涂层和控制CYP3A4抑制剂释放的第二控释涂层。
用于直肠或阴道给药的组合物优选为栓剂,其可以通过将本申请的化合物与合适的无刺激性赋形剂或载体如可可脂、聚乙二醇或栓剂蜡混合来制备,所述无刺激性赋形剂或载体在环境温度下为固体但在体温下为液体,并且因此在直肠或阴道腔中熔化并释放活性化合物。
类似类型的固体组合物也可用作软硬填充的明胶胶囊中的填料,使用诸如乳糖或乳制品糖以及高分子量聚乙二醇等赋形剂。
活性化合物也可以是具有一种或多种赋形剂的微胶囊形式,如上所述。片剂、糖衣丸、胶囊、丸剂和颗粒的固体剂型可以用包衣和外壳制备,如肠溶包衣、释制包衣和药物制剂领域熟知的其他包衣。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。这类剂型还可以包括,如通常的做法,除惰性稀释剂之外的另外的物质,例如压片润滑剂和其他压片助剂,如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,剂型也可以包括缓冲剂。
本申请化合物的局部或经皮施用的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾、吸入剂或贴剂。活性组分在无菌条件下与药学上可接受的载体和可能需要的任何防腐剂或缓冲剂混合。眼科制剂、滴耳液、眼膏、粉末和溶液也考虑在本申请的范围内。
除了本申请的活性化合物之外,软膏、糊剂、乳膏和凝胶还可含有赋形剂,如动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或其混合物。
除本申请的化合物外,粉末和喷雾还可含有赋形剂,如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾还可以含有常规推进剂,如氯氟烃。
透皮贴剂还有一个额外的优点,即提供化合物到身体的受控递送。这种剂型可以通过将化合物溶解或分散在适当的介质中来制备。吸收促进剂也可用于增加化合物在皮肤上的通量。可以通过提供速率控制膜或通过将化合物分散在聚合物基质或凝胶中来控制速率。
在一些实施方案中,CYP3A4抑制剂是:抗心律失常剂;抗组胺;唑类抗真菌剂;苯二氮卓;钙通道阻滞剂;HIV抗病毒剂;HMG CoA还原酶抑制剂;大环内酯类抗生素;促动力剂;蛋白酶抑制剂;或其任何组合。在一些实施方案中,CYP3A4抑制剂是:阿普唑仑;胺碘酮;氨氯地平;阿瑞匹坦;阿立哌唑;阿司咪唑;阿托伐他汀;波普瑞韦;丁螺环酮;氯霉素;扑尔敏;西咪替丁;环丙沙星;西沙必利;克拉霉素;考比司他(GS-9350);考比司他(GS-9350)的类似物或衍生物;环孢素;地拉韦啶;地西泮→3-OH;二硫代氨基甲酸二乙酯;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;柚子汁;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;咪唑安定;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;去甲氟西汀;匹莫奇特;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(FK506);三苯氧胺;特拉匹韦;泰利霉素;曲唑酮;三唑仑;troleandromycin,维拉帕米;特拉匹韦;长春新碱;伏立康唑;或其任何组合。在一些实施方案中,CYP3A4抑制剂是考比司他(GS-9350)或者考比司他(GS-9350)的类似物或衍生物。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抑制剂是无定形的或结晶。在一些实施方案中,剂型增加menin抑制剂的口服生物利用度。在一些实施方案中,剂型增加menin抑制剂的Cmax。在一些实施方案中,剂型增加menin抑制剂的AUC。在一些实施方案中,剂型增加menin抑制剂的Cmax为没有CYP3A4抑制剂施用menin抑制剂的Cmax的约20X至约40X,或约25X至约35X。在一些实施方案中,剂型增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约15X至约35X,或约20X至约30X。在一些实施方案中,剂型增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约35X。在一些实施方案中,剂型增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约30X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约25X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约20X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约15X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约10X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约5X。在一些实施方案中,剂型包含有效增加menin抑制剂的AUC为没有CYP3A4抑制剂施用menin抑制剂的AUC的约2X至约4X。在一些实施方案中,与没有CYP3A4抑制剂施用menin抑制剂的Tmax和T1/2相比,剂型不显著影响menin抑制剂的Tmax和T1/2。在一些实施方案中,剂型还包括氯丁嘧啶、异环磷酰胺、多柔比星、美沙拉秦、沙利度胺、来那度胺、坦罗莫司、依维莫司、氟达拉滨、福他替尼、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、地塞米松、强的松、CAL-101、伊布单抗、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,剂型还包括环磷酰胺、羟基柔红霉素、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,剂型还包括苯达莫司汀和利妥昔单抗。在一些实施方案中,剂型还包括氟达拉滨、环磷酰胺和利妥昔单抗。在一些实施方案中,剂型还包括环磷酰胺、长春新碱和强的松,以及任选的利妥昔单抗。在一些实施方案中,剂型还包括依托泊苷、多柔比星、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,剂型还包括地塞米松和来那度胺。
