CN107427522A - 用于治疗黑素瘤的阿吡莫德 - Google Patents
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- CN107427522A CN107427522A CN201580072613.9A CN201580072613A CN107427522A CN 107427522 A CN107427522 A CN 107427522A CN 201580072613 A CN201580072613 A CN 201580072613A CN 107427522 A CN107427522 A CN 107427522A
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Abstract
本发明涉及用于利用阿吡莫德治疗黑素瘤的方法以及相关组合物和方法。
Description
相关申请
本申请要求2014年11月7日提交的美国专利申请序列号62/077,127、2015年2月12日提交的美国专利申请序列号62/115,228、和2015年2月23日提交的美国专利申请序列号62/119,540的优先权,所述美国专利申请的内容特此以引用的方式完全并入。
发明领域
本发明涉及包含阿吡莫德的组合物和将其用于治疗黑素瘤的方法。
发明背景
黑素瘤是在使我们的皮肤带色的细胞(黑素细胞)中发展的皮肤癌的严重形式。黑素瘤是美国的第六最常见癌症,并且每年诊断的黑素瘤病例数比任何其他癌症都更快地增加。2015年美国将诊断估计73,870个侵袭性黑素瘤新病例。2015年估计9,940人将死于黑素瘤。黑素瘤占小于百分之二的皮肤癌病例,但占皮肤癌死亡的绝大多数。50位男女中有1人在其一生中将被诊断患有皮肤的黑素瘤。
可通常经由受患区域的外科手术来完全去除早期黑素瘤。但一旦黑素瘤已转移,则很难治疗它。在大多数情况下,一旦它已转移则不可能完全消除或治愈癌症。取决于转移灶在哪和多大,治疗可涉及化学疗法、外科手术、基因疗法、免疫疗法、放射疗法、以及这些的组合。仍需要针对黑素瘤的更有效和毒性更低的治疗选项。
发明内容
本发明部分基于以下意外发现:阿吡莫德是黑素瘤细胞、尤其是对其他疗法有抗性的黑素瘤细胞中的高细胞毒性药剂,并且进一步与某些化疗药剂组合。
在一个方面中,本公开提供一种用于在有其需要的受试者中治疗黑素瘤的组合物,所述组合物包含治疗有效量的阿吡莫德,或者其药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物。在一个实施方案中,阿吡莫德是二甲磺酸阿吡莫德。在实施方案中,组合物是口服剂型或适合于静脉内施用的剂型。在实施方案中,黑素瘤是III或IV期黑素瘤、难医治的黑素瘤、或者恶性或转移性黑素瘤。
在实施方案中,组合物进一步包含至少一种另外的活性剂。在实施方案中,至少一种另外的活性剂是治疗剂或非治疗剂、或它们的组合。在实施方案中,至少一种另外的活性剂是治疗剂。在实施方案中,治疗剂选自蛋白激酶抑制剂、铂基抗肿瘤剂、拓扑异构酶抑制剂、核苷代谢抑制剂、烷化剂、嵌入剂、微管蛋白结合剂、PD-1/PDL-1通路抑制剂、以及它们的组合。在实施方案中,治疗剂选自:维罗非尼,达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇(Nab-paclitaxel),卡莫司汀,顺铂,卡铂,长春碱,伊匹木单抗,派姆单抗(Keytruda™)),白介素-2 (IL-2,Proleukin™),派姆单抗(Keytruda™),达拉非尼(Tafinlar™),维罗非尼(Zelboraf™),曲美替尼(Mekinist™),达沙替尼(Sprycel™),伊马替尼(Gleevec™),和尼洛替尼(Tasigna™)以及它们的组合。在实施方案中,治疗剂是维罗非尼。在实施方案中,治疗剂是PD-1/PDL-1通路抑制剂。在实施方案中,PD-1/PDL-1通路抑制剂选自派姆单抗(Keytruda)、阿维鲁单抗、阿特珠单抗(MPDL3280A)、纳武单抗(BMS-936558)、匹地利珠单抗(pidilizumab)(MK-3475)、MSB0010718C、和MEDI4736。
在实施方案中,组合物进一步包含被选定以改善阿吡莫德的一种或多种副作用的非治疗剂。在实施方案中,非治疗剂选自昂丹司琼、格拉司琼、多拉司琼和帕洛诺司琼。在实施方案中,非治疗剂选自吲哚洛尔和利培酮。
在一个方面中,本公开提供一种用于在有其需要的受试者中治疗黑素瘤的方法,所述方法包括向受试者施用治疗有效量的包含阿吡莫德的组合物,其中所述阿吡莫德是阿吡莫德自身(即,阿吡莫德游离碱)或者其药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物。在一个实施方案中,阿吡莫德是二甲磺酸阿吡莫德。
在实施方案中,所述方法进一步包括向受试者施用至少一种另外的活性剂。至少一种另外的活性剂可为治疗剂或非治疗剂、或它们的组合。至少一种另外的活性剂可以含有阿吡莫德的单剂型,或以单独剂型施用。
在实施方案中,至少一种另外的活性剂是酪氨酸激酶抑制剂。在实施方案中,酪氨酸激酶抑制剂是B-Raf酶抑制剂。在实施方案中,至少一种另外的活性剂是维罗非尼。在一个实施方案中,所述方法包括在用于治疗黑素瘤的组合治疗方案中一起施用阿吡莫德和维罗非尼。在一个实施方案中,黑素瘤是晚期黑素瘤。在一个实施方案中,晚期黑素瘤对仅维罗非尼有抗性。
在实施方案中,至少一种另外的活性剂是选自以下的治疗剂:蛋白激酶抑制剂,铂基抗肿瘤剂,拓扑异构酶抑制剂,核苷代谢抑制剂,烷化剂,嵌入剂,微管蛋白结合剂,BRAF抑制剂,以及它们的组合。在实施方案中,治疗剂是蛋白激酶抑制剂、烷化剂、嵌入剂、微管蛋白结合剂、以及它们的组合。在实施方案中,治疗剂选自维罗非尼、依鲁替尼、利妥昔单抗、多柔比星、长春新碱、万珂、和依维莫司、以及它们的组合。在实施方案中,至少一种另外的活性剂是选自以下的治疗剂:维罗非尼,达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇,卡莫司汀,顺铂,卡铂,长春碱,伊匹木单抗,派姆单抗(Keytruda™)),白介素-2 (IL-2,Proleukin™),派姆单抗(Keytruda™),达拉非尼(Tafinlar™),维罗非尼(Zelboraf™),曲美替尼(Mekinist™),达沙替尼(Sprycel™),伊马替尼(Gleevec™),和尼洛替尼(Tasigna™)以及它们的组合。在实施方案中,至少一种另外的活性剂是Bcl-2抑制剂。在一个实施方案中,Bcl-2抑制剂是ABT-199或navitoclax。
在实施方案中,至少一种另外的活性剂是被选定以改善阿吡莫德的一种或多种副作用的非治疗剂。在一个实施方案中,非治疗剂选自昂丹司琼、格拉司琼、多拉司琼和帕洛诺司琼。在实施方案中,非治疗剂选自吲哚洛尔和利培酮。
在实施方案中,组合物是口服剂型。在其他实施方案中,组合物是适合于静脉内施用的剂型。在一个实施方案中,在剂型适合于静脉内施用的情况下,通过单次注射或通过滴注袋来施用。在其他实施方案中,组合物是适合于通过乳膏、洗剂或凝胶来局部施用的剂型。
在本文所述方法的实施方案中,受试者是人黑素瘤患者。在实施方案中,需要治疗的人黑素瘤患者是患有晚期、恶性或转移性黑素瘤的人。在实施方案中,需要治疗的人黑素瘤患者是其癌症对标准化疗方案难治性的人。在实施方案中,需要治疗的人黑素瘤患者是其黑素瘤已在用标准化疗方案治疗之后复发的人。
在实施方案中,黑素瘤选自表浅蔓延型黑素瘤、恶性小痣、肢端色斑性黑素瘤、和结节型黑素瘤。在一个实施方案中,标准化疗方案包括选自以下的一种或多种治疗剂:达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇,卡莫司汀,顺铂,卡铂,和长春碱。在一个实施方案中,免疫治疗方案包括选自以下的一种或多种治疗剂:抗CTLA4抗体(例如,伊匹木单抗);PD-1/PDL-1通路抑制剂,例如派姆单抗(Keytruda)、阿维鲁单抗、阿特珠单抗(MPDL3280A)、纳武单抗(BMS-936558)、匹地利珠单抗(MK-3475)、MSB0010718C、和MEDI4736;AMP-224,和白介素-2 (IL-2,阿地白介素,Proleukin)。在一个实施方案中,靶向治疗方案包括选自以下的一种或多种治疗剂:BRAF抑制剂(例如,达拉非尼(Tafinlar)和维罗非尼(Zelboraf),MEK抑制剂(例如,曲美替尼(Mekinist))和KIT抑制剂(例如,达沙替尼(Sprycel)、伊马替尼(Gleevec)、和尼洛替尼(Tasigna))。
