CN110035752A - 使用吲唑基苯甲酰胺衍生物治疗癌症的组合疗法 - Google Patents
使用吲唑基苯甲酰胺衍生物治疗癌症的组合疗法 Download PDFInfo
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- CN110035752A CN110035752A CN201780058961.XA CN201780058961A CN110035752A CN 110035752 A CN110035752 A CN 110035752A CN 201780058961 A CN201780058961 A CN 201780058961A CN 110035752 A CN110035752 A CN 110035752A
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Abstract
本发明涉及用于治疗和/或预防癌症的组合疗法。
Description
相关申请的交叉引用
本申请要求2016年9月23日提交的美国临时申请号62/399,306的优先权，其内容以其整体在此引入作为参考。
背景技术
技术领域
本发明涉及用于治疗和/或预防与细胞增殖相关的疾病和/或病症，如癌症的组合疗法。
相关技术的描述
癌症的特征在于异常的细胞增殖。癌细胞表现出许多性质，该性质使其对宿主造成危险，通常包括侵入其他组织并诱导毛细血管向内生长的能力，这保证了该增殖的癌细胞具有足够的血液供应。癌细胞的标志是对正常细胞中调节细胞分裂的控制机制的异常反应，并继续分裂直到它们最终杀死宿主。
血管发生是正常条件下高度调节的过程，然而许多疾病是由持续不受控制的血管发生驱动的。不受控制的血管发生可直接引起特定疾病或加剧现有病理症状。例如，眼睛新生血管形成不仅是最常见的失明原因，而且是许多眼病的主要原因。此外，在一些现有情况下(例如关节炎)，新形成的毛细血管侵入关节并破坏软骨，或者在糖尿病的情况下，在视网膜中形成的新毛细血管侵入玻璃体，出血并导致失明。实体瘤的生长和转移也依赖于血管发生(Folkman，J.，Cancer Research，46,467-473(1986)，Folkman，J.，Journal of theNational Cancer Institute，82,4-6(1989))。已经表明，例如，扩大到大于2mm的肿瘤必须通过诱导新的毛细血管的生长而获得自己的血液供应。一旦这些新的血管被嵌入到肿瘤中，它们就提供了肿瘤细胞进入循环并转移到远端部位(如肝、肺或骨)的方式(Weidner，N.等人，The New England Journal of Medicine，324(1)，1-8(1991))。在不受控制的血管发生的情况下，设计为控制、阻止和/或抑制血管发生的治疗方法可消除或缓解这些病症和疾病。
大多数化学治疗剂作用于被认为参与恶性表型发展的特定分子靶标。然而，信号传导途径的复杂网络调节细胞增殖，并且大多数恶性癌症由这些途径中的多种遗传异常促进。因此，作用于一个分子靶标的治疗剂不太可能完全有效地治愈患有癌症的患者。
热休克蛋白90(Hsp90)伴侣蛋白稳定了超过200种不同的已知客户蛋白(clientprotein)，帮助它们在细胞中占据其正当位置时正确折叠。由于Hsp90在成熟和维持对肿瘤细胞活力和生长至关重要的众多蛋白质中的关键作用，目前关注伴侣蛋白Hsp90的抑制剂。针对所研究的肿瘤类型的可能的、相关的Hsp90客户蛋白包括NSCLC群体中的突变的STK11/LKB1(Boudeau，J.等人Biochem.J.370，849-857(2003))和NF1 null(De Raedt，T.等人Cancer Cell 20(3):400–13(2011))和SCLC群体中的DNA甲基转移酶-1(Yamaki，H.，等人JAntibiot(Tokyo)64(9)，635-44(2011))。