本文所述的药物组合物可以配制用于通过任何常规手段施用,包括但不限于口服、肠胃外(例如静脉内,皮下或肌内)、面颊、鼻内、直肠或透皮施用途径。如本文所用,术语“受试者”,“个体”和“患者”可互换使用,并且是指动物,优选哺乳动物,包括人或非人。这些术语都不要求医疗专业人员的许可(连续或其他)。
本文所述的药物组合物配制成任何合适的剂型,包括但不限于固体口服剂型、控释制剂、快速熔融制剂、泡腾制剂、片剂、粉末、丸剂、胶囊、缓慢释放制剂、延长释放制剂、脉冲释放制剂、多颗粒制剂以及混合的速释和控释制剂。
常规药理学技术包括例如一种或多种方法的组合:(1)干混合,(2)直接压缩,(3)研磨,(4)干或非水造粒,(5)湿法造粒,或(6)融合。参见例如Lachman et al,The Theoryand Practice of Industrial Pharmacy(1986)。其他方法包括例如喷雾干燥、盘涂层、熔体造粒、造粒、流化床喷雾干燥或涂布(例如wurster涂层)、切向涂层、顶喷、压片、挤出等。
本文所述的药物剂型可包括一种或多种药学上可接受的添加剂,例如相容性载体、粘合剂、填充剂、悬浮剂、调味剂、甜味剂、崩解剂、分散剂、表面活性剂、润滑剂、着色剂、稀释剂、增溶剂、润湿剂、增塑剂、稳定剂、渗透促进剂、润湿剂、抗发泡剂、抗氧化剂、防腐剂或其一种或多种组合。在其他方面,使用标准涂层程序,例如Remington′s PharmaceuticalSciences,20th Edition(2000)中描述的那些,在药物组合物周围提供薄膜涂层。在单位剂量的组合物中活性成分(例如,所公开的化合物或盐、水合物、溶剂化物或其异构体的制剂)的量是有效量,并且根据所涉及的特定处理而变化。本领域技术人员将认识到,有时需要根据患者的年龄和状况对剂量进行常规改变。剂量还将取决于施用的途径。考虑多种途径,包括口服、肺、直肠、肠胃外、透皮、皮下、静脉内、肌内、腹膜内、吸入、面颊、舌下、胸膜内、鞘内、鼻内等。用于局部或透皮施用本申请化合物的剂型包括粉末、喷雾剂、软膏、糊剂、乳膏、乳液、凝胶、溶液、贴剂和吸入剂。在一些实施方案中,将活性化合物在无菌条件下与药学上可接受的载体以及所需的任何防腐剂、缓冲剂或推进剂混合。
含有本申请的活性化合物的药物组合物可以以通常已知的方式制造,例如通过常规混合、溶解、造粒、糖锭剂制造、研磨、乳化、包封、封装或冻干方法。药物组合物可以使用一种或多种药学上可接受的载体以常规方式配制,所述载体包含赋形剂和/或助剂,其促进活性化合物加工成可药学使用的制剂。当然,适当的制剂取决于所选择的施用途径。
用于配制和施用本申请所公开的化合物的技术可以在Remington.:the Scienceand Practice of Pharmacy,19th edition,Mack Publishing Co.,Easton,PA(1995)中找到。在一个实施方案中,本文所述的化合物及其药学上可接受的盐与药学上可接受的载体或稀释剂组合用于药物制剂中。合适的药学上可接受的载体包括惰性固体填料或稀释剂和无菌水溶液或有机溶液。化合物将以足以在本文所述范围内提供所需剂量的量存在于这种药物组合物中。
给药和治疗方案
在一些实施方案中,与CYP3A4抑制剂组合施用的menin抑制剂的量为50mg/天直至并包括1000mg/天。
在一些实施方案中,menin抑制剂的每日剂量在约10mg至约500mg之间。在一些实施方案中,menin抑制剂的每日剂量在约200mg和约500mg之间。在一些实施方案中,menin抑制剂的每日剂量在约250mg和约460mg之间。在一些实施方案中,menin抑制剂的每日剂量为约226mg。在一些实施方案中,menin抑制剂的每日剂量为452mg。
在一些实施方案中,每天一次给予,每天两次给予,每天三次给予,每天四次给予剂量以等于每日剂量。在一些实施方案中,menin抑制剂以113mg的单位剂量施用。在一些实施方案中,每天一次给予,每天两次给予,每天三次给予,每天四次给予单位剂量。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,每天两次给予两个单位剂量。
