CN104427986A - 治疗胃肠道基质瘤的方法 - Google Patents
治疗胃肠道基质瘤的方法 Download PDFInfo
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Classifications
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Abstract
本发明涉及使用包含(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂的组合治疗胃肠道基质瘤(GIST),尤其是在伊马替尼(imatinib)疗法或伊马替尼和舒尼替尼(sunitinib)疗法之后恶化的GIST的方法。
Description
本发明涉及一种使用包含(a)c-kit抑制剂和(b)PI3K抑制剂或FGFR抑制剂的组合治疗人类患者群体的胃肠道基质瘤(GIST)的方法。
GIST是最常见的胃肠道间叶性肿瘤。这些肿瘤被认为是由构成在胃和肠中发现的肠肌层从的Cajal间质细胞引起的。原发性GIST最经常发生于胃(50-60%)、小肠(20-30%)和大肠(10%)中,且食道、肠系膜、网膜和腹膜后腔涉及其余病例。根据瑞典基于群体的发病率估计,美国每年诊断出约5000个GIST新病例。GIST主要发生于中年和老年人中,其中平均发病年龄为大约60岁且无明显性别偏好。
GIST可呈现多种表型特征,其中许多表型特征与患者的预后相关。因此,共识会议强调以肿瘤大小和有丝分裂指数对原发性GIST进行风险分级,其中该风险与肿瘤复发相关。目前,基于病理标准的风险分级比使用良性或恶性GIST这类术语更可取。患有原发性胃GIST的患者似乎比那些患有肠肿瘤的患者遭遇略好。GIST倾向于在局部和以腹膜及肝转移形式复发,其中淋巴结转移较罕见。外科切除术是用于原发性GIST的疗法的主要手段,且使用细胞毒性化疗通常难以治愈该疾病。已发现使用先前用于对Cajal间质细胞染色的免疫组织化学标记(CD117)可使这类肿瘤染色呈阳性,这有利于GIST的诊断。用于免疫组织化学反应中的抗体识别干细胞因子受体(KIT)的细胞外结构域。目前,KIT表达是GIST的主要诊断标准,且其他胃肠道KIT-阳性间叶性肿瘤几乎不可能与GIST混淆;显著例外包括转移性黑素瘤和恶性血管瘤。大约95%的GIST对CD117染色呈阳性。在大多数这类病例中,可在编码KIT蛋白的基因(通常在外显子11,9和13)中发现体细胞突变。这些突变使得受体获得功能,从而变得组成性激活(无论是否存在配体)。
用于原发性GIST患者的疗法的主要手段是外科切除术。然而,单独手术通常不能治愈;据报道,5年疾病特异存活率为54%。原发性GIST的切除术2年内超过50%的复发率且在再次切除后接近90%的复发率强调对有效的术后治疗的需求。
伊马替尼(Imatinib)已在世界范围内获准用于治疗患有KIT-阳性(CD117)及不可切除和/或转移性GIST的成年患者,且其通过延长整体存活期和无进展生存期(PFS)并提高5年存活率明显地改变这类患者的预后。全世界都使用400mg/天至800mg/天范围内剂量的伊马替尼来治疗患有不可切除和/或转移性KIT-阳性GIST的患者。此外,与400mg/天相比,800mg/天的伊马替尼显著改良患有具有KIT外显子9突变的晚期GIST患者的无进展生存期(PFS)。
由于伊马替尼具有用于治疗患有不可切除和/或转移性GIST的患者的疗效,进行了双盲、随机的III期研究(ACOSOGZ9001)以确定与安慰剂相比在完全切除术之后使用400mg/天的伊马替尼辅助治疗GIST成年患者12个月是否改进无复发存活期(RFS)。该研究结果表明使用伊马替尼的治疗显著延长了RFS。基于这些数据,全世界批准使用400mg/天的剂量的伊马替尼在切除GIST之后辅助治疗成年患者。现已获得来自SSGXVIII/AIO的结果,该SSGXVIII/AIO是III期多中心、开放标记、随机研究,其用以评价在手术后且估计处于疾病复发的高风险下的GIST患者中经12个月或36个月每日一次施用400mg伊马替尼的疗效和安全性。该研究数据证实,在外科切除术之后的GIST患者中,实施36个月的伊马替尼辅助疗法耐受良好,且在延长RFS和整体存活期方面优于12个月的疗法。