神经内分泌肿瘤(NET)是最常发生在胃肠道和支气管肺(BP)系统中的内分泌肿瘤。大多数患者出现晚期疾病，对此很少有治疗方案。分子遗传学研究表明，NET的发展可涉及不同的基因，每个基因可与几种不同的异常相关，包括点突变、基因缺失、DNA甲基化、染色体缺失和染色体增益。例如，前肠NET经常具有MEN1基因的删除和突变，而中肠NET具有染色体18、11q和16q的缺失，而后肠NET表达转化生长因子-α和表皮生长因子受体。此外，在肺NET中，染色体3p的缺失是最常见的变化，并且p53突变和5q21的染色体缺失与更具侵袭性的肿瘤和较差的存活相关。此外，视黄酸受体-β、E-钙粘蛋白和RAS相关结构域家族基因的甲基化频率随肺NET的严重程度增加而增加。因此，NET的发展和进展与特定的遗传异常相关联，这些遗传异常表明可涉及不同的分子途径。小肠神经内分泌肿瘤(SINET)是小肠最常见的恶性肿瘤。通过大规模平行外显子组测序分析48个SI-NET，每106个核苷酸平均检测到0.1个(范围，0-0.59)体细胞单核苷酸变异体(SNV)。197种改变蛋白质的体细胞SNV影响了癌症基因的优势，包括FGFR2、MEN1、HOOK3、EZH2、MLF1、CARD11、VHL、NONO和SMAD1。在35名患者中发现了候选治疗相关的改变，包括SRC、SMAD家族基因、AURKA、EGFR、HSP90和PDGFR。这些受影响的癌症基因中的大多数是Hsp90客户蛋白并且被Hsp90抑制下调(Wu Z等，Molecular&Cellular Proteomics11(6)：M111.016675(2012))。
附图简述
图1提供了实施例1中公开的治疗的每个患者的最佳肿瘤反应。SD是病情稳定；PD是疾病进展；ORR是总体反应率。
图2提供了如实施例1中公开的治疗的每个患者的最佳肿瘤反应，该患者先前用2个或更少的在先的治疗线(lines of treatment)治疗。SD是病情稳定；PD是疾病进展；ORR是总体反应率。
图3提供了根据肿瘤位置、等级、增殖标记物Ki67值和在先治疗线的数量的治疗持续时间。
图4提供了胃肠道(GI)、肺和未知(Unk)肿瘤的治疗持续时间，基于肿瘤类型，≤2个在先治疗线且Ki67<20％。SD是病情稳定；PD是疾病进展；ORR是总体反应率。
图5显示了患有肺类癌NET的患者的反应。CT扫描显示标记有两个直径(cm)的左髂骨腺病变。基线肿瘤在6.51cm和4.25cm处测量，并且在4个治疗周期后，在3.75cm和2.42cm处测量肿瘤。
发明内容
本发明人已发现本发明的Hsp90抑制剂与依维莫司的组合可有效治疗癌症。
在一方面，本发明提供在需要的受试者中治疗癌症的方法，该方法包括向受试者给药:
a)Hsp90抑制剂，其为4-(6,6-二甲基-4-氧代-3-三氟甲基-4,5,6,7-四氢-吲唑-1-基)-2-(反式-4-羟基-环己基氨基)-苯甲酰胺、甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯，或它们药学上可接受的盐，其中所述Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2；和
b)依维莫司，其给药量为约2mg至约20mg。
在另一方面，本发明提供在需要的受试者中治疗癌症的方法，该方法包括向受试者按照剂量日程表给药治疗有效量的以下物质:
a)Hsp90抑制剂，其为4-(6,6-二甲基-4-氧代-3-三氟甲基-4,5,6,7-四氢-吲唑-1-基)-2-(反式-4-羟基-环己基氨基)-苯甲酰胺、甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯，或它们药学上可接受的盐；和
b)依维莫司；
其中所述剂量日程表包括至少两个28天的治疗周期，且其中:
(i)该Hsp90抑制剂在每个28天的治疗周期中隔日给药，从第1天开始且持续至少21天；和
(ii)依维莫司在每个28天的治疗周期中从第1天开始每天给药。
在该方面一个实施方案中，Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2；且依维莫司的给药量为约2mg至约20mg。
发明详述
在描述所公开的方法之前，应当理解，本发明描述的方面不限于具体实施方案或组合物，并且因此当然可以变化。还应当理解，本发明使用的术语仅用于描述特定方面，除非本发明特别定义，不旨在限制。