在一些实施方案中,施用的menin抑制剂的量为约40mg/天。在一些实施方案中,施用的menin抑制剂的量为约50mg/天。在一些实施方案中,施用的menin抑制剂的量为约60mg/天。在一些实施方案中,施用的menin抑制剂的量为约70mg/天。在一些实施方案中,施用的menin抑制剂的量为约80mg/天。在一些实施方案中,施用的menin抑制剂的量为约90mg/天。在一些实施方案中,施用的menin抑制剂的量为约100mg/天。在一些实施方案中,施用的menin抑制剂的量为约110mg/天。在一些实施方案中,施用的menin抑制剂的量为约120mg/天。在一些实施方案中,施用的menin抑制剂的量为约130mg/天。在一些实施方案中,施用的menin抑制剂的量为约140mg/天。在一些实施方案中,施用的menin抑制剂的量为约150mg/天。在一些实施方案中,施用的menin抑制剂的量为约160mg/天。在一些实施方案中,施用的menin抑制剂的量为约170mg/天。在一些实施方案中,施用的menin抑制剂的量为约180mg/天。在一些实施方案中,施用的menin抑制剂的量为约190mg/天。在一些实施方案中,施用的menin抑制剂的量为约200mg/天。在一些实施方案中,施用的menin抑制剂的量为约210mg/天。在一些实施方案中,施用的menin抑制剂的量为约220mg/天。在一些实施方案中,施用的menin抑制剂的量为约230mg/天。在一些实施方案中,施用的menin抑制剂的量为约240mg/天。在一些实施方案中,施用的menin抑制剂的量为约250mg/天。在一些实施方案中,施用的menin抑制剂的量为约260mg/天。在一些实施方案中,施用的menin抑制剂的量为约270mg/天。在一些实施方案中,施用的menin抑制剂的量为约280mg/天。在一些实施方案中,施用的menin抑制剂的量为约290mg/天。在一些实施方案中,施用的menin抑制剂的量为约300mg/天。在一些实施方案中,施用的menin抑制剂的量为约310mg/天。在一些实施方案中,施用的menin抑制剂的量为约320mg/天。在一些实施方案中,施用的menin抑制剂的量为约330mg/天。在一些实施方案中,施用的menin抑制剂的量为约340mg/天。在一些实施方案中,施用的menin抑制剂的量为约350mg/天。在一些实施方案中,施用的menin抑制剂的量为约360mg/天。在一些实施方案中,施用的menin抑制剂的量为约370mg/天。在一些实施方案中,施用的menin抑制剂的量为约380mg/天。在一些实施方案中,施用的menin抑制剂的量为约390mg/天。在一些实施方案中,施用的menin抑制剂的量为约400mg/天。在一些实施方案中,施用的menin抑制剂的量为约450mg/天。在一些实施方案中,施用的menin抑制剂的量为约500mg/天。在一些实施方案中,施用的menin抑制剂的量为约550mg/天。在一些实施方案中,施用的menin抑制剂的量为约560mg/天。在一些实施方案中,每日剂量分为多次施用,并且每天一次给予,每天两次给予,每天三次给予,每天四次给予。在一些实施方案中,每天一次施用,每天两次施用,每天三次施用menin抑制剂。在一些实施方案中,每天一次施用menin抑制剂。在一些实施方案中,每天两次施用menin抑制剂。
在一些实施方案中,以50mg QD、113mg QD、113mg q12h、226mg q12h、339mg q12h,452mg q12h或565mg q12h施用menin抑制剂。在一些实施方案中,menin抑制剂是式II的化合物,并且以50mg QD、113mg QD、113mg q12h、226mg q12h、339mg q12h,452mg q12h或565mg q12h施用。在一些实施方案中,menin抑制剂是包含式II的化合物的药物制剂,并且以50mg QD 、113mg QD、113mg q12h、226mg q12h、339mg q12h、452mg q12h或565mg q 12h施用。在一些实施方案中,menin抑制剂是包含式II的化合物的胶囊,并以50mg QD、113mgQD、113mg q12h、226mg q12h、339mg q12h,452mg q12h或565mg q12h施用。
在一些实施方案中,与menin抑制剂组合施用的CYP3A4抑制剂的每日剂量为50mg/天直至并包括1000mg/天。在一些实施方案中,每个剂量每天一次给予,每天两次给予,每天三次给予,每天四次给予。在一些实施方案中,CYP3A4剂量取决于特定的CYP3A4抑制剂。在一些实施方案中,每种CYP3A4抑制剂的每日剂量根据批准的其他适应症标记进行施用。在一些实施方案中,施用的CYP3A4抑制剂的量为约40mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约50mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约60mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约70mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约80mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约90mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约100mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约110mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约120mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约130mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约140mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约150mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约160mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约170mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约180mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约190mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约200mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约210mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约220mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约230mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约240mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约250mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约260mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约270mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约280mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约290mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约300mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约310mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约320mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约330mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约340mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约350mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约360mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约370mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约380mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约390mg/天。在一些实施方案中,施用的CYP3A4抑制剂的量为约400mg/天。在一些实施方案中,每个剂量每天一次给予,每天两次给予,每天三次给予,每天四次给予。
在一些实施方案中,与CYP3A4抑制剂共施用的menin抑制剂的AUC0-24在约50和约10000ng*h/mL之间。在一些实施方案中,与CYP3A4抑制剂共施用的menin抑制剂的Cmax在约5ng/mL和约1000ng/mL之间。
在一些实施方案中,CYP3A4抑制剂是泊沙康唑,并且menin抑制剂是式II的化合物。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,其与包含式II的化合物的药物组合物组合施用。在一些实施方案中,CYP3A4抑制剂是包含泊沙康唑的药物组合物,其与包含式II的化合物的药物组合物组合施用。在一些实施方案中,泊沙康唑以100mg每日剂量、200mg每日剂量、300mg每日剂量、400mg每日剂量或800mg每日剂量施用。在一些实施方案中,泊沙康唑以300mg注射每天一次进行施用。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,其以300mg注射每天两次,然后300mg注射每天一次进行施用。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,并且泊沙康唑以300mg片剂每天一次进行施用。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,并且泊沙康唑在治疗第一天以2X每日剂量进行施用。在一些实施方案中,泊沙康唑作为口服混悬液进行施用。在一些实施方案中,泊沙康唑口服混悬液的每日剂量为100mg。在一些实施方案中,CYP3A4抑制剂是泊沙康唑,并且泊沙康唑在治疗第一天以2X每日剂量进行施用。在一些实施方案中,泊沙康唑作为口服混悬液进行施用。在一些实施方案中,泊沙康唑口服混悬液的每日剂量为800mg。在一些实施方案中,泊沙康唑口服混悬液的每日剂量为800mg,分为两次400mg施用每天两次。
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,利托那韦以每天1200mg施用。在一些实施方案中,利托那韦以600mg每天两次施用。在一些实施方案中,利托那韦以300mg每天两次施用,并且以2至3天的间隔每天两次增加100mg。
在一些实施方案中,CYP3A4抑制剂是科比司他。在一些实施方案中,科比司他以药物组合物施用。在一些实施方案中,科比司他药物组合物是片剂。在一些实施方案中,科比司他每日剂量是150mg。在一些实施方案中,科比司他以150mg每天一次施用。