在实施方案中,所述方法是使用包括阿吡莫德和用于治疗黑素瘤的化疗方案的组合疗法治疗黑素瘤的方法。在一个实施方案中,阿吡莫德作为对化疗方案的附加疗法来施用。在实施方案中,化疗方案包括选自以下的PD-1/PDL-1通路抑制剂中的一种或多种:派姆单抗(Keytruda),阿维鲁单抗,阿特珠单抗(MPDL3280A),纳武单抗(BMS-936558),匹地利珠单抗(MK-3475),MSB0010718C,和MEDI4736。在实施方案中,化疗方案包括达卡巴嗪、替莫唑胺、白蛋白结合型紫杉醇、卡莫司汀、顺铂、卡铂、和长春碱中的一种或多种以用于治疗恶性或转移性黑素瘤。在实施方案中,化疗方案包括针对转移性黑素瘤的维罗非尼、达拉非尼和曲美替尼中的一种或多种。在一个实施方案中,化疗方案包括高剂量白介素-2和伊匹木单抗中的一种或多种。
在实施方案中,本公开提供用于在黑素瘤细胞中诱发或增强自噬或凋亡的方法。根据该实施方案,黑素瘤细胞可为体外或体内。在一个实施方案中,黑素瘤细胞为体外并且衍生自Yulac614、RPM19951、MEL-JUSO、SK-MEL-2、SK-MEL-31、A101D和A2058细胞。在一个实施方案中,黑素瘤细胞为体内,在哺乳动物受试者中除皮肤外的部位处。在一个实施方案中,黑素瘤细胞是晚期黑素瘤。在一个实施方案中,黑素瘤细胞是转移细胞或已转移的细胞。
本公开还提供一种用于鉴定利用包括阿吡莫德和维罗非尼的组合疗法治疗的人黑素瘤患者的方法,所述方法包括针对V600E BRAF蛋白突变、V600K BRAF蛋白突变、或它们的遗传等价物中的一者或多者对受试者癌症的生物样本进行测定,其中具有这些突变中任一者的受试者被鉴定为利用包括阿吡莫德和维罗非尼的组合疗法治疗的患者。
附图简述
图1:利用500种未经批准的含和不含维罗非尼(6 μM)的药物的库筛选Yulac614黑素瘤细胞,阿吡莫德被鉴定为当与维罗非尼组合时发挥协同活性的药物。
图2:仅维罗非尼(58.6-30,000 nM) (黑色线)或与阿吡莫德(500 nM)一起(灰色线)的10点浓度反应曲线。
图3:用仅维罗非尼(灰色条)或维罗非尼和阿吡莫德的组合(黑色条)处理的抗维罗非尼细胞系中的IC50值。
图4:用仅维罗非尼(灰色条)或维罗非尼和阿吡莫德的组合(黑色条)处理的抗维罗非尼细胞系中的IC50值。
发明详述
本公开提供涉及阿吡莫德用于治疗需要这种治疗的受试者、优选人受试者中的黑素瘤的用途的组合物和方法。本公开基于阿吡莫德对诸如黑素瘤的一系列癌细胞的细胞毒活性的意外发现,大体上涉及阿吡莫德的新用途。另外,本发明提供基于利用阿吡莫德和至少一种另外的治疗剂的组合疗法的用来治疗黑素瘤的新颖治疗方法。本文所述的组合疗法利用阿吡莫德的独特细胞毒活性,当与包括例如抗癌剂的其他治疗剂组合时阿吡莫德可提供协同效应。
如本文所使用的,术语“阿吡莫德”可指阿吡莫德自身(即,阿吡莫德游离碱),或可涵盖阿吡莫德的药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物,如下文所述的。在实施方案中,阿吡莫德是二甲磺酸阿吡莫德。阿吡莫德的结构示于式I中:
(I)
阿吡莫德的IUPAC名是:(E)-4-(6-(2-(3-甲基亚苄基)肼基)-2-(2-(吡啶-2-基)乙氧基)嘧啶-4-基)吗啉)并且CAS号是541550-19-0。
阿吡莫德可例如根据美国专利号7,923,557和7,863,270、以及WO 2006/128129中所描述的方法来制备。
如本文所使用的,术语“药学上可接受盐”是形成自例如阿吡莫德组合物的酸性和碱性基的盐。例示性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、苯磺酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐(glucaronate)、糖质酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、以及双羟萘酸盐(例如,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。在一个优选实施方案中,阿吡莫德的盐包含甲磺酸盐。
术语“药学上可接受盐”还指自具有诸如羧酸官能团的酸性官能团的阿吡莫德组合物和药学上可接受的无机或有机碱制备的盐。
术语“药学上可接受盐”还指自具有诸如氨基官能团的碱性官能团的阿吡莫德组合物和药学上可接受的无机或有机酸制备的盐。
本文所述的化合物的盐可通过常规化学方法自母体化合物合成,所述化学方法诸如Pharmaceutical Salts: Properties, Selection, and Use,P. Hemrich Stalil (编者),Camille G. Wermuth (编者),ISBN:3-90639-026-8,2002年8月中所描述的方法。大体上,此类盐可通过使母体化合物与适当的酸在水中或在有机溶剂中、或在两者的混合物中反应来制备。
本文所述的化合物的一种盐形式可通过技术人员众所周知的方法来转化至游离碱并且任选地转化至另一种盐形式。例如,可通过使盐溶液经过含有胺固定相的柱(例如Strata-NH2柱)来形成游离碱。或者,盐于水中的溶液可用碳酸氢钠处理以分解盐并沉淀析出游离碱。然后,游离碱可使用常规方法与另一种酸组合。
如本文所使用的,术语“多晶型物”意指本发明的化合物(例如,阿吡莫德)或其复合物的固体晶形。相同化合物的不同多晶型物可展现不同的物理、化学和/或光谱性质。不同的物理性质包括但不限于稳定性(例如,对热或光的稳定性)、可压缩性和密度(在制剂和产品制造中很重要)、和溶解速率(可影响生物可利用性)。稳定性的差异可起因于化学反应性(例如,差异氧化,使得剂型由一种多晶型物组成时比由另一种多晶型物组成时更迅速地变色)或机械特性(例如,随着动力学有利的多晶型物转化至热力学更稳定的多晶型物,片剂在存储时碎裂)或两者(例如,一种多晶型物的片剂在高湿度下更容易破裂)的变化。多晶型物的不同物理性质可影响其加工。例如,由于例如其颗粒的形状或大小分布,一种多晶型物可能比另一种更可能形成溶剂化物或可能更难以过滤或洗涤除去杂质。
如本文所使用的,术语“水合物”意指本发明的化合物(例如,阿吡莫德)或其盐,其进一步包括受非共价分子间力约束的化学计算量或非化学计算量的水。
如本文所使用的,术语“包合物”意指呈含有空间(例如,通道)的晶格形式的本发明的化合物(例如,阿吡莫德)或其盐,所述空间具有截留于其内的客体分子(例如,溶剂或水)。
如本文所使用的,术语“药物前体”意指可在生物学条件下(体外或体内)水解、氧化、或以其他方式反应来提供本发明的化合物的本文所述的化合物(例如,阿吡莫德)的衍生物。药物前体可仅在这种在生物学条件下的反应后变得有活性,或它们可以其未反应形式具有活性。在本发明中涵盖的药物前体的实例包括但不限于:包含生物可水解部分的本文所述的化合物(例如,阿吡莫德)的类似物或衍生物,所述生物可水解部分诸如生物可水解的酰胺、生物可水解的酯、生物可水解的氨基甲酸酯、生物可水解的碳酸酯、生物可水解的酰脲、和生物可水解的磷酸酯类似物。药物前体的其他实例包括本文所公开的式中任一者的化合物的衍生物,其包含-NO、-NO2、-ONO或-ONO2部分。药物前体通常可使用众所周知的方法来制备,诸如由Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178,949-982 (Manfred E. Wolff编,第5版)所描述的那些方法。
如本文所使用的,术语“溶剂化物“或”药学上可接受的溶剂化物”是自一种或多种溶剂分子缔合至本文所公开的化合物中的一者(例如,阿吡莫德)形成的溶剂化物。术语溶剂化物包括水合物(例如,半水合物、单水合物、二水合物、三水合物、四水合物等)。
如本文所使用的,术语“类似物”指的是结构上与另一种相似但在组成上略微不同(如一个原子被不同元素的原子替换,或存在特别的官能团,或一种官能团被另一种官能团替换)的化合物。因此,类似物是在功能和外观上、而不是在结构或起源上与参考化合物相似或可比拟的化合物。如本文所使用的,术语“衍生物”指的是具有共有核结构并且被如本文所述的各种基团取代的化合物。