在整个说明书中，除非上下文另有要求，否则词语“包含(comprise)”和“包括(include)”和其变体(例如，“包含(comprises或comprising)”、“包括(includes或including)”)将被理解为暗示包含所陈述的组分、特征、元素或步骤或组分、特征、元素或步骤的组，但不排除任何其他整数或步骤或整数或步骤的组。
如说明书和所附权利要求中所使用的，单数形式“一”、“一个”和“该”包括复数指示物，除非上下文另有明确规定。
术语“药物组合物”以其最广泛的含义使用，包括含有至少一种活性物质和任选的载体、辅料(adjuvant)、成分等的所有药学上可适用的组合物。术语“药物组合物”还包括含有以衍生物或前药的形式的活性物质的组合物，例如药学上可接受的盐和酯。用于不同给药途径的药物组合物的制备属于药物化学领域技术人员的能力范围。
鉴于本发明，本发明描述的方法可以由本领域普通技术人员设置以满足期望的需要。通常，所公开的方法提供癌症治疗的改进。令人惊讶的是，发明人发现本发明的方法在治疗癌症方面更有效。例如，当使用本发明的方法治疗患有NET的受试者(患者)时，17名患者中的3名(18％)具有部分反应率，并且17名患者中的11名(64％)具有稳定的疾病作为最佳反应。此外，受试者长时间保持接受SNX-5422与依维莫司的组合，包括2名接受持续治疗超过2年(即≥30个周期)的受试者。相反，当患有NET的患者仅使用依维莫司治疗，没有SNX-5422时，约2％的患者具有部分反应率(Yao CJ等人Everolimus for the treatment ofadvanced,non-functional neuroendocrine tumours of the lung orgastrointestinal tract(RADIANT-4):a randomised,placebo-controlled,phase 3study.Lancet 2016；387:968–77)。此外，RADIANT-4研究不允许招募具有多于一个的在先治疗线、在先的mTor抑制剂使用、或低分化或高级别神经内分泌肿瘤的患者。SNX-5422与依维莫司的组合研究包括具有神经内分泌肿瘤的任何分化组织学、在先mTor抑制剂使用的患者，并且17名患者中的11名具有两个、三个、四个、五个或甚至六个在先的治疗线。
本发明的方法特别可用于治疗神经内分泌癌、乳腺癌、肾癌、膀胱癌、头颈癌、子宫颈癌、食管癌、肺癌、淋巴瘤、白血病、多发性骨髓瘤、结肠癌或肝癌。在一些实施方案中，本发明的方法用于治疗神经内分泌癌。在其他实施方案中，本发明的方法用于治疗胃和/或肠(胃肠)的神经内分泌癌。在其他实施方案中，本发明的方法用于治疗胰腺神经内分泌癌。在其他实施方案中，本发明的方法用于治疗肺的神经内分泌癌。在一些其他实施方案中，本发明的方法用于治疗类癌，例如肺、肝或胃肠的类癌。
在本发明一些实施方案中，需要的受试者为人类受试者或患者。在一些实施方案中所述受试者，例如人，之前已用抗癌疗法(例如，外科手术、化疗、放射治疗、激素治疗和免疫疗法)治疗。在一些其它实施方案中所述受试者之前未用抗癌疗法治疗。
本发明的方法需要Hsp90抑制剂或其药学上可接受的盐。在一些实施方案中，所述Hsp90抑制剂为4-(6,6-二甲基-4-氧代-3-三氟甲基-4,5,6,7-四氢-吲唑-1-基)-2-(反-4-羟基-环己基氨基)-苯甲酰胺:
或其药学上可接受的盐。SNX-2112的合成和表征数据描述于美国专利号7,358,370，其以其整体在此引入作为参考。
在一些实施方案中，所述Hsp90抑制剂为甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯:
或其药学上可接受的盐。SNX-5422的合成和表征数据描述于美国专利号7,358,370，其以其整体在此引入作为参考。
在本发明的方法中Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2、或约50mg/m2至约100mg/m2、或约75mg/m2至约100mg/m2。在一个实施方案中，所述Hsp90抑制剂的给药量从约50mg/m2逐渐增加至约100mg/m2。在另一实施方案中，所述Hsp90抑制剂的给药量为约100mg/m2。在另一实施方案中，所述Hsp90抑制剂的给药量为约75mg/m2。在另一实施方案中，所述Hsp90抑制剂的给药量为约50mg/m2。
