CN114641292A - 波齐替尼与vegfr2抑制剂的组合及其用途 - Google Patents
波齐替尼与vegfr2抑制剂的组合及其用途 Download PDFInfo
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Abstract
包含波齐替尼或其药学上可接受的盐和VEGFR2抑制剂的药物组合以及使用该组合治疗有需要的受试者中的癌症的方法。该药物组合在治疗具有一个或多个EGFR或HER2突变的癌症中表现出协同作用。
Description
技术领域
本文公开了包含波齐替尼或其药学上可接受的盐和VEGFR抑制剂的药物组合以及使用该组合来治疗有需要的受试者中的癌症的方法。
背景技术
近年来,据报道,EGFR靶向治疗中耐药性的表达减少所用药物的响应时间。据报道,患有EGFR激活突变的非小细胞肺癌(NSCLC)的患者采用吉非替尼或厄洛替尼治疗约8至16个月后对该药产生耐药性,据观察,约60%的患者因EGFR T790M突变而产生耐药性(Helena A.Yu等人,Cancer Res.19(8),2240,2013)。此外,在采用抗体药物曲妥珠单抗治疗的HER2阳性转移性乳腺癌患者中,已知66%至88%的患者由于各种机制而表现出新发耐药性或获得性耐药性(Alice Chung等人,Clin.Breast Cancer 13(4),223,2013)。在这方面,EGFR靶向治疗剂的开发是有限的,因为由于原发和继发耐药性的产生,其疗效不能长期保持,尽管EGFR靶向治疗剂对HER2过表达或突变的实体癌有相当好的治疗效果。因此,迫切需要用于牙科和医学应用的改进和替代的材料。
发明内容
本专利文件提供用于降低或防止肿瘤尺寸增大或达到转移状态的风险的方法,由此达到阻止癌症进展或发展的目标。
本专利文件的一个方面提供了用于治疗受试者的肿瘤的药物组合。该组合包括波齐替尼或其药学上可接受的盐和血管内皮生长因子受体(VEGFR)抑制剂。在一些实施方案中,抑制剂是VEGFR2抑制剂。在一些实施方案中,VEGFR2抑制剂是雷莫芦单抗。
本专利文件的一方面提供了一种用于治疗受试者的肿瘤的试剂盒。该试剂盒包括波齐替尼或其药学上可接受的盐和血管内皮生长因子受体2(VEGFR2)抑制剂。在一些实施方案中,VEGFR2抑制剂是雷莫芦单抗。该试剂盒还可能包括指导信息和使用说明。
本申请文件的另一个方面提供了治疗受试者的肿瘤的方法,包括将本文所述的药物组合施用有需要的受试者。
在一些实施方案中,肿瘤选自非小细胞肺癌、乳腺癌、胃癌、结肠癌、胰腺癌、前列腺癌、骨髓瘤、头颈癌、卵巢癌、食道癌和转移性细胞癌。在一些实施方案中,药物组合中的VEGFR2抑制剂是雷莫芦单抗。
在一些实施方案中,受试者在外显子18、外显子19、外显子20或外显子21处有突变表达。在一些实施方案中,该方法包括确定受试者具有一个或多个HER2外显子20突变。在一些实施方案中,该方法包括确定受试者具有一个或多个EGFR外显子20突变,该突变选自A775insV G776C、A775insYVMA、G776C V777insC、G776del insVV、G776del insVC、P780insGSP、Y772dupYVMA、V773M、G776delinsLC、V777L、V777insCG、G778dupGSP、P780insGSP、L786V。在一些实施方案中,该方法包括确定受试者具有一个或多个EGFR外显子20突变,该突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH、N771dupNPH、A767insTLA、S768I、V769L、V769insGSV、D770del insGY、D770insG、D770insY H773Y、N771insHH、P772insDNP、H773insAH、H773insH、V774insHV、S784F、R776C、V774M、V769M、G796D、S784F、C775Y、S811F、T790M、V774A和D770A。
在一些实施方案中,该方法包括确定受试者具有一个或多个HER2外显子21突变,该突变选自氨基酸832-883之间的1-18个核苷酸的点突变、插入和缺失。在一些实施方案中,该方法包括确定受试者在选自V842、R868和L869的一个或多个残基处具有一个或多个HER2外显子21突变。
在一些实施方案中,肿瘤是非小细胞肺癌。在一些实施方案中,肿瘤是转移性癌症。在一些实施方案中,该癌症化疗或放疗难以治疗、对化疗耐药或已经复发。
在一些实施方案中,受试者先前已经接受了针对肿瘤的一线、两线、三线或更多线的治疗。在一些实施方案中,受试者之前没有接受过EGFR酪氨酸激酶抑制剂的治疗。在一些实施方案中,受试者已经接受了用EGFR酪氨酸激酶抑制剂的先前治疗。在一些实施方案中,对药物组合的施用和/或剂量进行控制,以治疗或预防受试者的CNS转移。
本专利文件的另一方面提供了一种治疗或预防受试者CNS转移的方法,包括向所述受试者施用本文所述的药物组合,其中所述受试者已被诊断患有癌症。在一些实施方案中,癌症是非小细胞肺癌(NSCLC)。在一些实施方案中,受试者已被确定患有CNS转移。在一些实施方案中,受试者已被确定没有CNS转移。在一些实施方案中,受试者先前已经接受了针对肿瘤的一线、两线、三线或更多线的治疗。在一些实施方案中,受试者此前没有接受过EGFR酪氨酸激酶抑制剂的治疗。
具体实施方式
本专利文件公开了一种药物组合以及使用该组合治疗与HER1、HER2或HER4或HER1、HER2或HER4的突变体过表达或扩增相关的癌症的方法。当与单独施用治疗有效量的单独组分相比时,施用治疗有效量的本发明组合优于单独组分,因为该组合提供以下一种或多种改进的性质:i)比最有效的单一药物具有更大的抗癌作用,ii)协同的或高度协同的抗癌活性,iii)提供增强的抗癌活性并减少副作用的施用方案,iv)降低毒性作用,v)治疗窗口的拓宽,vi)一种或多种组分的生物利用度增加,或vii)单个组分的细胞凋亡增加。
尽管以下文本可以参考或举例说明药物组合的具体实施方案或使用该组合治疗癌症的方法,但并不旨在将组合或方法的范围限制为此类特定参考或实施例。基于实际和经济方面的考虑,本领域技术人员可以进行各种修改,例如药物组合中单个组分的量和组合施用的具体间隔。
如本文所使用,除非另有说明,冠词“a(一个)”和“an(一个)”是指“一个或多个”或“至少一个”。即,不定冠词“a(一)”或“an(一个)”对实施方案的任何元件或组件的引用不排除存在多于一个元件或组件的可能性。
如本文所使用,术语“约”通常是指指定数字的正负10%。例如,“约10%”可能表示9%到11%的范围,“约20”可能表示从18到22。“约”的其他含义可以从上下文中明显看出,例如四舍五入,因此,例如“约为1”也可以表示从0.5到1.4。如本文所使用,术语“和/或”包括一个或多个相关列出的项目的任何和所有组合。诸如“至少一个”之类的表达式在元素列表之前时,会修改整个元素列表,而不修改列表中的各个元素。当提及施用方案时,术语“天”、“每天”等是指一个日历日内的时间,该时间从午夜开始并在下一个午夜结束。
如本文所使用,术语“治疗(treating)”或“治疗(treatment)”及其任何派生词是指治疗性疗法。就特定情况而言,治疗是指:(1)改善或预防该病症的一种或多种症状的生物学表现,(2)与(a)导致或导致该病症的生物级联中的一个或多个点,或(b)病症的一种或多种生物学表现发生干扰,(3)减轻与病症或其治疗相关的一种或多种症状、作用或副作用,或(4)减缓病症的进展或一种或更多的条件的生物学表现。由此也考虑预防性治疗。本领域技术人员将理解“预防”不是一个绝对的术语。在医学中,“预防”被理解为是指预防性施用药物以显著降低病症或其生物学表现的可能性或严重性,或延迟此类病症或其生物学表现的发作。预防性治疗是合适的,例如,当受试者被认为具有患癌的高风险时,例如当受试者具有强烈的癌症家族史或当受试者已暴露于致癌物时。
如本文所使用,术语“有效量”是指将引起例如研究人员或临床医生正在寻找的组织、系统、动物或人的生物学或医学反应的药物或药剂的量。此外,术语“治疗有效量”是指与未接受该量的相应受试者相比,导致疾病、病症或副作用的改善治疗、愈合、预防、或缓解或降低疾病或病症的进展速度的任何量。该术语还包括在其范围内有效增强正常生理功能的量。本领域普通技术人员可以使用常规程序容易地确定具体剂量。