黑素瘤
黑素瘤是由黑素细胞(皮肤中的含色素细胞)形成的一类皮肤癌,其被发现于皮肤的表皮中。表皮是构成皮肤的细胞两个主要层的上层或外层,并且通过基膜与皮肤的更深层隔开。当诸如黑素瘤的皮肤癌变得更进一步时,其一般穿透表皮并且穿过膜生长入皮肤的更深层以进入血液供应,从而使肿瘤能够转移。
黑素瘤存在四种基本类型。其中三种原位起始——意指它们仅占据皮肤的顶层,并且有时变成侵袭性的;第四者从一开始就是侵袭性的。侵袭性黑素瘤更严重,因为它们已较深地穿透入皮肤并且可能已扩散至身体的其他区域。
表浅蔓延型黑素瘤是到目前为止最常见的类型,占全部病例的约70%。这是最常见于年轻人中的一种。如名称所表明的,这种黑素瘤在更深地穿透之前沿皮肤顶层生长相当长时间。
恶性小痣与表浅蔓延型相似,因为它也留在接近皮肤表面持续很长一段时间,并且通常显现为扁平或轻度***的斑驳的棕黄色、褐色或深褐色变色。这种类型的原位黑素瘤最常发现于中老年人中,出现在脸、耳、手臂和上躯干上长期暴露于日光、损坏的皮肤上。当这种癌症变成侵袭性时,它被称作恶性色斑型黑素瘤。
肢端色斑性黑素瘤也在更深地穿透之前表浅蔓延。然而,它与其他者相当不同,因为它通常显现为指甲下或者脚底或手掌上的黑色或褐色变色。这种类型的黑素瘤有时发现于深色皮肤的人上,并且通常可比表浅蔓延型黑素瘤和恶性小痣更快速进展。它是非洲裔美国人和亚洲人中最常见的黑素瘤,并且在高加索人之中最不常见。
结节型黑素瘤在它被首次诊断时通常是侵袭性的。当它变成肿块时被确认是恶性。它通常为黑色,但偶尔为蓝色、灰色、白色、褐色、棕黄色、红色或肤色。
治疗方法
本公开提供用于在有其需要的受试者中治疗黑素瘤的方法,所述方法通过向受试者施用治疗有效量的阿吡莫德,或者阿吡莫德的药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物来进行。在实施方案中,阿吡莫德是二甲磺酸阿吡莫德。本公开进一步提供阿吡莫德在制备用于治疗黑素瘤的药剂中的用途。
在本文所述方法的情形下,施用于受试者的阿吡莫德的量是治疗有效量。术语“治疗有效量”指的是足以在受治疗的受试者中治疗、改善黑素瘤的症状、降低黑素瘤的严重性、或者使黑素瘤稳定或消退,或者增强或改进诸如维罗非尼的另一种疗法的疗效的量。
根据本文所述的方法,“有其需要的受试者”是患有黑素瘤的受试者。在一个方面中,受试者是患有恶性黑素瘤或晚期黑素瘤的人患者。在这种情形下,“期”指的是癌症的临床期。例如,0至2期黑素瘤或者3期或4期黑素瘤。在一个实施方案中,受试者是患有3期黑素瘤或4期黑素瘤的人患者。有其需要的受试者可为对当前可利用的疗法“无反应性”或“难治性”的人,例如受试者的癌症可能对利用维罗非尼的治疗有抗性或难治性。在这种情形下,术语“无反应性”和“难治性”指的是受试者对疗法的反应并不如根据标准医疗实践中对临床反应的定义般在临床上显著。
组合疗法
本公开还提供包括利用阿吡莫德的组合疗法的方法。如本文所使用的,“组合疗法”或“联合疗法”包括作为意图提供来自基本疗法和另外的治疗剂的相互作用的有益效果的特定治疗方案的部分,来施用治疗有效量的基本疗法(例如,阿吡莫德)与至少一种另外的治疗剂。“组合疗法”不意图涵盖作为偶然和任意地导致未预期或预测的有益效果的单独的单一疗法方案的部分来施用两种或更多种治疗性化合物。
在一个实施方案中,所述方法是将包括阿吡莫德和化疗方案的组合疗法用于治疗黑素瘤的治疗黑素瘤的方法。在一个实施方案中,化疗方案选自达卡巴嗪、替莫唑胺、白蛋白结合型紫杉醇、卡莫司汀、顺铂、卡铂、长春碱、以及它们的组合。
在实施方案中,至少一种另外的活性剂可为治疗剂,例如抗癌剂或癌症化疗剂,或者非治疗剂,以及它们的组合。就治疗剂而言,组合的有益效果包括但不限于由治疗活性化合物的组合产生的药物动力学或药效学相互作用。就非治疗剂而言,组合的有益效果可涉及与组合中的治疗活性剂相关联的毒性、副作用、或不利事件的减轻。
在实施方案中,至少一种另外的药剂是减轻阿吡莫德的一种或多种副作用的非治疗剂,所述一种或多种副作用选自恶心、呕吐、头痛、眩晕、头昏眼花、困倦和紧张中的任何者。在该实施方案的一个方面中,非治疗剂是5-羟色胺受体、也被称为5-羟色胺受体或5-HT受体的拮抗剂。在一个方面中,非治疗剂是5-HT3或5-HT1a受体的拮抗剂。在一个方面中,非治疗剂选自昂丹司琼、格拉司琼、多拉司琼和帕洛诺司琼。在另一个方面中,非治疗剂选自吲哚洛尔和利培酮。
在实施方案中,至少一种另外的药剂是治疗剂。在一个实施方案中,治疗剂是抗癌剂。在实施方案中,抗癌剂是维罗非尼。在一个实施方案中,阿吡莫德与维罗非尼一起以单剂型或以单独剂型施用。在一个实施方案中,剂型是口服剂型。在另一个实施方案中,剂型适合于静脉内施用。
在实施方案中,抗癌剂是获批准用于治疗黑素瘤的药物。此类药物的非限制性实例包括阿地白介素、达拉非尼、达卡巴嗪、DTIC-Dome (达卡巴嗪)、甘乐能(intronA)(重组干扰素α-2b)、伊匹木单抗、keytruda (派姆单抗)、mekinist (曲美替尼)、纳武单抗、聚乙二醇干扰素α-2b、PEG-Intron (聚乙二醇干扰素α-2b)、派姆单抗、Proleukin (阿地白介素)、重组干扰素α-2b、sylatron (聚乙二醇干扰素α-2b)、tafinlar (达拉非尼)、曲美替尼、维罗非尼、yervoy (伊匹木单抗)、zelboraf (维罗非尼)
在实施方案中,抗癌剂选自EZH2的抑制剂,例如EPZ-6438。在一个实施方案中,抗癌剂选自紫杉酚、长春新碱、多柔比星、坦罗莫司、卡铂、奥法木单抗、利妥昔单抗、以及它们的组合。
在实施方案中,抗癌剂是Bcl-2抑制剂。在一个实施方案中,Bcl-2抑制剂是ABT-199或navitoclax。
在实施方案中,至少一种另外的药剂选自苯丁酸氮芥、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、fostamatinib、紫杉醇、多西他赛、奥法木单抗、利妥昔单抗、***、***、CAL-101、替伊莫单抗、托西莫单抗、硼替佐米、喷司他丁、内皮他丁、或它们的组合。
在实施方案中,至少一种另外的药剂是单克隆抗体,诸如像,阿仑珠单抗,贝伐珠单抗,卡妥索单抗,西妥昔单抗,依决洛单抗,吉妥珠单抗,奥法木单抗,帕尼单抗,利妥昔单抗,曲妥珠单抗,依库珠单抗,依法珠单抗,莫罗单抗(muromab)-CD3,那他珠单抗,阿达木单抗,阿非莫单抗,培舍珠单抗,戈利木单抗,英利昔单抗,巴利昔单抗,卡那单抗(canakinumab),达克珠单抗,美泊利单抗,托珠单抗,优特克单抗(ustekinumab),替伊莫单抗,托西莫单抗,阿巴伏单抗,阿德木单抗,阿仑珠单抗,抗CD30单抗Xmab2513,抗MET单抗MetMab,阿泊珠单抗,apomab,阿西莫单抗,巴利昔单抗,双特异性抗体2B1,布利妥莫单抗(blinatumomab),本妥昔单抗,卡罗单抗喷地肽,西妥木单抗(cixutumumab),claudiximab,conatumumab,达西珠单抗(dacetuzumab),地舒单抗,依库珠单抗,依帕珠单抗,厄马索单抗,伊瑞西珠单抗(etaracizumab),figitumumab,fresolimumab,加利昔单抗,ganitumab,吉妥珠单抗奥佐米星,glembatumumab,替伊莫单抗,伊珠单抗奥佐米星,伊匹木单抗,来沙木单抗,林妥珠单抗,林妥珠单抗,鲁卡木单抗(lucatumumab),马帕木单抗,马妥珠单抗,米拉珠单抗(milatuzumab),单抗CC49,耐昔妥珠单抗,尼妥珠单抗,奥法木单抗,奥戈伏单抗,培妥珠单抗,ramacurimab,雷珠单抗,西利珠单抗,sonepcizumab,tanezumab,托西莫单抗,曲妥珠单抗,tremelimumab,西莫白介素单抗,维妥珠单抗,维西珠单抗,伏洛昔单抗,以及扎芦木单抗。
在实施方案中,至少一种另外的抑制剂是BRAF抑制剂、MEK抑制剂、PD-1/PD-L1抑制剂或检查点抑制剂。
在实施方案中,PD-1/PDL-1通路抑制剂选自派姆单抗(Keytruda)、阿维鲁单抗、阿特珠单抗(MPDL3280A)、纳武单抗(BMS-936558)、匹地利珠单抗(MK-3475)、MSB0010718C、和MEDI4736。