本发明的方法需要依维莫司(也称为42-O-(2-羟基乙基)雷帕霉素、Afinitor、Certican、或Zortress)。依维莫司((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-二羟基-12-{(1R)-2-[(1S,3R,4R)-4-(2-羟基乙氧基)-3-甲氧基环己基]-1-甲基乙基}-19,30-二甲氧基-15,17,21,23,29,35-六甲基-11,36-二氧杂-4-氮杂-三环[30.3.1.04,9]三十六-16,24,26,28-四烯-2,3,10,14,20-五酮)具有以下化学结构:
在本发明的方法中，依维莫司的给药量为约5mg至约20mg，或约7mg至约20mg，或约8mg至约20mg，或约10mg至约20mg，或约2mg至约18mg，或约2mg至约15mg，或约2mg至约12mg，或约2mg至约10mg，或约5mg至约15mg，或约7mg至约15mg，或约8mg至约15mg，或约10mg至约15mg，或约5mg至约18mg，或约5mg至约15mg，或约5mg至约12mg，或约5mg至约10mg，或约8mg至约12mg，或约9mg至约11mg，或约9.5mg至约10.5mg，或约10mg。在一个实施方案中，依维莫司的给药量为约10mg。
在一些实施方案中，依维莫司在给药Hsp90抑制剂后给药。在一些实施方案中，在给药Hsp90抑制剂后至少6小时至10小时给药依维莫司。在一些实施方案中，在给药Hsp90抑制剂后至少6小时、或至少8小时、或至少10小时给药依维莫司。在一些实施方案中，在给药Hsp90抑制剂后不超过16小时、或不超过14小时、或不超过12小时给药依维莫司。
在本发明的方法的示例性、非限制性实施方案中，Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2；且依维莫司的给药量为约2mg至约20mg。在本发明的方法的另一示例性、非限制性实施方案中，Hsp90抑制剂的给药量为约50mg/m2至约100mg/m2；且依维莫司的给药量为约8mg至约12mg。在本发明的方法的另一示例性、非限制性实施方案中，Hsp90抑制剂的给药量为约50mg/m2至约100mg/m2；且依维莫司的给药量为约10mg。在本发明的方法的另一示例性、非限制性实施方案中，Hsp90抑制剂的给药量为约75mg/m2；且依维莫司的给药量为约10mg。
在本发明的一些方法中，Hsp90抑制剂和依维莫司可在本发明的方法中同时、分开或相继给药。
在本发明的其它方法中，Hsp90抑制剂和依维莫司根据剂量日程表给药。在一个实施方案中，所述剂量日程表包括两个、或三个、或四个、或五个、或六个28天的治疗周期，且其中:
(i)该Hsp90抑制剂在每个28天的治疗周期中隔日给药，持续至少21天；且
(ii)依维莫司每天给药一次，从第一个28天的治疗周期的第1天开始。
在一个实施方案中，所述剂量日程表包括四个28天的治疗周期。在另一实施方案中，所述剂量日程表包括六个28天的治疗周期。
药物组合物
在一些实施方案中，该方法包括给药在具有至少一种药学上可接受的载体、溶剂、辅料或稀释剂的药物组合物中的Hsp90抑制剂。
本发明所述的Hsp90抑制剂可以在含有常规无毒的药学上可接受的载体、辅料和媒介物的剂量单位制剂中以口服、局部、肠胃外、吸入或喷雾或直肠给药。本发明所用术语肠胃外包括经皮、皮下、血管内(例如静脉内)、肌内或鞘内注射或输注技术等。本发明所述的药物组合物可为适合于口服使用的形式，例如片剂、含片剂、锭剂、水性或油性悬浮液、可分散的粉末或颗粒剂、乳剂、硬或软胶囊或糖浆或酏剂。