如本文所使用,术语“组合”意指包括两种或更多种药物组分,其需要同时施用或以任何方式分开顺序地施用治疗有效量的组分药物。优选地,如果施用不是同时的,则组分药物在彼此接近的时间内施用。合适地,两种药物在约24、约12、约11、约10、约9、约8、约7、约6、约5、约4、约3、约2或约1小时内各施用一次。如本文所使用,例如,当波齐替尼和雷莫芦单抗的施用间隔小于约45分钟时,这被认为是同时施用。
如本文所使用,术语“药学上可接受的载体和/或赋形剂”是指与受试者和活性成分药理学和/或生理学相容的载体和/或赋形剂。药学上可接受的载体包括但不限于pH调节剂、表面活性剂、佐剂和离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲溶液;表面活性剂包括但不限于阳离子、阴离子或非离子表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文所使用“有需要的受试者”是指患有与HER1、HER2或HER4或其任何突变体的过表达相关的病症或疾病的受试者或患者,他们将受益于施用包含波齐替尼和VEGFR2抑制剂(血管内皮生长因子受体2抑制剂,例如雷莫芦单抗)的药物组合。
如本文所使用术语“野生型”在本领域中被理解并且是指在没有遗传修饰的情况下在天然群体中出现的多肽或多核苷酸序列。同样如本领域所理解的“突变体”包括与分别在野生型多肽或多核苷酸中发现的相应氨基酸或核酸相比,对氨基酸或核酸具有至少一种修饰的多肽或多核苷酸序列。包括在术语突变体中的是单核苷酸多态性(SNP),其中与最普遍发现的(野生型)核酸链相比,核酸链的序列中存在单个碱基对差异。通过已知方法鉴定HER1、HER2或HER4是野生型还是或变型或具有HER1、HER2或HER4基因扩增或HER1、HER2或HER4蛋白过度表达的癌症。
如本文所使用,术语“抗体”是指通常由两对多肽链(每对具有轻(L)链和重(H)链)组成的免疫球蛋白。抗体轻链可分为κ轻链或λ轻链。重链可分为μ、δ、γ、α或ε,抗体的同种型分别定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链中,可变区和恒定区通过具有约12个或更多氨基酸的“J”区连接,并且重链进一步包含具有约3个或更多氨基酸的“D”区。每条重链由重链可变区(VH)和重链恒定区(CH)组成。重链由3个结构域(CH1、CH2和CH3)组成。每条轻链由一个轻链可变区(VL)和一个轻链恒定区(CL)组成。抗体的恒定区可以介导免疫球蛋白与包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分在内的宿主组织或因子结合。
如本文所使用,术语抗体的“抗原结合片段”是指包含全长抗体的片段的多肽,该片段保留特异性结合至全长抗体所结合的同一抗原的能力,和/或与全长抗体竞争特异性结合抗原。
如本文所使用,术语“受试者”指的是人或动物。
本发明的一个方面提供了一种药物组合,包括波齐替尼或其药学上可接受的盐、血管内皮生长因子受体(VEGFR)抑制剂和一种或多种药学上可接受的载体。波齐替尼,即1-[4-[4-(3,4-二氯-2-氟苯氨基)-7-甲基喹唑啉-6-基]氧基哌啶基-1-基]-2-丙烯-1-酮,具有式1表示的结构。
药学上可接受的盐形式的波齐替尼可以包括但不限于无机酸或有机酸的酸加成盐。作为无机酸加成盐,可以列举由盐酸、氢溴酸、硫酸、焦硫酸、硝酸、磷酸、高氯酸、溴酸形成的波齐替尼盐等。有机酸加成盐的实施例可包括甲酸、乙酸、丙酸、草酸、琥珀酸、苯甲酸、柠檬酸、马来酸、丙二酸、苹果酸、酒石酸、葡萄糖酸、乳酸、扁桃酸、乙醇酸、丙酮酸、戊二酸、抗坏血酸、棕榈酸、羟基马来酸、羟基苯甲酸、苯乙酸、肉桂酸、甲磺酸、苯磺酸、甲苯磺酸、乙二磺酸、龙胆酸、富马酸、乳糖酸、水杨酸、苯二甲酸、亚甲基双羟萘酸酸、天冬氨酸、谷氨酸、樟脑磺酸(camsylic acid)、苯磺酸(besylic acid)或乙酰水杨酸(阿司匹林)。在一些实施方案中,波齐替尼是盐酸盐的形式。
血管内皮生长因子受体抑制剂或“VEGFR抑制剂”是指抑制VEGF特异性酪氨酸激酶受体VEGFR1、VEGFR2、VEGFR3或其任何组合的活性的任何试剂。VEGFR抑制剂的非限制性实施例包括阿昔替尼、舒尼替尼、瓦他拉尼、索拉非尼、GW-786034、CP-547632、AG-013736、乐伐替尼、莫特塞尼、帕唑帕尼、瑞戈非尼、雷莫芦单抗、CDP-791或它们的任何组合。在进一步的实施方案中,MNK特异性抑制剂与VEGFR抑制剂和PD-1特异性抗体或其结合片段组合使用。在更进一步的实施方案中,MNK特异性抑制剂与VEGFR抑制剂和PD-L1特异性抗体或其结合片段组合使用。在更进一步的实施方案中,MNK特异性抑制剂与VEGFR抑制剂和CTLA4特异性抗体或其结合片段或融合蛋白组合使用。在更进一步的实施方案中,MNK特异性抑制剂与VEGFR抑制剂和LAG3特异性抗体或其结合片段或融合蛋白组合使用。
在一些实施方案中,VEGFR抑制剂(例如索拉非尼)是VEGFR1抑制剂、VEGFR2抑制剂和/或VEGFR3抑制剂。在一些实施方案中,VEGFR抑制剂是VEGFR2抑制剂。VEGFR2抑制剂可以是特异性结合VEGFR2并抑制或降低一种或多种VEGFR2生物学功能的任何蛋白质或小分子。“特异性结合”是指识别并与VEGFR2相互作用但基本上不识别其他分子并与其他分子相互作用的分子。在一些实施方案中,VEGFR2抑制剂结合KD小于500、100、1.0、0.1、0.01或0.001nM的VEGFR2。
VEGFR2抑制剂的实施例包括抗体,例如重链抗体、天然缺乏轻链的抗体、衍生自常规四链抗体的单结构域抗体、工程化抗体以及除了那些衍生自抗体的单结构域支架。VEGFR2抑制剂的非限制性实施例包括CDP-791(UCB)、雷莫芦单抗(IMC-1121b,ImCloneSystems公司)和AVE-005(VEGF陷阱,再生元制药公司)。VEGFR2抑制剂的其他实施例包括部分,例如亲和体、afflins、anticalins、avimers(亲和聚体)、DARPins、微体、跨体(trans-bodies);或源自脂质运载蛋白、锚蛋白、四连蛋白、C型凝集素、蛋白A、γ-结晶、半胱氨酸结(cysteine knot)以及转铁蛋白的抑制剂。在一些实施方案中,VEGFR2抑制剂是雷莫芦单抗。
本公开的另一个方面提供了一种通过施用本文所述的药物组合来治疗受试者中的肿瘤的方法。在一些实施方案中,可以以0.1mg至50mg的量施用波齐替尼。例如,盐酸盐形式的波齐替尼可以口服施用,例如片剂。波齐替尼可以以4-25mg的剂量施用,例如以5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24mg的剂量施用。施用可以是每天、每隔一天、每3天或每周一次。施用可以按连续时间表进行,例如以28天为周期。
在一些实施方案中,VEGFR2抑制剂可以每公斤患者体重0.5至10mg的量施用。在一些实施方案中,VEGFR2抑制剂以1.5至5.5mg/kg体重的量施用。在一些实施方案中,VEGFR2抑制剂是雷莫芦单抗。
本文所述的药物组合可以同时施用,或通过任何方式单独依次施用治疗有效量的组分药物波齐替尼与VEGFR2抑制剂(例如雷莫芦单抗)或其药学上可接受的盐或溶剂化物的组合。优选地,如果施用不是同时的,则化合物在彼此接近的时间施用。此外,组分药物是否以相同的剂型施用并不重要,例如一种化合物可以局部施用,另一种化合物可以口服施用。在一些实施方案中,两种化合物均口服施用。
在一些实施方案中,药物组合在“指定期间”内施用。如本文所使用,术语“指定期间”及其派生词是指施用本发明组合的组分药物之一和另一种组分药物之间的时间间隔。除非另有定义,指定期间可以包括同时施用。在二组分药物组合的一个实施方案中,当本发明的两种化合物每天施用一次时,指定期间是指在一天中以相关顺序施用波齐替尼和另一次波齐替尼的时间。当一种或两种组分药物每天施用一次以上时,指定期间根据每种化合物在特定日期的第一次施用进行计算。在计算指定期间时,不考虑在指定日期第一次施用之后的本发明化合物的所有施用。
在一些实施方案中,如果组合的组分药物在“指定期间”施用而不同时施用,则它们均在彼此间隔约24、12、11、10、9、8、7、6、5、4、3、2或1小时内施用——在这种情况下,指定期间约为24、12、11、10、9、8、7、6、5、4、3、2或1小时。如本文所使用,对于二组分药物的组合的实施方案,波齐替尼和其他组分药物在间隔小于约45分钟内的施用被认为是同时施用。
在一些实施方案中,当组合“指定期间”施用时,化合物将共同施用“持续时间”。如本文所使用,术语“持续时间”及其派生词是指两种组分药物均在“指定期间”内施用持续指定的连续天数,任选地紧随着连续的数天,在这数天中只施用一种组分化合物。