在组合疗法的情形下,阿吡莫德的施用可与一种或多种另外的活性剂的施用同时或相继进行。在实施方案中,组合疗法的不同组分可以不同频率施用。一种或多种另外的药剂可在施用本发明的化合物之前(例如,在之前5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周、或12周)、同时、或之后(例如,在之后5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周、或12周)施用。
一种或多种另外的活性剂可配制成与阿吡莫德以单一剂型共施用,如本文中更详细描述的。一种或多种另外的活性剂可与包含阿吡莫德的剂型分开施用。当另外的活性剂与阿吡莫德分开施用时,它可通过与阿吡莫德相同或不同的施用途径来施用。
优选地,阿吡莫德与一种或多种另外的药剂组合施用在受治疗的受试者中提供协同反应。在这种情形下,术语“协同”指的是组合的效力比单独的任一单疗法的加性效应更有效。组合疗法的协同效应可允许使用相比于在组合外至少一种药剂的剂量和/或频率而言在组合中所述至少一种药剂更低剂量和/或更不频繁的施用。组合的另外有益效果可在避免或减少与单独使用组合中的任一疗法(也称为单一疗法)相关联的不利或不需要的副作用中显现。
“组合疗法”还涵盖治疗性化合物与一种或多种非药物疗法(例如,外科手术或放射治疗)组合施用。在组合疗法进一步包括非药物治疗的情况下,非药物治疗可以任何合适的时间进行,只要实现来自治疗性化合物和非药物治疗的组合的相互作用的有益效果。例如,在适当的情况下,当暂时从治疗性化合物的施用中去除非药物治疗时,仍实现有益效果,大概到数天或甚至数周为止。
根据本文所述方法中的任何者,治疗有效量的阿吡莫德的范围可为约0.001 mg/kg至约1000 mg/kg,约0.01 mg/kg至约100 mg/kg,约10 mg/kg至约250 mg/kg,约0.1 mg/kg至约15 mg/kg;或其中范围的低端是0.001 mg/kg与900 mg/kg之间的任何量并且范围的上端是0.1 mg/kg与1000 mg/kg之间的任何量的任何范围(例如,0.005 mg/kg和200 mg/kg,0.5 mg/kg和20 mg/kg)。如本领域技术人员所认识到的,取决于受治疗的疾病、施用途径、赋形剂使用以及与其它治疗性治疗共同使用,诸如使用其它药剂的可能性,有效剂量还将变化。参见,例如美国专利号7,863,270,其以引用的方式并入本文。
在实施方案中,阿吡莫德以每日30-1000 mg (例如,每日30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、125、150、175、200、225、250、275或300 mg)的剂量方案施用至少1周(例如,1、2、3、4、5、6、7、8、9、10、11、12、36、48或更多周)。优选地,阿吡莫德以每日100-1000 mg的剂量方案施用4或16周。替代地或随后,阿吡莫德以每日两次100 mg-300 mg的剂量方案施用8周、或任选52周。替代地或随后,阿吡莫德以每日两次50 mg-1000 mg的剂量方案施用8周、或任选52周。
治疗有效量的阿吡莫德可每日施用一次,每日二至五次,每日至多两次或至多三次,或每日至多八次。在实施方案中,阿吡莫德按以下施用:每日三次,每日两次,每日一次,在3周周期内十四天给药(每日四次、每日三次或每日两次、或每日一次)和7天断药,在3周周期内至多五或七天给药(每日四次、每日三次或每日两次、或每日一次)和14-16天断药,或每两天一次,或一周一次,或每2周一次,或每3周一次。
如本文所述方法的情形下使用的“受试者”优选为人受试者而且还可包括其他哺乳动物。哺乳动物可为例如任何哺乳动物,例如,人、灵长类、脊椎动物、鸟、小鼠、大鼠、禽、狗、猫、母牛、马、山羊、骆驼、绵羊或猪。术语“患者”指的是人受试者。
本公开还提供一种用于使用阿吡莫德来治疗黑素瘤的单一疗法。如本文所使用的,“单一疗法”指的是向有其需要的受试者施用单活性或治疗性化合物,即,阿吡莫德。
如本文所使用的,“治疗(treatment, treating或treat)”描述为了对抗疾病、病症或障碍而对患者进行的管理和护理,并且包括施用阿吡莫德组合物来减轻疾病、病症或障碍的症状或并发症,或来消除疾病、病症或障碍。
在实施方案中,施用阿吡莫德导致受治疗黑素瘤的症状或并发症的消除,但消除并非所需的。在一个实施方案中,症状的严重性降低。在癌症的情形下,此类症状可包括严重性或进展的临床标志,包括肿瘤分泌生长因子、降解胞外基质、变得血管化、失去对并列组织的粘附、或转移的程度,以及转移灶的数量。
根据本文所述的方法来治疗黑素瘤可导致肿瘤大小的减小。肿瘤大小的减小还可被称作“肿瘤消退”。优选地,在治疗之后,肿瘤大小相对于其治疗前的大小减小5%或更大;更优选地,肿瘤大小减小10%或更大;更优选地,减小20%或更大;更优选地,减小30%或更大;更优选地,减小40%或更大;甚至更优选地,减小50%或更大;并且最优选地,减小大于75%或更大。肿瘤的大小可通过任何可再现的测量方法来测量。肿瘤的大小可测量为肿瘤的直径。
根据本文所述的方法来治疗黑素瘤可导致肿瘤体积的减小。优选地,在治疗之后,肿瘤体积相对于其治疗前的大小减小5%或更大;更优选地,肿瘤体积减小10%或更大;更优选地,减小20%或更大;更优选地,减小30%或更大;更优选地,减小40%或更大;甚至更优选地,减小50%或更大;并且最优选地,减小大于75%或更大。肿瘤体积可通过任何可再现的测量方法来测量。
根据本文所述的方法来治疗黑素瘤可导致肿瘤的数量减少。优选地,在治疗之后,肿瘤数相对于治疗前的数量减少5%或更大;更优选地,肿瘤数减少10%或更大;更优选地,减少20%或更大;更优选地,减少30%或更大;更优选地,减少40%或更大;甚至更优选地,减少50%或更大;并且最优选地,减少大于75%。肿瘤的数量可通过任何可再现的测量方法来测量。肿瘤的数量可通过计数肉眼可见的肿瘤或以指定放大率来测量。优选地,指定放大率为2×、3×、4×、5×、10×、或50×。
根据本文所述的方法来治疗黑素瘤可导致在远离原发肿瘤位点的其他组织或器官中转移病灶的数量减少。优选地,在治疗之后,转移病灶的数量相对于治疗前的数量减少5%或更大;更优选地,转移病灶的数量减少10%或更大;更优选地,减少20%或更大;更优选地,减少30%或更大;更优选地,减少40%或更大;甚至更优选地,减少50%或更大;并且最优选地,减少大于75%。转移病灶的数量可通过任何可再现的测量方法来测量。转移病灶的数量可通过计数肉眼可见的转移病灶或以指定放大率来测量。优选地,指定放大率为2×、3×、4×、5×、10×、或50×。
根据本文所述的方法来治疗黑素瘤可导致与接受仅载体的群体相比受治疗受试者的群体的平均存活时间增加。优选地,平均存活时间增加多于30天;更优选地,增加多于60天;更优选地,增加多于90天;并且最优选地,增加多于120天。群体的平均存活时间的增加可通过任何可再现的方法来测量。群体的平均存活时间的增加可例如通过计算在开始用活性化合物治疗之后群体的平均存活时长来测量。群体的平均存活时间的增加还可例如通过计算在用活性化合物治疗的第一轮完成之后群体的平均存活时长来测量。
根据本文所述的方法来治疗黑素瘤可导致与接受利用非阿吡莫德的药物的单一疗法的群体相比受治疗受试者的群体的平均存活时间增加。优选地,平均存活时间增加多于30天;更优选地,增加多于60天;更优选地,增加多于90天;并且最优选地,增加多于120天。群体的平均存活时间的增加可通过任何可再现的方法来测量。群体的平均存活时间的增加可例如通过计算在开始用活性化合物治疗之后群体的平均存活时长来测量。群体的平均存活时间的增加还可例如通过计算在用活性化合物治疗的第一轮完成之后群体的平均存活时长来测量。
根据本文所述的方法来治疗黑素瘤可导致与接受仅载体的群体相比受治疗受试者的群体的死亡率降低。根据本文所述的方法来治疗黑素瘤可导致与未受治疗的群体相比受治疗受试者的群体的死亡率降低。根据本文所述的方法来治疗黑素瘤可导致与接受利用非阿吡莫德的药物的单一疗法的群体相比受治疗受试者的群体的死亡率降低。优选地,死亡率降低多于2%;更优选地,降低多于5%;更优选地,降低多于10%;并且最优选地,降低多于25%。受治疗受试者的群体的死亡率的降低可通过任何可再现的方法来测量。群体的死亡率的降低可例如通过计算在开始用活性化合物治疗之后群体的每单位时间疾病相关性死亡的平均数量来测量。群体的死亡率的降低还可例如通过计算在用活性化合物治疗的第一轮完成之后群体的每单位时间疾病相关性死亡的平均数量来测量。