用于口服使用的组合物可以根据本领域已知的用于制备药物组合物的方法制备，并且该组合物可以包含选自甜味剂、调味剂、着色剂和防腐剂的一种或多种试剂以提供药学上精致和适口的制剂。片剂含有与适于制造片剂的无毒的药学上可接受的赋形剂混合的活性成分。这些赋形剂可以是例如惰性稀释剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如玉米淀粉或海藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的，也可以通过已知技术进行包衣。在一些情况下，这样的包衣可以通过已知技术来制备，以延迟在胃肠道中的崩解和吸收，从而在更长的时间内提供持续的作用。例如，可以使用延时材料如单硬脂酸甘油酯或二硬脂酸甘油酯。
用于口服使用的制剂也可以呈现为硬明胶胶囊，其中所述活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合，或作为软明胶胶囊，其中活性成分与水或油介质，例如花生油、液体石蜡或橄榄油混合。
用于口服使用的制剂也可以呈现为锭剂。
水性混悬液含有与适用于制备水性混悬液的赋形剂混合的活性物质。这种赋形剂是悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯胶；分散剂或润湿剂可以是天然存在的磷脂，例如卵磷脂或烯烃氧化物与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂族醇的缩合产物，例如十七碳乙氧基鲸蜡醇，或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物，如聚氧乙烯山梨糖醇单油酸酯，或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物，例如聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液还可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂，例如蔗糖或糖精。
肠胃外给药的制剂可以是水性或非水性等渗无菌注射溶液或悬浮液的形式。这些溶液和混悬液可以由具有一种或多种所提及用于口服给药制剂的载体或稀释剂的无菌粉末或颗粒制备。可将所述化合物溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠和/或各种缓冲液中。其他辅料和给药方式在制药领域中是广泛已知的。
实施例
通过以下实施例进一步说明本发明的方法，所述实施例不应解释为将本发明的范围或精神限制于其中所述的具体步骤。
实施例1
从第1天开始，SNX-5422每隔一天给药一次，持续21天(11次给药)，然后是7天无药物期。SNX-5422每天早晨给药，以50mg/m2开始，具有标准的3+3剂量递增。施用的实际剂量基于体表面积，使用在每个周期开始时测量的体重和在筛选时的高度计算。然后将计算的剂量在给药图表上四舍五入至最接近的mg。依维莫司在晚上每天一次(SNX-5422给药后至少8小时)以10mg给药28天，基于EVR毒性允许剂量递减。符合条件的患者将有不可切除的胃肠胰腺或肺NET和少于5个在先的抗癌治疗线。
使用RECIST 1.1标准(Eisenhauer等人European Journal of Cancer 45：228-247(2009))，在每2个周期结束时±2周评估肿瘤反应。部分反应(PR)被定义为靶病变的直径总和至少减少30％，以基线总和直径为参考。疾病进展(PD)定义为靶病变直径总和至少增加20％，以研究的最小总和为参考。病情稳定记录为其中减少不足以符合PR或增加不足以符合PD。
结果：具有NET的17名患者(10名男性，7名女性；中位年龄59岁)参加了该研究。与依维莫司组合的SNX-5422的最大耐受剂量(MTD)测定为75mg/m2。
耐受性：表1中提供了最常见(即，总体上发生在6个或更多患者中)的治疗-紧急不良事件(TEAE)。所有患者报告至少一个TEAE。腹泻是最常报告的TEAE，整体发生在80％的患者中。在13名患者(65％)中，该事件被认为与SNX-5422和依维莫司的组合有关。与依维莫司相关的不良事件包括贫血、天冬氨酸转氨酶(AST)增加、血小板计数减少和疲劳。
表1.a
注：与依维莫司相关的TEAE用斜体字表示。