尽管伊马替尼具有疗效,但它仍不能满足转移性GIST治疗领域的医学需求,其中超过50%的晚期GIST患者在2年伊马替尼一线疗法之后发生恶化。
尼罗替尼(nilotinib)是抑制GIST-T1细胞生长的KIT抑制剂。然而,在存在FGF2的情况下,尼罗替尼的疗效显著降低。多韦替尼(dovtinib)(4-氨基-5-氟-3-[5-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)是双重KIT抑制剂和FGFR抑制剂,其在存在或不存在添加的FGF2的情况下将GIST-T1细胞生长抑制到相同的最大抑制程度(图5)。
基于FGFR途径在GIST中可以是存活途径的发现,组合KIT抑制剂及靶向GIST中的存活途径的双重KIT抑制剂和FGFR抑制剂可产生比通过单独施用KIT抑制剂所获得的治疗效果更好的治疗效果。
如本文所示,FGF2生长因子及其受体FGFR1在原发性GIST组织中过表达,这表示FGFR途径可以是在GIST中激活的存活途径。FGFR1而不是FGF2在GIST细胞系中过表达。然而,FGFR信号传导途径在GIST细胞系中存在外源性FGF2的情况下被激活。此外,GIST细胞系在存在添加的FGF2的情况下对KIT抑制剂的治疗较不敏感。FGFR抑制剂与KIT抑制剂的组合在存在FGF2的情况下,在GIST细胞中产生强协同活性,且显著改善疗效,表明包含FGFR抑制剂和KIT抑制剂的组合可以改善目前的治疗策略在GIST中的疗效。
更广义地说,本发明提供一种通过向有需要的患者施用治疗有效量的FGFR抑制剂来治疗GIST,优选不具有任何KIT突变(包括KIT突变和KIT抗性突变)的GIST的方法。
此外,基于GIST细胞系中的观察,目前惊奇地发现可以利用包含(a)c-kit抑制剂和(b)双重KIT抑制剂及FGFR抑制剂的组合成功地治疗患有在伊马替尼一线疗法之后恶化的GIST患者。
此外,得到结论:可利用包含(a)c-kit抑制剂和(b)双重KIT抑制剂及FGFR抑制剂的组合成功地治疗患有在伊马替尼和舒尼替尼(sunitinib)的连续疗法之后恶化的GIST患者。
因此,本发明提供一种治疗在人类患者中在伊马替尼疗法或伊马替尼和舒尼替尼的连续疗法之后恶化的GIST的方法,其包含(例如)同时或依次向该患者共同施用治疗有效量的(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂。更广泛地,本发明提供一种治疗有需要的人类患者的GIST的方法,其包含(例如)同时或依次向该患者共同施用治疗有效量的(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂。
另一方面,本发明涉及包含(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂的组合在制备用于治疗GIST(尤其是在伊马替尼一线疗法之后恶化的GIST)的药物中的用途。
本发明的另一方面涉及治疗GIST(尤其是在伊马替尼一线疗法之后恶化的GIST或在伊马替尼和舒尼替尼疗法之后恶化的GIST)的包含(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂的组合。
附图简要说明
图1:FGF2和FGFR1在原发性GIST中高度表达。通过MAS5算法使用150作为目标值来将30,094例原发性肿瘤表达曲线的原始数据(CEL文件)标准化。