根据本文所述的方法来治疗黑素瘤可导致肿瘤生长速率降低。优选地,在治疗之后,肿瘤生长速率相对于治疗前的数量降低至少5%;更优选地,肿瘤生长速率降低至少10%;更优选地,降低至少20%;更优选地,降低至少30%;更优选地,降低至少40%;更优选地,降低至少50%;甚至更优选地,降低至少50%;并且最优选地,降低至少75%。肿瘤生长速率可通过任何可再现的测量方法来测量。肿瘤生长速率可根据每单位时间肿瘤直径的变化来测量。在一个实施方案中,在治疗之后,肿瘤生长速率可为约零并且被测定为维持在相同的大小,例如,已停止生长。
根据本文所述的方法来治疗黑素瘤可导致肿瘤再生长减少。优选地,在治疗之后,肿瘤再生长少于5%;更优选地,肿瘤再生长少于10%;更优选地,少于20%;更优选地,少于30%;更优选地,少于40%;更优选地,少于50%;甚至更优选地,少于50%;并且最优选地,少于75%。肿瘤再生长可通过任何可再现的测量方法来测量。肿瘤再生长例如通过测量在治疗后先前肿瘤收缩之后肿瘤直径的增加来测量。肿瘤再生长的减少由肿瘤在治疗已停止后未能重新出现来指示。
如本文所使用的,术语“选择性”意指趋向于在一个群体中比在另一个群体中以更高频率发生。比较群体可为细胞群体。优选地,相比于正常细胞,阿吡莫德选择性作用于超增殖细胞或异常增殖细胞。如本文所使用的,“正常细胞”是不能被归类为“细胞增殖障碍”的部分的细胞。正常细胞没有未受调控或异常的生长或两者,所述生长可导致不需要的病症或疾病的发展。优选地,正常细胞拥有正常起作用的细胞周期检查点控制机制。优选地,阿吡莫德选择性起作用以调节一种分子靶标(例如,靶标激酶)但不显著调节另一种分子靶标(例如,非靶标激酶)。本公开还提供一种用于选择性抑制诸如激酶的酶的活性的方法。优选地,如果事件相比于群体B在群体A中超过两倍更频繁地发生,则事件相对于群体B在群体A中选择性发生。如果事件在群体A中超过五倍更频繁地发生,则事件选择性发生。如果事件在群体A中超过十倍更频繁地发生,则事件选择性发生;更优选地,超过五十倍;甚至更优选地,超过100倍;并且最优选地,相比于群体B在群体A中超过1000倍更频繁地发生。例如,如果细胞死亡相比于正常细胞而言在患病或超增殖的细胞中超过两倍更频繁地发生,则细胞死亡将被认为在患病或超增殖的细胞中选择性发生。
药物组合物和制剂
本公开提供包含阿吡莫德的组合物,所述组合物是适合用于哺乳动物、优选人中的药学上可接受组合物。在这种情形下,组合物可进一步包含至少一种药学上可接受的赋形剂或载体,其中量对治疗黑素瘤有效。在实施方案中,阿吡莫德是二甲磺酸阿吡莫德。
在实施方案中,阿吡莫德与至少一种另外的活性剂以单剂型组合。在一个实施方案中,组合物进一步包含抗氧化剂。
在实施方案中,至少一种另外的活性剂是选自以下的治疗剂:蛋白激酶抑制剂,铂基抗肿瘤剂,拓扑异构酶抑制剂,核苷代谢抑制剂,烷化剂,嵌入剂,微管蛋白结合剂,BRAF抑制剂,以及它们的组合。在实施方案中,治疗剂是蛋白激酶抑制剂、烷化剂、嵌入剂、微管蛋白结合剂、皮质类固醇、以及它们的组合。在实施方案中,治疗剂选自维罗非尼、依鲁替尼、利妥昔单抗、多柔比星、***龙、长春新碱、万珂、和依维莫司、以及它们的组合。
在实施方案中,至少一种另外的活性剂是BRAF抑制剂、MEK抑制剂、PD-1/PD-L1抑制剂、或检查点抑制剂。
在实施方案中,PD-1/PDL-1通路抑制剂选自派姆单抗(Keytruda)、阿维鲁单抗、阿特珠单抗(MPDL3280A)、纳武单抗(BMS-936558)、匹地利珠单抗(MK-3475)、MSB0010718C、和MEDI4736。
在实施方案中,至少一种另外的活性剂是选自以下的治疗剂:达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇,卡莫司汀,顺铂,卡铂,长春碱,伊匹木单抗,白介素-2 (IL-2,Proleukin),派姆单抗(Keytruda),达拉非尼(Tafinlar),维罗非尼(Zelboraf),曲美替尼(Mekinist),达沙替尼(Sprycel),伊马替尼(Gleevec),和尼洛替尼(Tasigna)以及它们的组合。
在实施方案中,至少一种另外的活性剂是被选定以改善阿吡莫德的一种或多种副作用的非治疗剂。在实施方案中,非治疗剂选自昂丹司琼、格拉司琼、多拉司琼和帕洛诺司琼。在实施方案中,非治疗剂选自吲哚洛尔和利培酮。
在实施方案中,至少一种另外的活性剂选自BRAF的抑制剂、Raf/MEK/ERK通路的抑制剂、mTOR通路的抑制剂、PI3K抑制剂、双重PI3K/mTOR抑制剂、SRC抑制剂、VEGF抑制剂、詹纳斯激酶(JAK)抑制剂、Raf抑制剂、Erk抑制剂、法尼基转移酶抑制剂、组蛋白脱乙酰酶抑制剂、抗有丝***剂、多药耐性运出抑制剂、抗生素、以及治疗性抗体。在一个实施方案中,至少一种另外的活性剂选自法尼基转移酶抑制剂(例如,替匹法尼)、抗有丝***剂(例如,多西他赛)、组蛋白脱乙酰酶抑制剂(例如,伏林司他)、和多药耐性运出抑制剂。
在实施方案中,mTOR抑制剂选自以下:雷帕霉素(也称为西罗莫司),依维莫司,坦罗莫司,ridaforolimus,umirolimus,唑罗莫司,AZD8055,INK128,WYE-132,Torin-1,吡唑并嘧啶类似物PP242、PP30、PP487、PP121,KU0063794,KU-BMCL-200908069-1,Wyeth-BMCL-200910075-9b,INK-128,XL388,AZD8055,P2281,和P529。参见,例如,Liu等人 Drug Disc. Today Ther. Strateg.,6(2):47-55 (2009)。
在实施方案中,mTOR抑制剂是反式-4-[4-氨基-5-(7-甲氧基-1H-吲哚-2-基)咪唑并[5,1-f][1,2,4]三嗪-7-基]环己烷羧酸(还被称为OSI-027),以及其任何盐、溶剂化物、水合物、和其它物理形态、晶体或非晶体。参见US 2007/0112005。OSI-027可根据US 2007/0112005来制备,所述专利以引用的方式并入本文。在一个实施方案中,mTOR抑制剂是OXA-01。参见,例如WO 2013152342 A1。
在实施方案中,PI3K抑制剂选自以下:GS-1101 (艾代拉里斯(Idelalisib)),GDC0941 (Pictilisib),LY294002,BKM120 (Buparlisib),PI-103,TGX-221,IC-87114,XL147,ZSTK474,BYL719,AS-605240,PIK-75,3-甲基腺嘌呤,A66,PIK-93,PIK-90,AZD6482,IPI-145 (Duvelisib),TG100-115,AS-252424,PIK294,AS-604850,GSK2636771,BAY 80-6946 (库潘尼西),CH5132799,CAY10505,PIK-293,TG100713,CZC24832和HS-173。
在实施方案中,双重PI3K/mTOR抑制剂选自以下:GDC-094,WAY-001,WYE-354,WAY-600,WYE-687,Wyeth-BMCL-200910075-16b,Wyeth-BMCL-200910096-27,KU0063794和KUBMCL-200908069-5,NVP-BEZ235,XL-765,PF-04691502,GDC-0980 (Apitolisib),GSK1059615,PF-05212384,BGT226,PKI-402,VS-558和GSK2126458。参见,例如,Liu等人Drug Disc. Today Ther. Strateg.,6(2):47-55 (2009),其以引用的方式并入本文。
在实施方案中,mTOR通路抑制剂是结合至mTOR通路中的蛋白(或编码蛋白的核酸)并且抑制所述蛋白(或所述核酸)的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、锁定核酸、或适配体)。例如,多肽或核酸抑制mTOR复合体1 (mTORC1)、mTOR的调节相关蛋白(Raptor)、哺乳动物致死性SEC13蛋白8 (MLST8)、40 kDa的富脯氨酸Akt底物 (PRAS40)、含DEP结构域mTOR互作蛋白(DEPTOR)、mTOR复合体2 (mTORC2)、mTOR的雷帕霉素不敏感伴侣(RICTOR)、类G蛋白β亚基(GβL)、哺乳动物应激激活蛋白激酶互作蛋白1 (mSIN1)、桩蛋白、RhoA、Ras相关性C3肉毒杆菌毒素底物1 (Rac1),细胞***调控蛋白42同系物(Cdc42)、蛋白激酶C α (PKCα)、丝氨酸/苏氨酸蛋白激酶Akt、磷酸肌醇3激酶(PI3K)、p70S6K、Ras、和/或真核翻译起始因子4E(eIF4E)结合蛋白(4EBP)、或编码这些蛋白中的一者的核酸。