关于“指定期间”施用,在至少一个实施方案中,在治疗过程中,两种组分药物将在指定期间内施用至少1、2、3、5、7、14或30天——在这种情况下,持续时间将至少为1、2、3、5、7、14或30天。如果在治疗过程中,两种组分药物都在指定期间内施用超过30天,则治疗被视为慢性治疗并将继续,直到发生改变的事件,例如重新评估癌症状况或患者病情的变化,需要对方案进行修改。
进一步关于“特定期间”施用,在另一个实施方案中,在使用两种组分药物的组合的治疗过程中,两种组分药物均将在特定期间内施用至少1天,然后单独施用波齐替尼至少1天、2、3、4、5、6或7天——在这种情况下,持续时间将至少为2、3、4、5、6、7或8天;适当地,在治疗过程中,两种化合物均将在特定期间内施用至少连续2天,然后单独施用波齐替尼至少连续1天、2、3、4、5、6或7天——在这种情况下,持续时间将至少为3、4、5、6、7、8或9天;适当地,在治疗过程中,两种组分药物均将在指定期间内施用至少连续3天,然后单独施用波齐替尼至少连续1天、2、3、4、5、6或7天——在这种情况下,持续时间将至少为4、5、6、7、8、9或10天;适当地,在治疗过程中,两种组分药物将在指定期间内连续施用至少4天,然后单独施用波齐替尼至少连续1天、2天、3天、4天或7天——在这种情况下,持续时间将至少为5、6、7、8或11天;适当地,在治疗过程中,两种组分药物将在指定期间内施用至少连续5天,然后单独施用波齐替尼至少连续1天、2天、3天、4天或5天——在这种情况下,持续时间将至少为6、7、8、9或10天。在另一个实施方案中,在治疗过程中,两种组分药物均将在指定期间内施用连续1至3天,然后单独施用波齐替尼连续3至7天。
在一些实施方案中,在治疗过程中,两种组分药物均将在指定期间内施用连续3至6天,然后单独施用波齐替尼连续1至4天。在一些实施方案中,在治疗过程中,两种组分药物均将在指定期间内连续施用2天,然后单独施用波齐替尼连续3至7天。在一些实施方案中,在治疗过程中,两种组分药物均将在指定期间内的每7天施用1至3天,而在7天期间的其他日期,将单独施用波齐替尼。在又一个实施方案中,在治疗过程中,两种组分药物均将在指定期间内每7天施用2天,并且在7天时间段的其他日期,单独施用波齐替尼。
进一步关于“指定期间”施用,在治疗过程中,对于二组分药物组合的实施方案,两者都将在指定期间内施用至少1天,然后单独施用另一种组分药物至少1、2、3、4、5、6或7天——在这种情况下,持续时间将至少为2、3、4、5、6、7或8天;适当地,在治疗过程中,两种组分药物均将在指定期间内施用至少连续2天,然后单独施用另一种组分药物至少1天、连续2、3、4、5、6、或7天——在这种情况下,持续时间将至少为3、4、5、6、7、8或9天;适当地,在治疗过程中,两种组分药物均将在指定期间内施用至少连续3天,然后单独施用另一种组分药物至少连续1、2、3、4、5、6、或7天——在这种情况下,持续时间将至少为4、5、6、7、8、9或10天;适当地,在治疗过程中,两种组分药物均将在特定期间内施用至少连续4天,然后单独施用另一种组分药物至少连续1、2、3、4或7天——在这种情况下,持续时间将至少为5、6、7、8或11天;适当地,在治疗过程中,两种组分药物均将在特定期间内施用至少连续5天,然后单独施用另一种组分药物至少连续1、2、3、4或5天——在这种情况下,持续时间将至少为6、7、8、9或10天。适当地,在治疗过程中,两种组分药物将在特定时期内连续施用1至3天,然后单独施用另一种组分药物,连续3至7天。适当地,在治疗过程中,两种组分药物将在特定时期内连续施用3至6天,然后单独施用另一种组分药物,连续1至4天。适当地,在治疗过程中,两种组分药物将在指定的时间段内连续施用2天,然后单独施用另一种组分药物,连续3至7天。适当地,在治疗过程中,两种组分药物均将在7天期间内施用1至3天的指定期间,并且在7天期间的其他日期,将单独施用另一种组分药物。适当地,在治疗过程中,两种组分药物均将在7天期间内施用2天的指定期间,并且在7天期间的其他日期,将单独施用另一种组分药物。
进一步关于“指定期间”施用,在治疗过程中,对于两种组分药物组合的实施方案,波齐替尼和其他组分药物(例如雷莫芦单抗)将在7天期间内施用1至3天的指定期间,并在7天期间的其他日期,将单独施用波齐替尼。适当地,该7天方案重复2个循环,即14天;适合地重复4个循环,即28天;适合地,连续施用。
在一些实施方案中,在治疗过程中,对于两种组分药物的组合的实施方案,泊齐替尼和其他组分药物将在7天的期间内的1至3天的指定期间内施用,并且在7天期间其他日期,将单独施用另一组分药物。在一些实施方案中,该7天方案重复2个循环,即14天;适当地,重复4个循环,即28天;适当地,连续施用。
在一些实施方案中,在治疗过程中,对于两种组分药物的组合的实施方案,泊齐替尼和其他组分药物将在14天的期间内的1至5天的指定期间内施用并且在14天期间的其他日期将单独施用波齐替尼。在一些实施方案中,该14天方案重复2个循环,即28天;适当地,连续施用。
在一些实施方案中,在治疗过程中,对于两种组分药物的组合的实施方案,泊齐替尼和其他组分药物将在14天的期间内的1至5天的指定期间内施用,并且在14天期间其他日期,将单独施用另一组分药物。在一些实施方案中,该14天方案重复2个循环,即28天;适当地,连续施用。
在一些实施方案中,如果组分药物在“指定期间”内没有被施用,则它们被依次施用。如本文所使用,术语“依次施用”是指例如两种组分药物的组合的实施方案,即波齐替尼和另一种组分药物中的一种连续施用1天或更多天,而波齐替尼和另一种组分中的另一种组分随后连续施用1天或更长时间。除非另有定义,“依次施用”和本文所述的所有施用方案在两种组分药物组合的情况下,不必从治疗开始时开始并在治疗结束时终止,只需要在治疗过程中的某个时间点,先施用波齐替尼和其他组分药物中的一种,然后再施用另一种,或指定的施用方案。此外,本文考虑的是在波齐替尼和另一种组分药物中的一种和另一种组分的依次施用之间使用的药物假期。如本文所使用,药物假期是在连续施用波齐替尼和另一种组分药物中的一种之后并且在施用另一种组分之前的数天期间,其中既不施用波齐替尼也不施用另一组分药物。适当地,药物假期将是选自以下的天数:1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天和14天。
关于依次施用,在对于两种组分药物的组合的一些实施方案中,波齐替尼和另一种组分药物中的一种连续施用1至30天,随后是可选的药物假期,随后连续施用另一种组分1至30天。
在两种组分药物的组合的一些实施方案中,另一种组分的药物将按顺序首先施用,然后是可选的药物假期,然后是波齐替尼的施用。
在一些实施方案中,将按顺序首先施用波齐替尼,然后是任选的药物假期,然后是另一组分药物的施用。
应当理解,“指定期间”施用和“顺序”施用之后可以是一个或多个循环的重复施用,或者可以随后是交替施用方案,并且药物假期可以在重复施用或交替施用方案之前。
在一些实施方案中,作为根据本发明的组合的一部分施用的波齐替尼的量将是选自约0.1mg至约50mg的量;适当地,该量将选自约0.5mg至约50mg;适当地,该量将选自约1mg至约50mg;适当地,该量将选自约5mg至约50mg;适当地,该量将选自约1mg至约30mg;适当地,该量将选自约5mg至约20mg;适当地,该量将选自约1mg至约10mg;适当地,该量将选自约0.1mg至约5mg;适当地,该量为1mg;适当地,该量为5mg;适当地,该量为10mg;适当地,该量为20mg;适当地,该量为30mg;适当地,该量将为50mg。因此,作为根据本发明的组合的一部分施用的波齐替尼的量将是选自约0.1mg至约50mg的量。例如,作为根据本发明的组合的一部分施用的波齐替尼的量适当地选自1mg、5mg、10mg、20mg、30mg和50mg。在一些实施方案中,选定量的波齐替尼在一片或多片剂的方式每天施用1至4次。在一些实施方案中,选定量的波齐替尼以每天一片或多片片剂的方式施用两次。在一些实施方案中,选定量的波齐替尼每天一片或多片片剂的方式施用一次。在一些实施方案中,波齐替尼的施用将以负荷剂量开始。在一些实施方案中,负荷剂量将是维持剂量的2至100倍的量;适当地为2到10倍;适当地为2到5倍;适当地为2倍;适当地为3倍;适当地为4倍;适当地为5倍。在一些实施方案中,负荷剂量将施用1至7天;适当地施用1到5天;适当地施用1到3天;适合地施用1天;适合地施用2天;适合地施用3天,接着是维持剂量方案。