在评估疗效的17名NET患者中，3名具有部分反应(18％)，11名病情稳定(64％)，且3名(18％)疾病进展，作为最佳反应。所有17名患者的最佳反应结果如图1所示。在12名疾病稳定的患者中，2名患者正在进行治疗(一名正在进行>26个周期)，3名患者退出研究，其余患者最终进展。一名患者已达到靶病变大小减少51％。目前四名患者正在进行中，其中两名患者已完成超过26个周期。图2提供了先前用2个或更少的在先治疗线治疗过的每位患者的最佳肿瘤反应。PD是疾病进展；ORR是总体反应率。3名患者有部分反应，7名患者病情稳定，1名患者疾病进展，作为最佳反应。如图3中所提供，在具有≤2个在先抗癌治疗线的患者和/或表现出Ki67<20％的患者中观察到对SNX-5422和依维莫司组合的最佳反应。
图4显示了6名患有胃肠道/肺/未知类癌的患者的治疗持续时间的结果，其中患者具有≤2个在先的抗癌治疗线并且还显示Ki67<20％。该组患者的总体反应率为50％。如图4所示，三名患者有部分反应。1名肺类癌患者接受10个治疗周期，且具有51％肿瘤减少；1名患者具有未知类癌，接受35个治疗周期，且具有36％的肿瘤减少；一名GI NET患者接受30个治疗周期，且具有31％的肿瘤减少。
图5提供了在4个治疗周期(CT扫描左髂骨腺病)后患有肺类癌NET的患者的反应。基线肿瘤测量为6.51cm和4.25cm，并且在4个治疗周期后降至3.75cm和2.42cm。这种减少代表PR。这些数据表明SNX-5422与依维莫司组合可用于治疗晚期NET患者。
应当理解，本发明描述的实施例和实施方案仅用于说明目的，并且可以建议本领域技术人员在本申请的精神和范围以及所附权利要求的范围内对其进行各种修改或改变以及并入。本发明引用的所有出版物、专利和专利申请均出于所有目的通过引用并入本发明。
Claims (16)
1.在需要的受试者中治疗癌症的方法，该方法包括向受试者给药:
a)Hsp90抑制剂，其为4-(6,6-二甲基-4-氧代-3-三氟甲基-4,5,6,7-四氢-吲唑-1-基)-2-(反式-4-羟基-环己基氨基)-苯甲酰胺、甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯、或它们药学上可接受的盐，其中所述Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2；和
b)依维莫司，其给药量为约2mg至约20mg。
2.在需要的受试者中治疗癌症的方法，该方法包括按照剂量日程表向受试者给药治疗有效量的以下物质:
a)Hsp90抑制剂，其为4-(6,6-二甲基-4-氧代-3-三氟甲基-4,5,6,7-四氢-吲唑-1-基)-2-(反式-4-羟基-环己基氨基)-苯甲酰胺、甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯、或它们药学上可接受的盐；和
b)依维莫司；
其中所述剂量日程表包括至少两个28天的治疗周期，且其中:
(i)该Hsp90抑制剂在每个28天的治疗周期中隔日给药，从第1天开始且持续至少21天；且
(ii)依维莫司在每个28天的治疗周期中从第1天开始每天给药。
3.权利要求2所述的方法，其中所述Hsp90抑制剂的给药量为约50mg/m2至约150mg/m2；且依维莫司的给药量为约2mg至约20mg。
4.权利要求1-3任一项所述的方法，其中所述Hsp90抑制剂为甘氨酸反式-4-({2-(氨基羰基)-5-[6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基]苯基}氨基)环己基酯。
5.权利要求1、3或4所述的方法，其中所述Hsp90抑制剂的给药量为约50mg/m2至约100mg/m2。
6.权利要求1、3或4所述的方法，其中所述Hsp90抑制剂的给药量从约50mg/m2逐渐增加至约100mg/m2。
7.权利要求1、3或4所述的方法，其中所述Hsp90抑制剂的给药量为约75mg/m2，或约100mg/m2。
8.权利要求1或3-7任一项所述的方法，其中依维莫司的给药量为约5mg至约20mg，或约7mg至约20mg，或约8mg至约20mg，或约10mg至约20mg，或约2mg至约18mg，或约2mg至约15mg，或约2mg至约12mg，或约2mg至约10mg，或约5mg至约15mg，或约7mg至约15mg，或约8mg至约15mg，或约10mg至约15mg，或约5mg至约18mg，或约5mg至约15mg，或约5mg至约12mg，或约5mg至约10mg，或约8mg至约12mg，或约9mg至约11mg，或约9.5mg至约10.5mg，或约10mg。