在实施方案中,SRC抑制剂选自以下:波舒替尼,塞卡替尼,达沙替尼,帕纳替尼,KX2-391,XL-228,TG100435/TG100855,和DCC2036。参见,例如,Puls等人 Oncologist.2011年5月;16(5):566-578。在一个实施方案中,SRC抑制剂是结合至SRC蛋白或编码SRC蛋白的核酸并且抑制SRC蛋白或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、锁定核酸、或适配体)。
在实施方案中,VEGF抑制剂选自贝伐珠单抗、舒尼替尼、帕唑帕尼、阿昔替尼、索拉非尼、瑞格菲尼、乐伐替尼、和莫特塞尼。在一个实施方案中,VEGF抑制剂是结合至VEGF蛋白、VEGF受体蛋白、或编码这些蛋白中的一者的核酸并且抑制所述蛋白或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。例如,VEGF抑制剂是可溶性VEGF受体(例如,可溶性VEGF-C/D受体(sVEGFR-3))。
在实施方案中,JAK抑制剂选自facitinib、鲁索替尼、巴瑞克替尼、CYT387 (CAS号1056634-68-4)、来他替尼、帕克替尼、和TG101348 (CAS号936091-26-8)。在一个实施方案中,JAK抑制剂是结合至JAK(例如,JAK1、JAK2、JAK3、或TYK2)或编码JAK蛋白的核酸并且抑制JAK或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。
在实施方案中,Raf抑制剂选自PLX4032 (维罗非尼)、索拉非尼、PLX-4720、GSK2118436 (达拉非尼)、GDC-0879、RAF265、AZ 628、NVP-BHG712、SB90885、ZM 336372、GW5074、TAK-632、CEP-32496和LGX818 (恩可非尼(Encorafenib))。在一个实施方案中,Raf抑制剂是结合至Raf(例如,A-Raf、B-Raf、C-Raf)或编码Raf蛋白的核酸并且抑制Raf或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。在一个实施方案中,MEK抑制剂选自AZD6244 (司美替尼)、PD0325901、GSK1120212 (曲美替尼)、U0126-EtOH、PD184352、RDEA119 (Rafametinib)、PD98059、BIX 02189、MEK162 (比尼替尼(Binimetinib))、AS-703026 (Pimasertib)、SL-327、BIX02188、AZD8330、TAK-733和PD318088。在一个实施方案中,MEK抑制剂是结合至MEK(例如,MEK-1、MEK-2)或编码MEK蛋白的核酸并且抑制MEK或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。
在实施方案中,Akt抑制剂选自MK-2206、KRX-0401 (哌立福辛)、GSK690693、GDC-0068 (Ipatasertib)、AZD5363、CCT128930、A-674563、PHT-427。在一个实施方案中,Akt抑制剂是结合至Akt(例如,Akt-1、Akt-2、Akt-3)或编码Akt蛋白的核酸并且抑制Akt或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。
在实施方案中,法尼基转移酶抑制剂选自LB42708或替匹法尼。在一个实施方案中,法尼基转移酶抑制剂是结合至法尼基转移酶或编码法尼基转移酶蛋白的核酸并且抑制法尼基转移酶或所述核酸的表达水平或活性的多肽(例如,抗体或其片段)或核酸(例如,双链小干扰RNA、短发夹RNA、微RNA、反义寡核苷酸、吗啉代、锁定核酸、或适配体)。在一个实施方案中,组蛋白调制抑制剂选自漆树酸、C646、MG149 (组蛋白乙酰转移酶)、GSK J4 Hcl(组蛋白脱甲基酶)、GSK343 (抗EZH2活性物)、BIX 01294 (组蛋白甲基移换酶)、MK0683(伏立诺他)、MS275 (恩替诺特)、LBH589 (帕比司他)、曲古抑菌素A、MGCD0103(Mocetinostat)、他喹莫德、TMP269、Nexturastat A、RG2833、PDX101 (贝利司他)。
在实施方案中,抗有丝***剂选自灰黄霉素、酒石酸长春瑞滨、紫杉醇、多西他赛、长春新碱、长春碱、埃博霉素A、埃博霉素B、ABT-751、CYT997 (Lexibulin)、酒石酸长春氟宁、Fosbretabulin、GSK461364、ON-01910 (Rigosertib)、Ro3280、BI2536、NMS-P937、BI6727 (Volasertib)、HMN-214和MLN0905。
在实施方案中,聚醚抗生素选自莫能菌素、尼日利亚菌素、缬氨霉素、盐霉素的钠盐。
“药物组合物”是呈药学上可接受的形式适合于向受试者施用的含有本文所述的化合物的制剂。如本文所使用的,短语“药学上可接受的”指的是那些化合物、材料、组合物、载体、和/或剂型,其在合理医学判断的范围内,适合于与人类和动物的组织接触使用而不具有过度毒性、刺激、过敏反应或者其他问题或并发症,与合理的收益/风险比相称。
“药学上可接受的赋形剂”意指可用于制备大体上安全、无毒和既不在生物学上又不以其他方式不合意的药物组合物中的赋形剂,并且包括兽医用途以及人药学用途可接受的赋形剂。药学上可接受的赋形剂的实例包括但不限于:无菌液体,水,缓冲盐水,乙醇,多元醇(例如,甘油、丙二醇、液态聚乙二醇等),油,去污剂,悬浮剂,碳水化合物(例如,葡萄糖、乳糖、蔗糖或葡聚糖),抗氧化剂(例如,抗坏血酸或谷胱甘肽),鳌合剂,低分子量蛋白,或它们的合适混合物。
药物组合物可散装或以剂量单位形式提供。尤其有利的是以剂量单位形式配制药物组合物以便于施用和剂量的一致性。如本文所用的术语“剂量单位形式”指的是适合作为用于待治疗的受试者的单一剂量的物理离散单位;每单位含有经计算产生与所需药物载体相关联的期望疗效的预定量的活性化合物。本发明的剂量单位形式的规格由活性化合物的独特特性和待实现的具体疗效来规定并且直接取决于所述特性和疗效。剂量单位形式可为安瓿、小瓶、栓剂、糖衣丸、片剂、胶囊、IV袋、或气溶胶吸入器上的单泵。
在治疗性应用中,在其他影响选定剂量的因素中,剂量视以下者变化:药剂,接受患者的年龄、体重和临床病症,以及施用疗法的临床医师或行医者的经验和判断。大体上,剂量应是治疗有效量。剂量可以测量结果的每日mg/kg单位提供(其剂量可针对患者的以kg计的体重、以m2计的体表面积和以年计的年龄调整)。药物组合物的有效量是提供由临床医师或其他有资格的观察者所注意到的客观上可鉴定的改善的量。例如,减轻障碍、疾病或病症的症状。如本文所使用的,术语“剂量有效方式”指的是药物组合物在受试者或细胞中产生所需生物效果的量。
例如,剂量单位形式可包含1纳克至2毫克,或0.1毫克至2克;或10毫克至1克,或50毫克至500毫克或1微克至20毫克;或1微克至10毫克;或0.1毫克至2毫克。
药物组合物可采取任何合适的形式(例如,液体、气溶胶、溶液、吸入剂、合剂、喷雾;或固体、粉末、软膏、糊剂、乳膏、洗剂、凝胶、贴剂等)以通过任何所需的途径(例如,肺部、吸入、鼻内、口服、口腔含化、舌下、胃肠外、皮下、静脉内、肌肉内、腹膜内、胸膜内、鞘内、透皮、经粘膜、直肠等)来施用。例如,本发明的药物组合物可呈用于通过吸入或吹入(经过口或鼻)的气溶胶施用的水溶液或粉末的形式,呈用于口服施用的片剂或胶囊的形式;呈适合于通过直接注射或通过添加至用于静脉内输注的无菌输注液来施用的无菌水溶液或分散体的形式;或呈用于透皮或经粘膜施用的洗剂、乳膏、泡沫、贴剂、悬浮液、溶液、或栓剂的形式。