在一些实施方案中,作为根据本发明的组合的一部分施用的、不是波齐替尼的第二组分药物的量将选自约0.1mg至约3,500mg/m2、约0.5mg至约3,500mg的量/m2;适当地,该量将选自约1.0mg至约3,500mg/m2;适当地,该量将选自约10.0mg至约3,500mg/m2;适当地,该量将选自约50.0mg至约3,500mg/m2;适当地,该量将选自约100.0mg至约3,500mg/m2;合适地,该量将选自约100.0mg至约3,000mg/m2;适当地,该量将选自约0.1mg至约20mg/m2;适当地,该量将选自约0.5mg至约10mg/m2;适当地,该量将选自约0.5mg至约10mg/kg;适当地,该量将选自约0.5mg至约50mg/m2;适当地,该量将选自约50mg至约1,000mg/m2;适当地,该量将选自约100mg至约500mg/m2;适当地,该量将选自约100mg至约300mg/m2;适当地,选定的量的不是波齐替尼的第二组分药物每天施用1至4次。在一些实施方案中,选定的量的第二组分药物每天施用1至4次。
如本文所使用,针对波齐替尼和其他另一组分药物指定的所有的量均表示为每剂中游离或未成盐和未溶剂化合物的施用量。
本文所述方法组合中的组成治疗剂/药物可以顺序或同时施用于有需要的受试者。该组分或组合可以通过胃肠道外、口服、鼻腔、直肠、局部或口腔施用。如本文所使用,术语“胃肠道外”是指皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内或颅内注射,以及任何合适的输注技术。
本文所述的组分或组合的无菌可注射组合可以是溶于无毒的胃肠道外可接受的稀释剂或溶剂中的溶液或悬浮液。此类溶液包括但不限于1,3-丁二醇、甘露醇、水、林格溶液和等渗氯化钠溶液。此外,不挥发油通常用作溶剂或悬浮介质(例如,合成的甘油单酯或甘油二酯)。脂肪酸,例如,但不限于油酸及其甘油酯衍生物可用于制备注射剂,例如天然的药学上可接受的油,但不限于橄榄油或蓖麻油、其聚氧乙基化形式也是如此。这些油溶液或悬浮液还可以包含长链醇稀释剂或分散剂,例如但不限于羧甲基纤维素或类似的分散剂。其他常用的表面活性剂,例如但不限于吐温类或司盘类或其他类似的乳化剂或生物利用度增强剂,它们通常用于制备药学上可接受的固体、液体或其他剂型,也可以用于制剂的目的。
在本文公开的任何实施方案中,VEGFR2抑制剂可以是雷莫芦单抗。
本文件的另一个方面提供了一种用于治疗受试者中与EGFR、HER1、HER2或HER4或EGFR、HER1、HER2或HER4突变体的过表达或扩增相关的肿瘤的试剂盒,该试剂盒包括第一部分和第二部分,其中第一部分包括波齐替尼,第二部分包括至少一种VEGFR2抑制剂(例如雷莫芦单抗)。该试剂盒还可以进一步包括药品说明书,其包括用于治疗与受试者中EGFR、HER1、HER2或HER4或其突变体的过表达或扩增相关的肿瘤的说明。
试剂盒的组分药物可以以适合顺序、分开和/或同时施用的形式提供。该试剂盒还可以提供说明,例如剂量和施用说明。这种剂量和施用说明可以是提供给医生的那种,例如通过药品标签,或者它们可以是那种由医生提供给例如病人的说明书。
可以采用各种组合。对于以下示例,波齐替尼或VEGFR2抑制剂(例如Ramucirumab)为“A”,抗癌疗法为“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/BA/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
考虑到药剂的毒性(如果有的话),将本实施方案的任何化合物或疗法施用患者将遵循用于施用此类化合物的通用协议。因此,在一些实施方案中,存在一个监测可归因于联合治疗的毒性的步骤。
在一些实施方案中,施用方案包括在波齐替尼和另一种组分药物中的一种与另一种药物的顺序施用之间的间歇或休息期。如本文所使用,停药期(休息期)是在连续施用波齐替尼和另一种组分药物之一之后,并且在施用另一种之前的几天期间,其中既不施用波齐替尼也不施用其他组分药物。适当地,药物假期是选自以下的天数:1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天和14天。
本文公开的方法适用于治疗癌症,所述癌症为口腔癌、口咽癌、鼻咽癌、呼吸道癌、泌尿生殖系统癌、胃肠道癌、中枢或外周神经系统组织癌、内分泌或神经内分泌癌或造血癌、神经胶质瘤、肉瘤、癌、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、李法美尼(Li-Fraumeni)肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌。在一些实施方案中,癌症是非小细胞肺癌(NSCLC)。
在一些实施方案中,该方法包括筛选需要治疗的受试者并确定野生型或突变型EGFR、HER1、HER2和HER4肿瘤细胞。具体的突变可以通过DNA扩增和测序技术、DNA和RNA检测技术来鉴定,包括但不限于Northern和Southern印迹,和/或各种生物芯片和阵列技术或原位杂交。野生型和突变型多肽可以通过多种技术检测,包括但不限于免疫诊断技术,例如ELISA、蛋白质印迹或免疫细胞化学。
待分析的样品可以是任何身体组织或流体,包括来自受试者肺癌的核酸。在某些实施方案中,样品将是包含循环肿瘤细胞或不含细胞DNA的血液样品。在其他实施方案中,样品可以是组织,例如肺组织。肺组织可以来自肿瘤组织,并且可以是新鲜冷冻的或福尔马林固定的、石蜡包埋的(FFPE)。在某些实施方案中,获取了肺肿瘤FFPE样品。
适用于本文所述方法的样品含有遗传物质,例如基因组DNA(gDNA)。基因组DNA通常从生物样本中提取,例如血液或口腔内壁的黏膜刮屑,但也可以从其他生物样本中提取,包括尿液、肿瘤或祛痰剂。样品本身通常将包括有核细胞(例如,血液或口腔细胞)或从包括正常或肿瘤组织的受试者中取出的组织。用于获得、处理和分析样品的方法和试剂在本领域中是已知的。在一些实施方案中,样品是在医疗保健提供者的帮助下获得的,例如抽血。在一些实施方案中,样品是在没有医疗保健提供者的帮助下获得的,例如,在样品是非侵入性获得的情况下,例如使用口腔拭子或刷子获得的包含口腔细胞的样品,或漱口水样品。
在某些情况下,可能会处理生物样品以进行DNA分离。例如,细胞或组织样品中的DNA可以与样品的其他成分分离。可以使用本领域已知的标准技术从生物样品中收获细胞。例如,可以通过离心细胞样品并重悬沉淀的细胞来收获细胞。可以将细胞重新悬浮在缓冲溶液例如磷酸盐缓冲盐水(PBS)中。在将细胞悬液离心以获得细胞沉淀后,可以将细胞溶解以提取DNA,例如gDNA。参见例如,Ausubel等人,(2003)。可以对样品进行浓缩和/或纯化以分离DNA。从受试者获得的所有样品,包括那些经过任何种类的进一步处理的样品,都被认为是从受试者获得的。常规方法可用于从生物样品中提取基因组DNA,包括例如苯酚提取。或者,可以使用Tissue Kit组织试剂盒(Qiagen,加利福尼亚州查茨沃斯)和Genomic DNA纯化试剂盒(Promega)等试剂盒提取基因组DNA。样品来源的非限制性例子包括尿液、血液和组织。
如本文所述,EGFR、HER1、HER2或HER4外显子是否存在突变可以使用本领域已知的方法来确定。例如,凝胶电泳、毛细管电泳、尺寸排阻色谱、测序和/或阵列可用于检测是否存在插入突变。在需要的情况下,可以使用本领域已知的方法例如PCR来完成核酸的扩增。在一个实施例中,样品(例如,包含基因组DNA的样品)从受试者获得。然后检查样品中的DNA以确定插入突变的身份,如本文所述。可以通过本文所述的任何方法检测插入突变,例如通过测序或通过将基因组DNA、RNA或cDNA中的基因与核酸探针例如DNA探针(其包括cDNA和寡核苷酸探针)或RNA探针杂交。核酸探针可以设计成特异性地或优先地与特定的变化杂交。
一组探针通常是指一组引物(通常是引物对)和/或可检测标记的探针,它们用于检测在可行的治疗建议中使用的目标遗传变异(例如,EGFR或HER2外显子20突变)。引物对用于扩增反应以确定跨越上述每个基因的靶遗传变异区域的扩增子。该组扩增子由一组匹配的探针检测。在一个示例性实施方案中,本方法可以使用TaqManTM(Roche MolecularSystems公司,加利福尼亚州普莱森顿市)测定,其用于检测一组靶基因变异,例如EGFR或HER2外显子20突变。在一个实施方案中,该组探针是一组用于产生扩增子的引物,这些扩增子通过核酸测序反应(例如下一代测序反应)来检测。在这些实施方案中,例如,可以采用AmpliSEQTM(Life Technologies/Ion Torrent公司,加利福尼亚州卡尔斯巴德市)或TruSEQTM(Illumina公司,加利福尼亚圣地亚哥市)技术。