在一些实施方案中,每天一次,每天两次或每天三次施用CYP3A4抑制剂。在一些实施方案中,每天一次施用CYP3A4抑制剂。在一些实施方案中,每天一次,每天两次,每天三次,每天四次施用CYP3A4抑制剂。在一些实施方案中,每天一次施用CYP3A4抑制剂。在一些实施方案中,共同施用menin抑制剂和CYP3A4抑制剂(例如,以单一剂型或分开的剂型),每天一次。在一些实施方案中,每天两次施用menin抑制剂,并且施用CYP3A4抑制剂(例如,以单一剂型或分开的剂型),每天四次。在一些实施方案中,每天两次施用menin抑制剂,并且施用CYP3A4抑制剂(例如,以单一剂型或分开的剂型),每天两次。在一些实施方案中,menin抑制剂和CYP3A4抑制剂是维持疗法。在一些实施方案中,menin抑制剂是维持疗法。
在一些实施方案中,本文公开的组合物用于预防、治疗或维持处理。在一些实施方案中,本文公开的组合物用于治疗性应用。在一些实施方案中,本文公开的组合物作为维持疗法施用,例如用于缓解期患者。
在患者状态没有改善的情况下,可以连续施用化合物;可替代地,施用的药物的剂量可以在一段时间内增加。药物长度的增加可以在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%。
如果患者的病况没有改善,可以根据症状增加施用的剂量或频率,或两者,至改善疾病、病症或病况的水平。
如果患者的状态确实有所改善,可以暂时减少或暂时暂停施用的药物剂量一段时间(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。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%。
一旦患者病况好转,必要时施用维持剂量。随后,可以根据症状将施用的剂量或频率或两者,至保持改善的疾病、病症或病状的水平。然而,一旦症状复发,患者可能需要长期间断治疗。
与该量相对应的给定试剂的量将取决于诸如特定化合物、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,但仍可以根据病例周围的特定情况以本领域公知的方式常规确定,包括例如所施用的特定试剂、施用的途径以及所治疗的受试者或宿主。然而,一般而言,用于成人治疗的剂量通常为0.02-5000mg/天,或约1-1500mg/天。所需剂量可以方便地以单剂量或分开剂量同时(或在短时间内)或以适当的间隔(例如每天两次、三次、四次或更多亚剂量)施用。
本文描述的药物组合物可以是适用于精确剂量的单次施用的单位剂型。在单位剂型中,制剂分为含有适量一种或多种化合物的单位剂量。单位剂型可以是含有离散量制剂的包装形式。非限制性实例是包装片剂或胶囊,以及小瓶或安瓿中的粉末。水悬浮组合物可包装在单剂量不可再封闭容器中。
可替代地,可以使用多剂量可再封闭容器,在这种情况下,通常在组合物中包括防腐剂。仅作为示例,用于肠胃外注射的制剂可以以单位剂量形式呈现,包括但不限于安瓿或多剂量容器,并添加防腐剂。
上述范围仅仅是提示性的,因为与个体治疗方案有关的变量数量很大,并且与这些推荐值的显著偏离并不少见。这种剂量可根据多种变量而改变,不限于所用化合物的活性、待治疗的疾病或病况、施用的方式、个体受试者的要求、待治疗疾病或病况的严重程度以及医生的判断。
这种治疗方案的毒性和治疗效果可以通过细胞培养物或实验动物中的标准药物程序来确定,包括但不限于LD50(对50%的人群致死的剂量)和ED5o(对50%的人群治疗有效的剂量)的确定。毒性和治疗作用之间的剂量比是治疗指数,它可以表示为LD50和ED50之间的比值。表现出高治疗指数的化合物是优选的。从细胞培养测定法和动物研究中获得的数据可用于制定一系列用于人体的剂量。此类化合物的剂量优选地在循环浓度范围内,包括毒性最小的ED50。剂量可在该范围内变化,这取决于所用的剂型和所用的施用途径。
在一些实施方案中,并行地施用menin抑制剂和menin抑制物。在一些实施方案中,同时、基本上同时或在相同的治疗方案内施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,顺序地施用menin抑制剂和CYP3A4抑制剂。
在一些实施方案中,并行地施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,同时、基本上同时或在相同的治疗方案内施用menin抑制剂和CYP3A4抑制剂。在一些实施方案中,顺序地施用menin抑制剂和CYP3A4抑制剂。
试剂盒/制造品
为了用于本文所述的治疗方法,本文还描述了试剂盒和制造品。这种试剂盒包括载体、包装或容器,其被分隔以接收一个或多个容器,例如小瓶、管等,每个容器包括将在本文描述的方法中使用的分开的元件之一。合适的容器包括例如瓶子、小瓶、注射器和试管。在一个实施方案中,容器由诸如玻璃或塑料的各种材料形成。
本文提供的制造品包含包装材料。药物包装材料的示例包括但不限于泡罩包装、瓶、管、袋、容器、瓶和适用于选定制剂和预期施用和治疗方式的任何包装材料。
例如,容器包括CYP3A4抑制剂,任选地以组合物形式或与本文公开的CYP3A4抑制剂组合。此类试剂盒可选地包括与其在本文所述方法中的使用相关的识别描述或标签或说明。
试剂盒通常包括列出内容和/或使用说明的标签,以及带有使用说明的包装插页。通常还将包括一组指令。
在一些实施方案中,标签位于容器上或与容器关联。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;当标签存在于也容纳容器的器皿(receptacle)或载具内时,标签与容器相关联,例如作为包装插页。在一些实施方案中,标签用于指示内容物将用于特定治疗应用。标签还指示内容物的使用指导,例如在本文描述的方法中。