药物组合物可呈口服可接受剂型的形式,包括但不限于胶囊,片剂,口腔含化形式,片剂(troches),锭剂,以及呈乳液、含水悬浮液、分散体或溶液形式的口服液体。胶囊可含有本发明的化合物与惰性填充剂和/或稀释剂的混合物,所述惰性填充剂和/或稀释剂诸如药学上可接受的淀粉(例如,玉米、马铃薯或木薯淀粉)、糖、人工增甜剂、诸如结晶纤维素和微晶纤维素的粉末状纤维素、面粉、明胶、树胶等。在用于口服用途的片剂的情况下,通常使用的载体包括乳糖和玉米淀粉。还可添加诸如硬脂酸镁的润滑剂。对于以胶囊形式的口服施用而言,可用的稀释剂包括乳糖和干燥的玉米淀粉。当口服施用含水悬浮液和/或乳液时,本发明的化合物可悬浮或溶解于与乳化剂和/或悬浮剂组合的含油相中。需要时,可添加某些增甜剂和/或增香剂和/或着色剂。
药物组合物可呈片剂的形式。片剂可包含单位剂量的本发明的化合物连同诸如糖或糖醇,例如乳糖、蔗糖、山梨醇或甘露醇的惰性稀释剂或载体。片剂可进一步包含非糖衍生的稀释剂,诸如碳酸钠、磷酸钙、碳酸钙;或者纤维素或其衍生物,诸如甲基纤维素、乙基纤维素、羟丙基甲基纤维素;和淀粉,诸如玉米淀粉。片剂可进一步包含诸如聚乙烯基吡咯烷酮的结合剂和成粒剂,崩解剂(例如可溶胀的交联聚合物,诸如交联羧甲基纤维素),润滑剂(例如硬脂酸酯),防腐剂(例如对羟苯甲酸酯),抗氧化剂(例如BHT),缓冲剂(例如磷酸盐或柠檬酸盐缓冲液),以及诸如柠檬酸盐/碳酸氢盐混合物的泡腾剂。
片剂可为包衣片剂。包衣可为保护膜包衣(例如蜡或清漆)或被设计成控制活性剂释放、例如缓释(在摄入后的预定滞后时间之后释放活性物)或在胃肠道中的特定位置处释放的包衣。后者可例如使用肠溶膜包衣、诸如以商标名Eudragit®出售的那些来实现。
片剂制剂可通过常规压缩、湿法制粒或干法制粒方法来制得,并且利用药学上可接受的稀释剂、结合剂、润滑剂、崩解剂、表面改性剂(包括表面活性剂)、悬浮剂或稳定剂,包括但不限于:硬脂酸镁,硬脂酸,滑石,月桂基硫酸钠,微晶纤维素,羧甲基纤维素钙,聚乙烯基吡咯烷酮,明胶,藻酸,金合欢胶,黄原胶,柠檬酸钠,复合硅酸盐,碳酸钙,甘氨酸,糊精,蔗糖,山梨醇,磷酸二钙,硫酸钙,乳糖,高岭土,甘露醇,氯化钠,滑石,干淀粉和糖粉。优选的表面改性剂包括非离子型和阴离子型表面改性剂。表面改性剂的代表性实例包括但不限于:泊洛沙姆188,氯化苯甲烃铵,硬脂酸钙,鲸蜡硬脂醇,聚西托醇乳化蜡,脱水山梨醇酯,胶体二氧化硅,磷酸盐,十二烷基硫酸钠,硅酸镁铝,以及三乙醇胺。
药物组合物可呈硬或软明胶胶囊的形式。根据这种制剂,本发明的化合物可呈固体、半固体、或液体形式。
药物组合物可呈适合于胃肠外施用的无菌水溶液或分散体的形式。如本文所用的术语胃肠外包括皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。
药物组合物可呈适合于通过直接注射或通过添加至用于静脉内输注的无菌输注液来施用的无菌水溶液或分散体的形式,并且包含含有水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇)、它们的合适混合物、或一种或多种植物油的溶剂或分散介质。本发明的化合物作为游离碱或药理学上可接受盐的溶液或悬浮液可在水中适合地与表面活性剂混合来制备。合适的表面活性剂的实例在下文给出。分散体还可例如在甘油、液态聚乙二醇和二者于油中的混合物中制备。
用于本发明的方法中的药物组合物可进一步包含除了制剂中存在的任何载体或稀释剂(诸如乳糖或甘露醇)以外的一种或多种添加剂。一种或多种添加剂可包含一种或多种表面活性剂或者由一种或多种表面活性剂组成。表面活性剂通常具有诸如脂肪酸的一种或多种长脂族链,所述长脂族链使得表面活性剂能够直接***细胞的脂质结构以增强药物渗透和吸收。通常用来表征表面活性剂的相对亲水性和疏水性的经验性参数是亲水-亲脂平衡(“HLB”值)。具有较低HLB值的表面活性剂更疏水,并且在油中具有较大溶解度,而具有较高HLB值的表面活性剂更亲水,并且在水溶液中具有较大溶解度。因此,亲水表面活性剂大体上被认为是HLB值大于约10的那些化合物,并且疏水表面活性剂大体上是HLB值小于约10的那些。然而,这些HLB值只是一个指导,因为对于许多表面活性剂而言,取决于所选定用于测定HLB值的经验性方法,HLB值可相差至多约8个HLB单位。
在用于本发明的组合物中的表面活性剂之中的是聚乙二醇(PEG)-脂肪酸以及PEG-脂肪酸单酯和二酯,PEG甘油酯,醇-油转酯产物,聚甘油脂肪酸,丙二醇脂肪酸酯,固醇和固醇衍生物,聚乙二醇脱水山梨醇脂肪酸酯,聚乙二醇烷基醚,糖和其衍生物,聚乙二醇烷基酚,聚氧乙烯-聚氧丙烯(POE-POP)嵌段共聚物,脱水山梨醇脂肪酸酯,离子型表面活性剂,脂溶性维生素和其盐,水溶性维生素和其两亲性衍生物,氨基酸和其盐,以及有机酸和其酯和酸酐。
本公开还提供包含用于本文所述方法中的药物组合物的包装和试剂盒。试剂盒可包含选自瓶、小瓶、安瓿、泡罩包装和注射器的一种或多种容器。试剂盒可进一步包括用于治疗和/或预防本发明的疾病、病症或障碍的说明书中的一者或多者、一个或多个注射器、一个或多个涂药器、或适合于重构本发明的药物组合物的无菌溶液。
除非有另外指示,否则本文使用的所有百分数和比率以重量计。本发明的其他特征和优点从不同实施例中显而易见。所提供的实施例例示出可用于实践本发明中的不同组分和方法学。实施例不限制要求保护的发明。基于本公开,技术人员可鉴定和采用可用于实践本发明的其它组分和方法学。
实施例
实施例1:阿吡莫德与维罗非尼之间的协同活性
Yulac614 (抗维罗非尼,参见Choi等人2014)细胞被用来进行药物组合研究以鉴定协同药物配对。500种未获批准的药物的库被用来在维罗非尼(IC20 = 6 μM)存在或不存在下进行药物筛选。药物库从10 mM储备溶液稀释至5 mM、0.5 mM和0.05 mM的亚储备溶液(1000×最终浓度)以给出5 μM、0.5 μM和0.05 μM的最终筛选浓度。
将30 nL库药物(1000×浓度)点样至384黑色壁板(Corning #3712)的适当孔中。制备一式两份的药物点样板并且向它们添加用DMSO (最终0.01%)或维罗非尼(最终6 μM)预处理的Yulac614细胞。Yulac614细胞生长于含有5% FBS (Sigma Aldrich F2442-500ML,批12D370)青霉素/链霉素(100×)(CellGro 参考30-002)的OptiMEM (LifeTechnologies)中。使用Multidrop Combi (Thermo Fisher Scientific)向每个孔分配30uL细胞以给出每个孔2,000个细胞的最终细胞密度。
在湿润培养箱中在5% CO2的气氛下37℃下孵育板72 h。根据制造商的说明书利用CellTiter-Glo®发光分析法(Promega)来测定细胞活力。活力表示为对照(DMSO)细胞的百分数。将仅药物的库的活力相比于药物+维罗非尼的库,并且鉴定显著的组合。
阿吡莫德被鉴定为与维罗非尼组合相比于仅任一药物而言显著降低Yulac614细胞活力的未获批准的药物。参见图1 。
为了验证维罗非尼和阿吡莫德的观察结果,将Yulac614细胞以每个孔5,000个细胞的密度、50 uL的最终体积接种至96孔板中。在存在和不存在阿吡莫德(IC20 = 500 nM)下,以10点浓度反应曲线(58.6-30,000 nM;2倍稀释)测试维罗非尼。向细胞添加50 uL的10点药物稀释系列(2×浓度)。在湿润培养箱中在5% CO2的气氛下37℃下孵育板。在添加化合物72小时之后,根据制造商的说明书通过CellTiter-Glo®发光分析法(Promega)来测定相对细胞活力,并且值表示为相对于受载体(DMSO)处理的对照细胞(设定至100%)的百分数。图2描绘出仅维罗非尼(58.6-30,000 nM) (黑色线)或与阿吡莫德(500 nM)一起(灰色线)的10点浓度反应曲线。结果说明阿吡莫德与维罗非尼组合比仅维罗非尼在降低Yulac614细胞的细胞活力上更有效。