可以使用本领域已知的技术进行核酸标记的分析,包括但不限于序列分析和电泳分析。序列分析的非限制性实施例包括Maxam-Gilbert测序、Sanger测序、毛细管阵列DNA测序、热循环测序(Sears等人,1992)、固相测序(Zimmerman等人,1992)、质谱测序例如基质辅助激光解吸/离子化飞行时间质谱法(MALDI-TOF/MS;Fu等人,1998年)和杂交测序(Chee等人,1996年;Drmanac等人,1993年;Drmanac等人,1998年)。电泳分析的非限制性实施例包括平板凝胶电泳,例如琼脂糖或聚丙烯酰胺凝胶电泳、毛细管电泳和变性梯度凝胶电泳。此外,可以使用来自Life Technologies/Ion Torrent PGM或Proton、Illumina HiSEQ或MiSEQ和Roche/454等公司的商用试剂盒和仪器来执行下一代测序方法。
核酸分析的其他方法可以包括直接手动测序(Church和Gilbert,1988;Sanger等人,1977;第5,288,644号美国专利);自动荧光测序;单链构象多态性分析(SSCP)(Schafer等人,1995);钳位变性凝胶电泳(CDGE);二维凝胶电泳(2DGE或TDGE);构象敏感凝胶电泳(CSGE);变性梯度凝胶电泳(DGGE)(Sheffield等人,1989);变性高效液相色谱法(DHPLC,Underhill等人,1997);红外基质辅助激光解吸/离子化(IR-MALDI)质谱法(WO 99/57318);流动性转变分析(Orita等人,1989年);限制酶分析(Flavell等人,1978年;Geever等人,1981年);定量实时PCR(Raca等人,2004);异源双链分析;化学错配切割(CMC)(Cotton等人,1985);RNase保护试验(Myers等人,1985);使用识别核苷酸错配的多肽,例如大肠杆菌mutS蛋白;等位基因特异性PCR,以及这些方法的组合。参见,例如,第2004/0014095号美国专利公布文本,其通过引用整体并入本文。
在一个实施例中,鉴定样品中的EGFR、HER1、HER2或HER4突变的方法包括使来自所述样品的核酸与能够与编码突变的HER2蛋白的核酸特异性杂交的核酸探针接触,或其包含突变的片段,并检测所述杂交。在一个具体的实施方案中,所述探针例如采用放射性同位素(3H、32P或33P)、荧光剂(罗丹明或荧光素)或显色剂进行可检测地标记。在一个具体实施方案中,探针是反义寡聚体,例如PNA、吗啉-氨基磷酸酯、LNA或2'-烷氧基烷氧基。探针可以具有约8个核苷酸至约100个核苷酸,或约10个至约75个,或约15个至约50个,或约20个至约30个核苷酸。在另一个方面,本申请的探针在用于鉴定样品中的EGFR或HER2突变的试剂盒中提供,其中该试剂盒包含与EGFR或HER2基因中的突变位点特异性杂交或与其相邻的寡核苷酸。该试剂盒可以进一步包括用于基于使用该试剂盒的杂交测试的结果而采用波齐替尼或阿法替尼治疗患有包含EGFR或HER2插入突变的肿瘤的患者的说明。
在一些实施方案中,该方法包括确定受试者中的肿瘤与EGFR、HER1、HER2和HER4或其突变体的至少一种基因的过表达或扩增相关,并且可能是组织的异常生长,如果它是形成肿块,通常称为具有EGFR、HER1、HER2、HER4及其突变体中的至少一种过表达或编码EGFR、HER1、HER2、HER4或其突变体的至少一种基因扩增的肿瘤。在一些实施方案中,拟用本文公开的方法治疗的肿瘤是相关的突变体,该突变体可能存在于外显子18、19、20和21中的任一个或其任何组合中。例如,突变体可以是具有外显子19缺失、T790M替换、L828R替换或其组合的HER1。在另一个实施方案中,突变可以位于HER2外显子20处,例如外显子20插入突变。在另一个实施方案中,外显子19或20或两者中可能存在一个或多个突变。例如,一个或多个EGFR外显子20突变包括氨基酸763-778之间的3-18个核苷酸的一个或多个点突变、插入和/或缺失。
在一些实施方案中,该方法包括确定受试者中的肿瘤与外显子18、外显子19、外显子20和外显子21中的一个或多个内的EGFR或HER2突变相关。在一些实施方案中,癌症与发生在外显子20突变中的EGFR或HER2突变相关。EGFR或HER2外显子20突变可适当地包括EGFR或HER2框内外显子20插入突变、EGFR或HER2外显子20点突变或其任何组合。HER2框内外显子20插入突变可选自A775_G776insYVMA,G776_V777insVC,P780_Y781insGSP及其组合。HER2框内外显子20插入突变可选自L775S,G776V,V777L及其组合。在一些实施方案中,HER2外显子20突变不是T790M点突变。
在一些实施方案中,该方法包括确定受试者中的肿瘤与选自A763、A767、S768、V769、D770、N771、P772和H773中的一个或多个残基处的2个、3个或4个EGFR外显子20突变相关。在一些实施方案中,可以确定受试者在残基C797处不具有EGFR突变。在一些实施方案中,一个或多个EGFR突变包括在外显子20中的A763、A767、S768、V769、D770、N771、P772和H773处的替换和/或缺失。在一些实施方案中,一个或多个外显子20突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771delinsGY、N771del insFH和N771dupNPH。
在一些实施方案中,该方法包括确定受试者中的肿瘤与发生在外显子21突变中的HER2突变相关。HER2外显子21突变可包含氨基酸832-883之间的1-18个核苷酸的一个或多个点突变、插入和/或缺失。在一些实施方案中,一个或多个HER2外显子21突变位于一个或多个选自V842、R868和L869的残基处。在一些实施方案中,一个或多个外显子21突变选自V842I、R868W和L869R。在一些实施方案中,一个或多个HER2外显子21突变位于一个或多个选自V842和R868的残基处。在一些实施方案中,一个或多个外显子21突变选自V842I和R868W。
在一些实施方案中,该方法包括确定受试者中的肿瘤与一种或多种HER2外显子20突变相关。在一些实施方案中,HER2外显子20突变可以包括氨基酸770-786之间的1-18个核苷酸,例如3-18个核苷酸的一个或多个点突变、插入和/或缺失。在一些实施方案中,一个或多个HER2外显子20突变可以位于残基Y772、V773、A775、G776、V777、G778、S779和/或P780处。在一些实施方案中,该方法包括确定受试者与一个或多个HER2外显子20突变相关,该突变选自A775insV G776C、A775insYVMA、G776C V777insC、G776del insVV、G776del insVC、P780insGSP、Y772dupYVMA、V773M、G776delinsLC、V777L、V777insCG、G778dupGSP、P780insGSP、L786V、G776delinsVC和G778insLPS。
在一些实施方案中,该方法包括确定受试者中的肿瘤与选自以下的一个或多个EGFR外显子20突变相关:A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH、N771dupNPH、A767insTLA、S768I、V769L、V769insGSV、D770del insGY、D770insG、D770insY H773Y、N771insHH、P772insDNP、H773insAH、H773insH、V774insHV、S784F、R776C、V774M、V769M、G796D、S784F、C775Y、S811F、T790M、V774A、D770A。
在一些实施方案中,受试者可能在EGFR残基C797处具有或发展出可能导致对TKI(如波齐替尼)产生的抗性的突变。因此,在一些实施方案中,该方法包括确定受试者位于EGFR C797和/或T790,例如C797S和/或T790M处不具有突变。
该专利文件的另一方面涉及使用本文所述的药物组合来改善正在接受与HER2或HER2突变体过表达或扩增相关的癌症治疗的受试者的不良反应概况的方法,该方法包括步骤:a)在21天3天的循环中,i)施用单剂量的雷莫芦单抗;ii)施用每日剂量的波齐替尼;b)任选地重复该循环,其中副作用选自心脏毒性血液学毒性、腹泻、皮疹、粘膜炎、疲劳、电解质异常和肝中毒。在一些实施方案中,癌症是NSCLC。