在某些实施方案中,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呈现。例如,包装包含金属或塑料箔,如泡罩包装。在一些实施方案中,包装或分配器装置伴随有施用指令。在一些实施方案中,包装或分配器还附有与容器相关联的通知,该通知的形式由管理药物的制造、使用或销售的政府机构规定,该通知反映了该机构对用于人类或兽医管理的药物形式的批准。例如,此类通知是美国食品和药物管理局批准的处方药标签,或批准的产品插页。在一些实施方案中,还制备含有在相容药物载体中配制的本文提供的化合物的组合物,将其置于适当的容器中,并标记用于治疗指示的病况。
实施例
以下用于实施本文公开的方法的成分、制剂、工艺和程序对应于上述内容,并不意味着限制上述实施方案。
实施例1:单独使用式I或式II的menin抑制剂并与CYP3A4抑制剂组合的治疗
年龄≥12岁的R/R急性白血病患者没有可用的疗法入组。以每12小时(q12h)方案给药menin抑制剂;考虑替代剂量方案。在28天周期中口服施用(PO)menin抑制剂,第1周期第1天(C1D1)施用第一剂量。患者继续治疗,直到进展性疾病(PD)或不可接受的毒性。
患者被分配到如下所述两个组中的一个:
·A组:患者不得接受任何强细胞色素P4503A4(CYP3A4)抑制剂/诱导剂。接受强CYP3A4抑制剂/诱导剂的患者必须在入组前至少7天停止用药。
·B组:患者必须接受伊曲康唑、酮康唑、泊沙康唑或伏立康唑(强CYP3A4抑制剂)用于在入组前至少7天进行抗真菌预防和同时接受治疗。患者不得接受任何其他强CYP3A4抑制剂/诱导剂。
确定了急性白血病患者中menin抑制剂的剂量。R/R急性白血病患者入组时不知道基因突变状态。精确剂量强度已四舍五入以适应胶囊大小限制(113mg/胶囊)。起始剂量为113mg q12h,如下表所示升至更高剂量或降低至更低剂量。
menin抑制剂的剂量水平
在3个适应症特异性群组中探讨了menin抑制剂和组合疗法的功效,如下所示:
·群组2A:MLLrALL/MPAL患者。
·群组2B:MLLrAML患者。
·群组2C:NPM1c AML患者。
每个群组采用Simon 2阶段设计,每个群组中多至34名患者。每个扩展群组的入组都是独立进行的。对于携带NPM1c或MLL基因重排且无可用治疗选择的R/R急性白血病患者,CR+CRh率>15%被认为是抗白血病活性的下限。
在遗传限定的群组中评估menin抑制剂的抗肿瘤活性。这些患者亚群患有表达预期menin抑制剂最有效的靶点的白血病。
剂量基于大鼠和狗28天GLP毒理学研究产生的数据。起始剂量设定为大鼠STD10的1/10或狗HNSTD的1/6中较低者的人体等效剂量。狗的HNSTD(50mg/kg;1000mg/m2)低于大鼠的STD10(400mg/kg;2400mg/m2);因此,狗的临床起始剂量为1/6HNSTD或166.7mg/m2,相当于成人的4.5mg/kg。选择225mg的menin抑制剂的总每日剂量作为起始剂量,四舍五入到最接近的胶囊大小,为226mg/天。以113mg PO q12h施用剂量。
在A组和B组中分别测定了R/R急性白血病患者中menin抑制剂和组合疗法的安全性、耐受性、MTD和RP2D。分别测定了A组和B组中menin抑制剂和组合疗法的PK参数。确定了menin抑制剂和组合疗法的短期和长期安全性和耐受性。确定了CR率(CR+CRh)。
确定次要目标:
·复合CR(CRc)率(CR+CRh+CR伴不完全血液学恢复[CRi]+CR伴血小板不完全恢复[CRp])。
·治疗4周后的CR率。
·最佳总体缓解率(BORR)(CRc+部分缓解[PR])。
·无复发生存率(RFS)。
·响应时间(TTR)和响应持续时间(DOR)
·总生存率(OS)。
·menin抑制剂和组合疗法的PK参数Cmax、Tmax、AUC0-t、AUC0-24、CL/F、Vz/F和t1/2。
测定了本发明的menin抑制剂和组合的抗白血病活性。本发明的menin抑制剂及组合与相关生物标志物的药效学、安全性和疗效关系,其可包括循环外周血单核细胞(PBMC)和/或骨髓的免疫表型、基因表达、突变分析和最小残留疾病(MRD)。
记录的R/R急性白血病。
A组:患者不得接受任何强细胞色素P4503A4(CYP3A4)抑制剂/诱导剂。接受强CYP3A4抑制剂/诱导剂的患者必须在入组前至少7天停止用药。
B组:患者必须接受伊曲康唑、酮康唑、泊沙康唑或伏立康唑(强CYP3A4抑制剂)用于在入组前至少7天的抗真菌预防治疗,同时接受用menin抑制剂治疗。患者不得接受任何其他强CYP3A4抑制剂/诱导剂。
群组2A:记录具有MLLr易位的R/RALL/MPAL。
群组2B:记录的具有MLLr易位的R/RAML。
群组2C:记录的具有NPM1c的R/RAML。
通过荧光原位杂交(11q23 MLL分解FISH)测试(Cancer Genetics Inc.,Rutherford,NJ)获得MLLr状态的中心确认。通过NPM1(核磷蛋白)基因分析,外显子12变体(CPT 81310)(Cancer Genetics Inc.,Rutherford,NJ)获得NPM1突变状态的中心确认。无法中心确认突变状态的患者被替换。
标准护理疗法后的标准化标准(如European LeukemiaNet criteria;International Working Group criteria)所定义的复发性或难治性AML/ALL或MPAL。初次治疗后患有持续性白血病的患者,或在治疗过程中或治疗过程后(包括异基因造血干细胞移植[HSCT])出现反应后的任何时间出现白血病复发的患者都符合条件。
先前疗法:
在入组前任何先前与治疗相关的毒性消退为≤1级,除了≤2级神经病变或脱发。
放射疗法:距离之前的全身照射(TBI)、颅脊髓照射和/或≥50%的骨盆照射至少60天,或距离局部姑息性照射疗法(小端口)至少14天。
干细胞输注:距离HSCT必须至少经过60天,距离供体淋巴细胞输注(DLI)必须经过至少4周(从第一次给药开始),且无调理。