在另一个实验中,Yulac (亲本,对维罗非尼敏感),Yulac 614、Yulac 616、YulacT-CRAF (全部抗维罗非尼),参见Choi等人2014)生长于含有5% FBS (Sigma AldrichF2442-500ML,批12D370)青霉素/链霉素(100×) (CellGro 参考30-002)的OptiMEM (LifeTechnologies)中。对于组合研究而言,将细胞以每个孔5000个细胞的密度、50 μL的最终体积接种至96孔板中。利用仅阿吡莫德(最终浓度13.7-30000 nM;3倍稀释和总共8个稀释物)、仅维罗非尼(最终浓度13.7-30000 nM;3倍稀释和总共8个稀释物)或各浓度的阿吡莫德与各浓度的维罗非尼的组合(8×8矩阵)来处理细胞。处理细胞72 h,之后使用CellTiterGlo® (Promega)来评估增殖。为了计算协同作用,使用CalcuSyn (版本2.11,Biosoft)来测定由Chou等人定义的组合指数(CI) (Chou TC,Talalay P. Quantitativeanalysis of dose-effect relationships: the combined effects of multiple drugsor enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55)。我们将分析限制于评估在临床可实现浓度内以及在分数效应(Fa)大于0.70 (即,利用药物的组合细胞活力降低大于70%)的情况下的CI值。因此,产生CI值>1的药物组合是拮抗的,CI=1是加性的并且CI<1是协同的。使用这种方法,发现阿吡莫德与维罗非尼在这些细胞系中的每一者中协同作用(参见表1)。使用GraphPad Prism4软件来计算IC50值以测定阿吡莫德对维罗非尼敏感性的变化。如图3中所示,维罗非尼与370 nM下的阿吡莫德组合相比于仅维罗非尼使IC50降低5.5至25倍。
表1:
细胞系 | 维罗非尼/阿吡莫德浓度(nM) | 受影响的分数 | 组合指数(CI) |
Yulac (亲本) | 1111 / 370 | 0.74 | 0.3 |
Yulac614 | 10000 / 370 | 0.84 | 0.3 |
Yulac614 | 10000 / 370 | 0.84 | 0.5 |
Yulac-CRAF | 10000 / 370 | 0.84 | 0.2 |
为了扩展这些发现,选择对维罗非尼展示固有抗性的一组黑素瘤细胞系来进一步对阿吡莫德进行研究。A101D、SK-MEL-2、SK-MEL-31、RPMI7951、A2058 (生长于补充有10%胎牛血清的DMEM中)和MEL-JUSO (生长于补充有10%胎牛血清的RPMI中)细胞获自ATCC。将细胞以最优密度、50 μL的最终体积接种在96孔板中。利用仅阿吡莫德(最终78.1-10000 nM;2倍稀释和总共8个稀释物)、仅维罗非尼(最终浓度234-30000 nM;2倍稀释和总共8个稀释物)或各浓度的阿吡莫德与各浓度的维罗非尼的组合(8×8矩阵)来处理细胞。处理细胞72 h,之后使用CellTiterGlo® (Promega)来评估增殖。为了计算协同作用,使用CalcuSyn (版本2.11,Biosoft)来测定如上述的组合指数(CI)。使用这种方法,发现阿吡莫德与维罗非尼在每种细胞系中协同作用(参见表2)。使用GraphPad Prism4软件来计算IC50值以测定阿吡莫德对维罗非尼敏感性的变化。如图4中所示,维罗非尼与185 nM下的阿吡莫德 (A101D、RPMI7951、A2058和MEL-JUSO细胞) 或312 nM下的阿吡莫德 (SK-MEL-2和SK-MEL-31) 组合相比于仅维罗非尼使IC50降低4.5至25倍。
表2.
细胞系 | 维罗非尼/阿吡莫德浓度(nM) | 受影响的分数 | 组合指数(CI) |
RPMI7951 | 3750 / 185 | 0.71 | 0.18 |
MEL-JUSO | 7500 / 185 | 0.78 | 0.05 |
SK-MEL-2 | 15000 / 312 | 0.72 | 0.1 |
SK-MEL-31 | 15000 / 312 | 0.78 | 0.03 |
A101D | 7500 / 185 | 0.91 | 0.11 |
A2058 | 15000 / 185 | 0.84 | 0.02 |
组合指数(CI)值用于指示用维罗非尼和阿吡莫德的组合处理的抗维罗非尼细胞系。CI值>1是拮抗,CI=1是加性并且CI<1是协同。
Claims (22)
1.一种用于在有其需要的受试者中治疗黑素瘤的组合物,所述组合物包含治疗有效量的阿吡莫德,或者其药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物。
2.权利要求1所述的组合物,其中所述阿吡莫德是二甲磺酸阿吡莫德。
3.权利要求1或2所述的组合物,其中所述组合物是口服剂型或适合于静脉内施用的剂型。
4.权利要求1至3中任何项所述的组合物,其中所述黑素瘤是III或IV期黑素瘤。
5.权利要求1至4中任何项所述的组合物,其进一步包含至少一种另外的活性剂。
6.权利要求5所述的组合物,其中所述至少一种另外的活性剂是治疗剂或非治疗剂,或它们的组合。
7.权利要求6所述的组合物,其中所述至少一种另外的活性剂是治疗剂。
8.权利要求7所述的组合物,其中所述治疗剂选自蛋白激酶抑制剂、铂基抗肿瘤剂、拓扑异构酶抑制剂、核苷代谢抑制剂、烷化剂、嵌入剂、微管蛋白结合剂,以及它们的组合。
9.权利要求8所述的组合物,其中所述治疗剂选自以下:达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇,卡莫司汀,顺铂,卡铂,长春碱,伊匹木单抗,白介素-2 (IL-2,Proleukin™),派姆单抗(Keytruda™),阿维鲁单抗,阿特珠单抗(MPDL3280A),纳武单抗(BMS-936558),匹地利珠单抗(MK-3475),MSB0010718C,MEDI4736,达拉非尼(Tafinlar™),维罗非尼(Zelboraf™),曲美替尼(Mekinist™),达沙替尼(Sprycel™),伊马替尼(Gleevec™),和尼洛替尼(Tasigna™)以及它们的组合。
10.权利要求9所述的组合物,其中所述治疗剂是维罗非尼。
11.权利要求7-10中任一项所述的组合物,其中所述组合物进一步包含被选定以改善所述阿吡莫德的一种或多种副作用的非治疗剂。
12.权利要求5或6所述的组合物,其中所述至少一种另外的药剂是被选定以改善所述阿吡莫德的一种或多种副作用的非治疗剂。
13.权利要求11或12所述的组合物,其中所述非治疗剂选自昂丹司琼、格拉司琼、多拉司琼和帕洛诺司琼。
14.权利要求11或12所述的组合物,其中所述非治疗剂选自吲哚洛尔和利培酮。
15.一种用于在受试者中治疗黑素瘤的阿吡莫德组合物,所述组合物包含二甲磺酸阿吡莫德以及烷化剂、嵌入剂、微管蛋白结合剂,和BRAF抑制剂中的一种或多种。
16.权利要求15所述的组合物,其中所述组合物包含以下中的一种或多种:达卡巴嗪,替莫唑胺,白蛋白结合型紫杉醇,卡莫司汀,顺铂,卡铂,长春碱,伊匹木单抗,派姆单抗(Keytruda™),阿维鲁单抗,阿特珠单抗(MPDL3280A),纳武单抗(BMS-936558),匹地利珠单抗(MK-3475),MSB0010718C,MEDI4736,白介素-2 (IL-2,Proleukin™),达拉非尼(Tafinlar™),维罗非尼(Zelboraf™),曲美替尼(Mekinist™),达沙替尼(Sprycel™),伊马替尼(Gleevec™),以及尼洛替尼(Tasigna™)。
17.权利要求16所述的组合物,其中所述组合物包含维罗非尼。
18.权利要求15至17中任何项所述的组合物,其中所述组合物进一步包含昂丹司琼、格拉司琼、多拉司琼、帕洛诺司琼、吲哚洛尔和利培酮中的一种或多种。
19.权利要求1至18中任一项所述的组合物,其中所述癌症是恶性或转移性黑素瘤。
20.一种用于鉴定利用包括阿吡莫德和维罗非尼的组合疗法治疗的人黑素瘤患者的方法,所述方法包括针对V600E BRAF蛋白突变、V600K BRAF蛋白突变、或它们的遗传等价物中的一者或多者对受试者的癌症的生物样本进行测定,其中具有这些突变中任一者的受试者被鉴定为利用包括阿吡莫德和维罗非尼的组合疗法治疗的患者。
21.一种用于在有其需要的受试者中治疗黑素瘤的方法,所述方法包括向所述受试者施用治疗有效量的阿吡莫德,或其药学上可接受盐、溶剂化物、包合物、水合物、多晶型物、药物前体、类似物或衍生物。
22.权利要求21所述的方法,其中所述阿吡莫德是二甲磺酸阿吡莫德。
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