该专利文件的另一方面涉及使用本文所述的药物组合来治疗受试者癌症的方法,其中癌症与EGFR、HER1、HER2或HER4或HER1、HER2或HER4突变的过表达或扩增有关。在一些实施方案中,该组合包括治疗有效量的波齐替尼和雷莫芦单抗,其中波齐替尼是口服施用的,而雷莫芦单抗是通过IV输注施用的。在一些实施方案中,癌症是NSCLC。
本专利文件的另一个方面涉及治疗或预防受试者的CNS转移的方法,其中该受试者已被诊断患有癌症。该方法包括施用本文所述的药物组合。在一些实施方案中,CNS转移是脑转移。在一些实施方案中,癌症是非小细胞肺癌(NSCLC)。在一些实施方案中,受试者已被确定患有CNS转移。在一些实施方案中,受试者已被确定没有CNS转移。在一些实施方案中,该组合包括治疗有效量的波齐替尼和雷莫芦单抗,其中波齐替尼是口服施用的,而雷莫芦单抗是通过IV输注施用的。在一些实施方案中,癌症是NSCLC。
在本文所述的任何方法的一些实施方案中,癌症被确定为局部晚期或转移性的。可以定义为转移性的癌症的实施例包括但不限于非小细胞肺癌、乳腺癌、卵巢癌、结肠直肠癌、胆管癌、膀胱癌、脑癌(包括胶质母细胞瘤和髓母细胞瘤)、宫颈癌、绒毛膜癌、子宫内膜癌、食道癌、胃癌、血液肿瘤、多发性骨髓瘤、白血病、上皮内瘤、肝癌、淋巴瘤、神经母细胞瘤、口腔癌、胰腺癌、前列腺癌、肉瘤、皮肤癌(包括黑色素瘤)、基底细胞癌、鳞状细胞癌、睾丸癌、间质瘤、生殖细胞瘤、甲状腺癌和肾癌。
在一些实施方案中,受试者已经接受了包括例如化学治疗、放射治疗、手术和其他抗增殖剂或免疫治疗在内的先前治疗。在一些实施方案中,受试者未接受过包括例如化学治疗、放射治疗、手术和其他抗增殖剂或免疫治疗在内的先前治疗。
在任何上述方法的一些实施方案中,癌症对化学治疗或放射治疗是难治的。在一些实施方案中,癌症对化学治疗具有抗性。在一些实施方案中,癌症已经复发。在一些实施方案中,癌症是转移的。
在本文所述的任何方法的一些实施方案中,癌症对抗增殖剂具有抗性。抗增殖剂的非限制性实施例包括烷化剂、铂剂、抗代谢物、拓扑异构酶抑制剂、抗肿瘤的抗生素、抗有丝分裂剂、芳香酶抑制剂、胸苷酸合酶抑制剂、DNA拮抗剂、法尼基转移酶抑制剂、泵抑制剂、组蛋白乙酰转移酶抑制剂、金属蛋白酶抑制剂、核糖核苷还原酶抑制剂、TNF-α激动剂/拮抗剂、内皮素受体拮抗剂、视黄酸受体激动剂、免疫调节剂、激素和抗激素剂、光动力剂和激酶抑制剂。
在任何上述方法的一些实施方案中,可以包括另外的治疗,包括例如化学治疗、放射治疗、手术和其他合适的免疫治疗。可以考虑的是,其他抗增殖剂可与本发明实施方案的某些方面组合使用以提高治疗的疗效。这些额外的试剂包括影响细胞表面受体和间隙(GAP)连接上调的试剂、细胞生长和分化试剂、细胞粘附抑制剂、提高过度增殖细胞对凋亡诱导剂的敏感性的试剂,或其他生物试剂。通过提高间隙连接的数量来增加细胞间信号传导将提升对邻近过度增殖细胞群的抗过度增殖作用。在其他实施方案中,细胞生长或分化试剂可以与本实施方案的某些方面组合使用以提高治疗的抗过度增殖功效。考虑使用细胞粘附抑制剂来提高本实施方案的功效。细胞粘附抑制剂的实施例是粘着斑激酶(FAK)抑制剂和洛伐他汀。进一步考虑提高过度增殖细胞对细胞凋亡的敏感性的其他试剂,例如抗体c225,可以与本发明实施方案的某些方面组合使用以提高治疗功效。
任何上述实施方案中的抗增殖剂的非限制性实施例包括烷化剂:白消安、达卡巴嗪、异环磷酰胺、六甲基三聚氰胺、噻替哌、达卡巴嗪、洛莫司汀、苯丁酸氮芥、丙卡巴肼、阿曲他明、磷酸雌莫司汀、氮芥、链脲佐菌素、替莫唑胺、塞莫司汀环磷酰胺;
铂类药物:螺铂、四铂、奥马铂、异丙铂、ZD-0473(AnorMED)、奥沙利铂、卡铂、洛铂(Aeterna)、沙铂(Johnson Matthey)、BBR-3464(Hoffmann-La Roche)、SM-11355(Sumitomo)、AP-5280(Access)、顺铂、卡铂(arboplatin)、顺铂、沙铂、奥沙利铂、奈达铂、四硝酸三核铂(triplatin tetranitrate)、替莫唑胺、丙卡巴肼;
抗代谢类药物:氮杂胞苷、氟尿苷、2-氯脱氧腺苷、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、2-氟脱氧胞苷、甲氨蝶呤、tomudex(雷替曲塞)、氟达拉滨、雷替曲塞、三甲曲沙、脱氧考福霉素、喷司他丁、羟基脲、地西他滨(SuperGen)、氯法拉滨(Bioenvision),伊洛福芬(irofulven,MGI Pharma)、DMDC(Hoffmann-La Roche)、乙炔基胞苷(Taiho)、吉西他滨、卡培他滨;
拓扑异构酶抑制剂:安吖啶、表柔比星、依托泊苷、替尼泊苷或米托蒽醌、7-乙基-10-羟基喜树碱、右雷佐生(TopoTarget)、皮沙酮(pixantrone,Novuspharma)、瑞贝卡霉素类似物(Exelixis)、BBR-3576(Novuspharma)、rubitecan(SuperGen)、伊立替康(CPT-11)、拓扑替康;
抗肿瘤的抗生素:戊柔比星、吡柔比星、伊达比星、苯甲酰腙柔红霉素、普卡霉素、泊非霉素、米托蒽醌(novantrone)、氨萘非特(amonafide)、唑那非特(azonafide)、蒽吡唑、奥沙蒽唑)(oxantrazole)、洛索蒽醌、MEN-10755(Menarini公司)、GPX-100(GemPharmaceuticals公司)、表柔比星、米托蒽醌、多柔比星;
抗有丝分裂剂:秋水仙碱、长春碱、长春地辛、多拉司他汀10(NCI)、根瘤菌素(Fujisawa)、米沃布林(mivobulin,Warner-Lambert)、西马多丁(BASF)、RPR 109881A(Aventis)、TXD 258(Aventis)、埃坡霉素B(Novartis)、T 900607(Tularik)、T 138067(Tularik)、念珠藻素(cryptophycin 52,Eli Lilly)、长春氟宁(Fabre)、澳瑞他汀PE(Teikoku Hormone)、BMS 247550(BMS)、BMS 184476(BMS)、BMS 188797(BMS)、taxoprexin(Protarga)、SB 408075(GlaxoSmithKline)、Vinorelbine、曲古他汀A(Trichostatin A)、E7010(Abbott)、PG-TXL(Cell Therapeutics)、IDN 5109(Bayer)、A 105972(Abbott)、A204197(Abbott)、LU 223651(BASF))、D 24851(ASTAMICA)、ER-86526(Eisai)、考布他汀A4(BMS)、isohomomohalichondrin-B(PharmaMar)、ZD 6126(AstraZeneca)、AZ10992(Asahi)、IDN-5109(Indena)、AVLB(Prescient NeuroPharma)、氮杂埃坡霉素B(BMS)、BNP-7787(BioNumerik)、CA-4前药(OXiGENE)、多拉司他汀-10(NIH)、CA-4(OXiGENE)、多西他赛、长春新碱、紫杉醇;
芳香酶抑制剂:氨鲁米特、阿他美坦(BioMedicines)、来曲唑、阿那曲唑、YM-511(Yamanouchi)、福美司坦、依西美坦;
胸苷酸合成酶抑制剂:培美曲塞(Eli Lilly)、ZD-9331(BTG)、诺拉曲塞(Eximias)、CoFactorTM(BioKeys);
DNA拮抗剂:曲贝替定(PharmaMar);葡磷酰胺(Baxter International)、白蛋白+32P(Isotope Solutions)、胸腺肽(thymectacin,NewBiotics)、依多曲肽(Novartis)、马磷酰胺(Baxter International)、阿哌喹酮(apaziquone,Spectrum Pharmaceuticals)、O-6-苄基鸟嘌呤(Paligent);法尼基转移酶抑制剂:阿格拉宾(NuOncology Labs)、洛那法尼(Schering-Plough)、BAY-43-9006(Bayer)、替吡法尼(Johnson&Johnson)、紫苏醇(DORBioPharma);
泵抑制剂:CBT-1(CBA Pharma)、他立喹达(Xenova)、MS-209(Schering AG)、唑喹达三盐酸盐(Eli Lilly)、比立克达二柠檬酸盐(Vertex);