免疫疗法:自既往免疫疗法(包括肿瘤疫苗和检查点抑制剂)后至少42天,和自接受嵌合抗原受体疗法或其他改良T细胞疗法后至少21天。
抗白血病疗法:自抗白血病疗法(例如,但不限于小分子或细胞毒性/骨髓抑制疗法)完成后至少14天,以下例外情况除外:经医学监督批准,可开始使用羟基脲进行细胞减少并且与menin抑制剂一起继续使用。诊断性腰椎穿刺时鞘内化疗,在menin抑制剂开始前至少24小时。允许患者接受鞘内化疗。
造血生长因子:自短效造血生长因子治疗完成后至少7天,和长效生长因子治疗的14天。
生物制剂(如单克隆抗体疗法):自使用生物试剂的疗法完成后,至少7天或5个半衰期,以较长者为准。
类固醇:自全身糖皮质激素疗法后至少7天,除非接受生理给药(相当于≤每天10mg强的松)或细胞减少疗法。细胞还原疗法必须获得医学监督员的批准。
menin抑制剂施用
根据患者的群组分配,以指定的剂量q12h服用menin抑制剂胶囊(113mg和156mg游离碱当量)用于PO施用。menin抑制剂在空腹,在饭后至少2小时和下一餐前1小时施用。
所有患者在28天的周期中PO q12h接受menin抑制剂,第一次研究药物剂量在C1D1施用。根据上述给药表,可以进行备选的给药方案。患者继续给药,直到出现PD或不可接受的毒性。
剂量分配:阶段1
menin抑制剂的起始剂量为113mg q12h(226mg总每日剂量)。随着CYP3A4剂量,menin抑制剂的给药递增。
满足以下标准的A组和B组的剂量独立确定:
·≤1/6的DLT可评估患者经历DLT。
·至少三分之二的患者在C1和C2中接受了至少80%的其处方剂量,除非是因为PD。
·至少有3名患者对于PK可评估。
·至少三分之二的患者在0至24小时(AUC0-24)的血浆浓度曲线下面积值≥15,000ng hr/mL。
-如果MTD未达到该暴露水平,但在任何剂量水平下都能看到功效,则符合上述安全性和耐受性标准的最高剂量水平将被选为RP2D
如果最高测试剂量不符合所有4个RP2D标准,则下一个较低剂量水平将扩大到总共6名患者。较低剂量水平的扩展将以顺序方式继续,直到确定符合RP2D标准的剂量。此外,与PK和多个周期后观察到的任何累积毒性相关的观察结果可包含在支持RP2D的基本原理中。
如果在第1周期结束时观察到100%CR率,且剂量水平在3+3剂量递增期内安全且可耐受(如错误!未找到参考源(Error!Reference source not found)一节所述),则该剂量将被定义为RP2D。
功效
进行疾病评估并评估疾病应答。
·完全缓解(CR):骨髓母细胞<5%;无循环爆发和Auer棒爆发;无髓外疾病;ANC≥1.0×109/L(1000/μL)和血小板计数≥100×109/L(100000/微升)
·CR伴有部分血液学恢复(CRh):骨髓母细胞<5%;无循环爆发和Auer棒爆发;无髓外疾病;残余中性粒细胞减少症(>0.5×109/L[1000/μL])和血小板减少症(>50×109/L[100000/μL])
·CR伴有不完全血液学恢复(CRi):骨髓母细胞<5%;无循环爆发和Auer棒爆发;无髓外疾病;残余中性粒细胞减少症(<1.0×109/L[1000/μL])或血小板减少症(<100×109/L[100000/μL])
·CR伴有不完全血小板恢复(CRp):骨髓母细胞<5%;无循环爆发和Auer棒爆发;无髓外疾病;ANC≥1.0×109/L(1000/μL)和血小板计数<100×109/L(100000/μL)。
·部分缓解(PR):骨髓母细胞百分比降低至5%至25%;预处理骨髓母细胞百分比降低至少50%;ANC≥1.0×109/L(1000/μL)和血小板计数≥100×109/L(100000/μL)。
药物动力学
将收集每个约5mL的血样,以测量menin抑制剂的血浆浓度。研究期间的其他时间点最多可收集24个另外的样品。
在C1D1、C1D8、C3D1和C5D1在给药前(给药前1小时内)和给药后0.25、0.5和1小时(±5分钟)、2和4小时(±15分钟)以及8小时(±30分钟)收集用于PK的血液样品,并离心制备血浆。仅对于B组,也应在给药前(给药前1小时内)在ClD3或4收集PK样品。在PK样品收集日,在研究中心人员的观察下,在研究中心服用menin抑制剂。
统计考虑因素
统计假设
该研究采用Simon minimax 2阶段设计。假设真实的CR+CRh率为35%。在复发和难治性急性白血病患者中,CR+CRh率>15%被认为是抗白血病活性的下限。
每个群组中入组21名患者。如果在单个群组中有4名或4名以上的患者出现应答,那么该群组中将有另外13名患者入组。如果在群组中的34名患者中观察到10名或10名以上CR+CRh患者,则该治疗值得进一步评估。
样本大小测定
第1阶段入组患者的实际数量取决于出现毒性的剂量水平以及为确定MTD和RP2D而调查剂量水平的数量。预计第一阶段将有多至54名患者入组,A组多至30名患者,B组多至24名患者。研究第一阶段未进行正式的样本大小计算。
每个阶段评估的每个群组中的患者数量以及继续下一阶段所需的应答者最小数量是基于Simon的2阶段设计的最小最大版本确定的,80%的幂和2.5%的单侧显著性水平。每个群组最多有34名患者入组。假设真实的CR+CRh率为35%。CR+CRh率大于15%被认为是抗白血病活性的较低阈值。根据上述限定的设计要素,在第一阶段,每个群组将有至多21名患者入组:如果4名或更多患者达到CR+CRh,则在第二阶段将有13名患者入组。否则,将终止该群组的入组。第二阶段完成后,如果群组中34名入组患者中有10名或更多患者达到CR+CRh,则可对该患者人群进行进一步评估。如果白血病亚型的真实CR+CRh率为15%或更低,则在第一阶段结束时终止入组的概率为61%。
因此,预计在本研究中,多至156名患者将入组并使用式I或式II的menin抑制剂与CYP3A4抑制剂组合进行治疗。