9.权利要求1或3-7任一项所述的方法，其中依维莫司的给药量为约10mg。
10.权利要求2-9任一项所述的方法，其中在给药Hsp90抑制剂后至少6小时至10小时给药依维莫司。
11.权利要求2-10任一项所述的方法，其中所述剂量日程表包括3个、或4个、或5个、或6个28天的治疗周期。
12.权利要求1-11任一项所述的方法，其中癌症为神经内分泌癌、乳腺癌、肾癌、膀胱癌、头颈癌、子宫颈癌、食管癌、肺癌、淋巴瘤、白血病、多发性骨髓瘤、结肠癌、或肝癌。
13.权利要求12所述的方法，其中神经内分泌癌为胰腺神经内分泌癌。
14.权利要求12所述的方法，其中神经内分泌癌为胃癌和/或肠癌(胃肠癌)。
15.权利要求12所述的方法，其中神经内分泌癌为肺癌。
16.权利要求12所述的方法，其中类癌为肺、肝、或胃肠的类癌。
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| US201662399306P | 2016-09-23 | 2016-09-23 | |
| US62/399,306 | 2016-09-23 | ||
| PCT/US2017/053266 WO2018058045A1 (en) | 2016-09-23 | 2017-09-25 | Combination therapies using indazolylbenzamide derivatives for the treatment of cancer |
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| EP (1) | EP3515436A1 (zh) |
| JP (1) | JP2019529454A (zh) |
| KR (1) | KR20190064602A (zh) |
| CN (1) | CN110035752A (zh) |
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| WO2017059434A1 (en) * | 2015-10-02 | 2017-04-06 | Esanex, Inc. | Use of tetrahydroindazolylbenzamide and tetrahydroindolylbenzamide derivatives for the treatment of cancer |
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2017
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| U.S.NATIONAL LIBRARY OF MEDICINE: ""Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors"", 《CLINICALTRIALS.GOV ARCHIVE》 * |
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| WO2018058045A1 (en) | 2018-03-29 |
| MX2019003002A (es) | 2019-07-04 |
| KR20190064602A (ko) | 2019-06-10 |
| EP3515436A1 (en) | 2019-07-31 |
| CA3038064A1 (en) | 2018-03-29 |
| JP2019529454A (ja) | 2019-10-17 |
| US20190269656A1 (en) | 2019-09-05 |
| AU2017331441A1 (en) | 2019-04-04 |
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