组蛋白乙酰转移酶抑制剂:泰克地那林(Pfizer)、SAHA(Aton Pharma)、MS-275(Schering AG)、新戊酰氧基丁酸甲酯(Titan)、缩酚酸肽(Fujisawa);
金属蛋白酶抑制剂:新伐司他(Aeterna Laboratories)、marimastat(BritishBiotech)、CMT-3(CollaGenex)、BMS-275291(Celltech);
核糖核苷还原酶抑制剂:麦芽糖酸镓(Titan)、三阿平(Vion)、替扎他滨(Aventis)、dodox(Molecules for Health);
tnf-α激动剂/拮抗剂:维如利金(virulizin,Lorus Therapeutics)、CDC-394(Celgene)、来那度胺(revimid,Celgene);
内皮素A受体拮抗剂:阿曲生坦(Abbott)、ZD-4054(AstraZeneca)、YM-598(Yamanouchi);
维甲酸受体激动剂:维甲酰酚胺(Johnson&Johnson)、LGD-1550(Ligand)、阿利维A酸(Ligand);
免疫调节剂:帕博利珠单抗(Pembrolizumab,原名拉伯利珠单抗(lambrolizumab,商品名Keytruda);干扰素、噬菌体(Antigenics)、GMK(Progenics)、腺癌疫苗(Biomira)、CTP-37(AVI BioPharma)、IRX-2(Immuno-Rx)、PEP-005(Peplin Biotech)、synchrovax疫苗(CTL Immuno)、黑色素瘤疫苗(CTL Immuno)、p21 RAS疫苗(GemVax)、MAGE-A3(GSK)、纳武单抗(BMS)、阿巴西普(BMS)、外泌体疗法(Anosys)、pentrix(Australian CancerTechnology)、ISF-154(Tragen)、癌症疫苗(Intercell)、norelin(Biostar)、BLP-25(Biomira)、MGV(Progenics)、β-alethine(Dovetail)、CLL疗法(Vasogen)、Ipilimumab(BMS)、CM-10(cCam Biotherapeutics)、MPDL3280A(Genentech);
激素和抗激素剂:雌激素、共轭雌激素、乙炔雌二醇、氯烯雌醚、双烯雌酚(idenestrol)、己酸羟孕酮、甲羟孕酮、睾酮、丙酸睾酮、氟甲睾酮、甲基睾酮、己烯雌酚、甲地孕酮、比卡鲁胺、氟他胺、尼鲁米特、地塞米松、泼尼松、氨鲁米特、亮丙瑞林、奥曲肽、米托坦、P-04(Novogen)、2-甲氧基雌二醇(EntreMed)、阿佐昔芬(Eli Lilly)、他莫昔芬、托瑞米芬、戈舍瑞林、亮丙瑞林(Leuporelin)、比卡鲁胺;
光动力剂:他拉泊芬(Light Sciences)、Theralux(Theratechnologies)、莫特沙芬钆(Pharmacyclics)、Pd-bacterioophorbide(Yeda)、lutetium texaphyrin(Pharmacyclics)、金丝桃素;以及
激酶抑制剂:阿法替尼、奥希替尼、伊马替尼(Novartis)、来氟米特(Sugen/Pharmacia)、ZD1839(AstraZeneca)、厄洛替尼(Oncogene Science)、卡奈替尼(Pfizer)、角鲨胺(Genaera)、SU5416(Pharmacia)、SU6668(Pharmacia)、ZD4190(AstraZeneca))、ZD6474(AstraZeneca)、vatalanib(Novartis)、PKI166(Novartis)、GW2016(GlaxoSmithKline)、EKB-509(Wyeth)、曲妥珠单抗(Genentech)、OSI-774(TarcevaTM)、CI-1033(Pfizer)、SU11248(Pharmacia)、RH3(York Medical)、染料木黄酮、根匍柄菌醇(Radicinol)、Met-MAb(Roche)、EKB-569(Wyeth)、kahalide F(PharmaMar)、CEP-701(Cephalon)、CEP-751(Cephalon)、MLN518(Millenium)、PKC412(Novartis)、脱氢雌马酚(Novogen)、C225(ImClone)、rhu-Mab(Genentech)、MDX-H210(Medarex)、2C4(Genentech)、MDX-447(Medarex)、ABX-EGF(Abgenix)、IMC-1C11(ImClone)、酪氨酸磷酸化抑制剂、吉非替尼(Iressa)、PTK787(Novartis)、EMD 72000(Merck)、大黄素、根匍柄菌醇(Radicinol)、维莫非尼(B-Raf酶抑制剂、Daiichi Sankyo)、SR-27897(CCK A抑制剂、Sanofi-Synthelabo)、托拉地新(环AMP拮抗剂、Ribapharm)、阿伏西地(CDK抑制剂,Aventis)、CV-247(COX-2抑制剂,Ivy Medical)、P54(COX-2抑制剂,Phytopharm)、CapCellTM(CYP450兴奋剂,BavarianNordic)、GCS-100(gal3拮抗剂,GlycoGenesys)、G17DT免疫原(胃泌素抑制剂,Aphton)、乙丙昔罗(氧生成剂,Allos Therapeutics)、PI-88(乙酰肝素酶抑制剂,Progen)、替米利芬(组胺拮抗剂,YM BioSciences)、组胺(组胺H2受体激动剂,Maxim)、噻唑呋林(IMPDH抑制剂,Ribapharm)、西仑吉肽(整合素拮抗剂,Merck KGaA)、SR-31747(IL-1拮抗剂,Sanofi-Synthelabo)、CCI-779(mTOR激酶抑制剂,Wyeth)、依昔舒林(PDE V抑制剂,CellPathways)、CP-461(PDE V抑制剂,Cell Pathways)、AG-2037(GART抑制剂,Pfizer)、WX-UK1(纤溶酶原激活物抑制剂,Wilex)、PBI-1402(PMN兴奋剂,ProMetic LifeSciences)、硼替佐米(proteasome inhibitor,Millennium)、SRL-172(T cell stimulant,SR Pharma)、TLK-286(谷胱甘肽S转移酶抑制剂,Telik)、PT-100(生长因子激动剂,Point Therapeutics)、midostaurin(PKC抑制剂,Novartis)、bryostatin-1(PKC兴奋剂,GPC Biotech)、CDA-II(细胞凋亡促进剂,Everlife)、SDX-101(细胞凋亡促进剂,Salmedix)、利妥昔单抗(CD20抗体,Genentech)、卡莫司汀、米托蒽醌、博来霉素、苦艾素、大黄酸、氧化铯、BRAF抑制剂、PDL1抑制剂、MEK抑制剂、贝伐单抗、血管生成抑制剂、达拉非尼、ceflatonin(细胞凋亡促进剂,ChemGenex)。
BCX-1777(PNP抑制剂,BioCryst)、豹蛙酶(核糖核酸酶兴奋剂,Alfacell)、加柔比星(RNA合成抑制剂,Dong-A)、替拉扎明(还原剂,SRI International)、N-乙酰半胱氨酸(还原剂,Zambon)、R-氟比洛芬(NF-kappaB抑制剂,Encore)、3CPA(NF-kappaB抑制剂,ActiveBiotech)、西奥骨化醇(维生素D受体激动剂,Leo)131-I-TM-601(DNA拮抗剂,TransMolecular)、依氟鸟氨酸(ODC抑制剂,ILEX Oncology)、米诺膦酸(破骨细胞抑制剂,Yamanouchi)、吲地苏兰(indisulam,p53兴奋剂,Eisai)、阿匹啶(aplidine,PPT抑制剂,PharmaMar)、吉妥单抗(CD33抗体,Wyeth Ayerst)、PG2(造血增强剂,Pharmagenesis)、ImmunolTM(三氯生漱口水,Endo)、三乙酰尿苷(尿苷前药,Wellstat)、SN-4071(肉瘤剂,Signature BioScience)、TransMID-107TM(免疫毒素,KS Biomedix)、PCK-3145(凋亡促进剂,Procyon)、多拉达唑(凋亡促进剂,Pola)、CHS-828(细胞毒性剂,Leo)、反式维甲酸(分化剂,NIH)、MX6(凋亡促进剂,MAXIA)、apomine(凋亡促进剂,冬青肿瘤学)、尿苷(凋亡促进剂,Bioniche)、Ro-31-7453(凋亡促进剂,La Roche)、布洛司他林(brostallicin,凋亡促进剂,Pharmacia)、β-拉帕醌、白树毒素、咖啡醇、咖啡白醇(kahweol)、咖啡酸、酪氨酸磷酸化抑制剂、PD-1抑制剂、CTLA-4抑制剂、索拉非尼、BRAF抑制剂。