分析
为了进行分析,定义了以下人群:
统计分析
本研究中收集的数据的汇总和统计分析的详细方法将记录在统计分析计划(SAP)中。SAP将在数据库锁定前完成,并将描述分析中包含的分析群体,以及用于解释丢失、未使用和虚假数据的程序。本节总结了主要和次要终点的计划统计分析。探索性终点的统计分析。将使用Kaplan-Meier方法分析事件发生时间数据,并且结果将按第25、第50(中位数)和第75个百分位数进行汇总,具有相关的双侧95%CI,以及截尾观察的百分比。
使用9.4版或更高版本(SAS Institute Inc,Cary NC)进行统计分析。制备描述为本研究创建的数据集和变量的编程规范。使用最新版本的CDISC研究数据表模型(SDTM)和分析数据集模型(ADaM)制备数据集。
药代动力学分析
使用经验证的生物分析测定法测定所施用的menin抑制剂的血浆浓度。从在C1D1、C1D8、C3D1和C5D1(如适用)测定的血浆浓度计算以下PK参数:Cmax、Tmax、AUC0-t、AUC0-24、CL/F、Vz/F和t1/2,当有足够数据可用时,通过常规非室分析。早晨给药后12h的浓度(对于晚上给药的给药前)用早晨给药前(对于早晨给药的给药前)收集的样品中的浓度进行估算,因为这些值应该相似。稳态下的AUC0-24可计算为q12h给药的AUC0-12的两倍。
血浆浓度和药代动力学参数的汇总统计由剂量群组和跨群组生成。
其他分析
药效学和生物标志物探索性分析将在数据库锁定前完成的统计分析计划中进行描述。
具有窄治疗范围的CYP3A4和CYP3A底物的强抑制剂和诱导剂
缩写:浓度-时间曲线下AUC面积;CYP3A4细胞色素P4503A4。
a增加底物的AUC≥5倍
b降低底物的AUC≥80%
c指暴露-应答关系表明,伴随使用CYP抑制剂,其暴露水平的小幅度增加可能导致严重的安全问题的药物(例如,尖端扭转)
注:以上列表并非穷举。另请参见:
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm
等效物
这里描述的实施例和实施方案是说明性的并且向本领域技术人员建议的修改或改变将包括在本公开中。如本领域技术人员将理解的,上述实施例中列出的特定组分可以用其他功能等同的组分代替,例如稀释剂、粘合剂、润滑剂、填充剂等。
Claims (33)
1.一种治疗有此需要的个体的方法,包括施用menin抑制剂和CYP3A4抑制剂的组合。
2.一种治疗有此需要的个体的方法,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。
6.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂选自由以下组成的组:波普瑞韦、奈法唑酮、克拉霉素、奈非那韦、考尼伐坦、泊沙康唑、葡萄柚汁、利托那韦、茚地那韦、沙奎那韦、伊曲康唑、特拉匹韦、酮康唑、泰利霉素、洛匹那韦、伏立康唑、考比司他、米贝拉地尔。
7.前述权利要求中任一项的方法,其中所述CYP3A4是唑类抗真菌剂。
8.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂是泊沙康唑。
9.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂是考比司他。
10.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂是酮康唑。
11.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂是利托那韦。
12.前述权利要求中任一项的方法,其中所述menin抑制剂和所述CYP3A4抑制剂为组合剂型。
13.权利要求1-11中任一项的方法,其中所述menin抑制剂和所述CYP3A4抑制剂为分开的剂型。
14.前述权利要求中任一项的方法,其中以亚治疗有效量施用所述menin抑制剂。
15.前述权利要求中任一项的方法,其中以治疗有效量施用所述CYP3A4抑制剂。
16.权利要求1-14中任一项的方法,其中以亚治疗有效量施用所述CYP3A4抑制剂。
17.前述权利要求中任一项的方法,其中同时施用所述menin抑制剂和所述CYP3A4抑制剂。
18.前述权利要求中任一项的方法,其中同时、基本同时或在相同的治疗方案内施用所述menin抑制剂和所述CYP3A4抑制剂。
19.前述权利要求中任一项的方法,其中顺序地施用所述menin抑制剂和所述CYP3A4抑制剂。
20.前述权利要求中任一项的方法,其中施用所述组合用于初始治疗期,随后继续施用所述menin抑制剂。
21.前述权利要求中任一项的方法,其中所述CYP3A4抑制剂的施用发生在所述menin抑制剂的施用前。
22.一种用于治疗个体的癌症的试剂盒,包括menin抑制剂和CYP3A4抑制剂的组合。
24.权利要求22-23中任一项的试剂盒,进一步包括关于如何使用所述试剂盒的说明书。
25.Menin抑制剂和CYP3A4抑制剂的组合物,其中所述menin抑制剂和所述CYP3A4抑制剂在人体内(例如,仅在人体内)相互接触。
27.一种制备组合物的方法,通过使menin抑制剂和CYP3A4抑制剂在位点处彼此接触。
29.Menin抑制剂和CYP3A4抑制剂的组合,其用于制备治疗癌症的药物。
30.权利要求1-21中任一项的方法,其中CYP3A4抑制剂是强CYP3A4抑制剂。
32.权利要求1-21或31中任一项的方法,其中所述menin抑制剂是富马酸盐。
33.权利要求1-21或31-32中任一项的方法,其中所述menin抑制剂是倍半富马酸盐。
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