在任何上述方法的一些实施方案中,抗增殖剂选自贝伐单抗(bevacizurnab)、硼替佐米、卡培他滨、西妥昔单抗、氟尿嘧啶、伊马替尼、伊立替康、亚叶酸、奥沙利铂、帕尼单抗、培美曲塞、替莫唑胺、顺铂、紫杉醇、厄洛替尼、舒尼替尼、拉帕替尼、索拉非尼、卡铂、多柔比星、多西他赛、吉西他滨、依托泊苷、吉非替尼、PD153035、西妥昔单抗、贝伐单抗、帕尼单抗、曲妥珠单抗、抗c-Met抗体、吉非替尼、ZD6474、EMD-72000、帕瑞妥单抗(pariitumab)、ICR-62、CI-1033、拉帕替尼、AEE788、EKB-569、EXEL 7647/EXEL 0999、厄洛替尼、伊马替尼、索拉非尼、舒尼替尼、达沙替尼、凡德替尼(vandetinib)、替西罗莫司、PTK787、帕唑帕尼、AZD2171、依维莫司、赛利西尼(seliciclib)、AMG 706、阿昔替尼、PD0325901、PKC-412、CEP701、XL880、博舒替尼、BIBF1120、BIBF1120、尼罗替尼、AZD6244、HKI-272、MS-275、BI2536、GX15-070、AZD0530、安佐司他(enzastaurin)、MLN-518、ARQ197、CM101、IFN-α、IL-12、血小板因子-4、苏拉明、SU5416、血小板反应素、VEGFR拮抗剂、血管静态类固醇加肝素、软骨源性血管生成抑制因子、基质金属蛋白酶抑制剂、巴马司他、马立马司他、血管抑制素、内皮抑制素、2-甲氧基雌二醇、替可加兰(tecogalan)、血小板反应素、αvβ3抑制剂、三羧氨基喹啉(linomide)和ADH-1、苯丁酸氮芥、环磷酰胺、异环磷酰胺、氯乙胺、左旋溶肉瘤素、尿嘧啶氮芥、噻替哌、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、卡铂、顺铂、沙铂、奥沙利铂、六甲密胺、ET-743、XL119、达卡巴嗪、氮芥、苯达莫司汀、曲磷酰胺、乌拉司汀、福莫司汀、尼莫司汀、泼尼莫司汀、雷莫司汀、司莫司汀、奈达铂、四硝酸三核铂(triplatintetranitrate)、甘露舒凡,曲舒凡(treosulfan)、替莫唑胺、卡波醌、三嗪酮、三乙烯三聚氰胺、丙卡巴肼、多柔比星、柔红霉素、表柔比星、伊达比星、蒽二酮、米托蒽醌、丝裂霉素C、博来霉素、放线菌素、普卡霉素(plicatomycin)、伊立替康、喜树碱、鲁比替康、贝洛替康、依托泊苷、替尼泊苷、拓扑替康、紫杉醇、taxol(紫杉醇)、多西他赛、BMS-275183、xyotax、tocosal、长春瑞滨、长春新碱、长春碱、长春地辛、长春利定、依托泊苷、替尼泊苷、伊沙匹隆、拉洛他赛(larotaxel)、奥特他赛(ortataxel)、特西他赛(tesetaxel)、伊斯平斯、氟尿嘧啶、氟尿苷、甲氨蝶呤、希罗达、arranon、亚叶酸、羟基脲、硫鸟嘌呤、巯基嘌呤、磷酸氟达拉滨、克拉屈滨、天冬酰胺酶、吉西他滨、培美曲塞、硼替佐米、氨基蝶呤、雷替曲塞、氯法拉滨、依诺他滨、沙帕他滨、阿扎胞苷。
本领域技术人员将理解,本文描述的发明不限于已经具体示出和描述的内容。相反,本发明的范围由所附权利要求限定。还应理解,以上描述仅代表实施方案的说明性实施方案。该描述并未试图详尽列举所有可能的变化。替代实施方案可能尚未针对药物组合的特定组分或方法的步骤呈现,并且可能由所述成分的不同组合产生,或者其他未描述的替代实施方案可用于组合或方法,不应被视为放弃这些替代实施方案。应当理解,许多那些未描述的实施方案在所附权利要求的字面范围内,并且其他实施方案是等同的。
Claims (28)
1.一种用于治疗受试者中的肿瘤的药物组合,包括:
波齐替尼或其药学上可接受的盐;和
血管内皮生长因子受体2(VEGFR2)抑制剂。
2.根据权利要求1所述的药物组合,其中,所述VEGFR2抑制剂是雷莫芦单抗。
3.根据权利要求1所述的药物组合,其中,所述波齐替尼为单盐酸盐形式。
4.一种用于治疗受试者中的肿瘤的试剂盒,包括:
波齐替尼或其药学上可接受的盐;和
血管内皮生长因子受体2(VEGFR2)抑制剂。
5.根据权利要求4所述的试剂盒,其中,所述VEGFR2抑制剂是雷莫芦单抗。
6.根据权利要求4所述的试剂盒,还包括指导信息和使用说明。
7.一种用于治疗受试者中的肿瘤的方法,包括向受试者施用根据权利要求1至3中任一项所述的药物组合。
8.根据权利要求7所述的方法,其中,所述肿瘤选自非小细胞肺癌、乳腺癌、胃癌、结肠癌、胰腺癌、前列腺癌、骨髓瘤、头颈癌、卵巢癌、食道癌和转移性细胞癌。
9.根据权利要求7所述的方法,其中,所述药物组合中的VEGFR2抑制剂为雷莫芦单抗。
10.根据权利要求7所述的方法,其中,所述受试者在外显子18、外显子19、外显子20或外显子21处表达突变。
11.根据权利要求7所述的方法,进一步包括确定所述受试者具有一个或多个HER2外显子20突变。
12.根据权利要求7所述的方法,进一步包括确定所述受试者具有一个或多个选自以下的EGFR外显子20突变:A775insV G776C、A775insYVMA、G776C V777insC、G776del insVV、G776del insVC、P780insGSP、Y772dupYVMA、V773M、G776delinsLC、V777L、V777insCG、G778dupGSP、P780insGSP、L786V。
13.根据权利要求7所述的方法,进一步包括确定所述受试者具有一个或多个选自以下的EGFR外显子20突变:A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH、N771dupNPH、A767insTLA、S768I、V769L、V769insGSV、D770del insGY、D770insG、D770insY H773Y、N771insHH、P772insDNP、H773insAH、H773insH、V774insHV、S784F、R776C、V774M、V769M、G796D、S784F、C775Y、S811F、T790M、V774A、D770A。
14.根据权利要求7所述的方法,进一步包括确定所述受试者具有一个或多个HER2外显子21突变,所述突变选自氨基酸832-883之间的1-18个核苷酸的点突变、插入和缺失。
15.根据权利要求7所述的方法,进一步包括确定所述受试者在选自V842、R868和L869的一个或多个残基处具有一个或多个HER2外显子21突变。
16.根据权利要求7所述的方法,其中,所述肿瘤是非小细胞肺癌。
17.根据权利要求7所述的方法,其中,所述肿瘤是转移性癌症。
18.根据权利要求7所述的方法,其中,所述癌症对化学治疗或放射治疗是难治的,对化学治疗具有抗性或已经复发。
19.根据权利要求7所述的方法,其中所述受试者先前接受过针对所述肿瘤的一线、二线、三线或更多种线的治疗。
20.根据权利要求7所述的方法,其中,所述受试者先前未接受过EGFR酪氨酸激酶抑制剂的治疗。
21.根据权利要求7所述的方法,其中,所述受试者接受过采用EGFR酪氨酸激酶抑制剂的先前治疗。
22.根据权利要求7所述的方法,其中,对所述药物组合的施用和/或剂量进行控制,以治疗或预防受试者的CNS转移。
23.一种治疗或预防受试者CNS转移的方法,其中,所述受试者已被诊断患有癌症,包括向所述受试者施用根据权利要求1至3中任一项所述的药物组合。
24.根据权利要求23所述的方法,其中,所述癌症是非小细胞肺癌(NSCLC)。
25.根据权利要求23所述的方法,其中,所述受试者已被确定为具有CNS转移。
26.根据权利要求23所述的方法,其中,所述受试者已被确定为没有CNS转移。
27.根据权利要求23所述的方法,其中所述受试者先前接受过针对所述肿瘤的一线、二线、三线或更多种线的治疗。
28.根据权利要求23所述的方法,其中,所述受试者先前未接受过EGFR酪氨酸激酶抑制剂的治疗。
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CN109893654A (zh) * | 2017-12-11 | 2019-06-18 | 江苏恒瑞医药股份有限公司 | Vegfr抑制剂治疗肿瘤的方法 |
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