图2:FGF2表达在KIT-阳性的原发性胃肠道基质瘤(GIST)中实质性高于在其他人类原发性肿瘤组织中的表达。GAPDH蛋白印迹(Western Blot)作为内参显示。
图3:FGFR途径在GIST细胞系中存在多种浓度的添加的FGF2的情况下被激活。使用FRS2Tyr-磷酸化作为FGFR信号传导激活的读出值,且通过GIST细胞系中的蛋白印迹来测量。总FRS2水平作为内参显示。
图4:通过GIST细胞系中的蛋白印迹测量的伊马替尼和多韦替尼的KIT抑制。
图5:GIST-T1细胞在存在添加的FGF2的情况下比在不存在添加的FGF2的情况下对尼罗替尼较不敏感,且多韦替尼和尼罗替尼相比,在存在FGF2的情况下恢复GIST-T1的最大生长抑制。
图6:GIST882细胞在存在添加的FGF2的情况下比在不存在添加的FGF2的情况下对尼罗替尼较不敏感,且多韦替尼和尼罗替尼相比,在存在FGF2的情况下恢复GIST882的最大生长抑制。
图7:在不存在和存在20ng/ml FGF2的情况下伊马替尼和多韦替尼在GIST-T1(A)和GIST882(B)中的组合效应。左图展示每一单一药剂和组合处理相对于经DMSO处理的细胞的抑制百分比。伊马替尼(CGP057148B)浓度是自底部向顶部沿左列递增,多韦替尼浓度是沿底部行自左向右递增。中间图展示左图中每一点的过量抑制。基于Loewe协同性模型来测定过量抑制,该Loewe协同性模型测量相对于若两种药物仅为加和性作用所预期的效应的生长效应。正数表示协同性,负数表示拮抗作用。右图是展现两种化合物间的相互作用的等效线图。连接伊马替尼和多韦替尼的剂量的直线代表加和效应。位于直线下方和左侧的曲线代表协同作用。
本文所用表述“c-kit抑制剂”包括(但不限于)4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-(4-(吡啶-3-基)嘧啶-2-基氨基)苯基]-苯甲酰胺(伊马替尼)、4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺(尼罗替尼)、马赛替尼(masitinib)、舒尼替尼、索拉非尼(sorafenib)、瑞格非尼(regorafenib)、莫特塞尼(motesanib)以及其各自药学上可接受的盐。
在一个优选的实施方式中,所用c-kit抑制剂是伊马替尼。伊马替尼在专利申请案US 5,521,184中被具体公开,其内容以引用方式并入本申请。伊马替尼也可以根据WO03/066613中公开的方法来制备。出于本发明的目的,伊马替尼优选以其单甲磺酸盐的形式使用。伊马替尼单甲磺酸盐可以根据US6,894,051中公开的方法来制备。本发明也包括US 6,894,051中公开的相应的多晶型物,例如结晶变体。
在本文所述方法的另一个优选实施方式中,以US 5,521,184,US 6,894,051或US 2005-0267125中所公开的剂型经口施用伊马替尼的单甲磺酸盐。伊马替尼的甲磺酸盐以商品名出售。优选的伊马替尼口服日剂量为200-600mg,尤其是400mg/天,其以单一剂量形式施用或分为多个剂量,例如每日两次给药。
在本发明的一个实施方式中,所用c-kit抑制剂是尼罗替尼。WO 04/005281公开了尼罗替尼与其制备方法,其以引用方式并入本申请中。尼罗替尼的药学上可接受的盐被WO2007/015871具体公开。出于本发明的目的,尼罗替尼优选使用其单盐酸盐一水合物形式。WO2007/015870公开了可用于本发明中的尼罗替尼及其药学上可接受的盐的某些多晶型物。
在本文所述方法的一个实施方式中,以WO2008/037716中所公开的剂型经口施用尼罗替尼的单盐酸盐。尼罗替尼的单盐酸盐以商品名出售。优选的伊马替尼口服日剂量为200-1200mg,例如800mg,其以单一剂量形式或分为多个剂量施用,例如每日两次给药。
本文所用表述“FGFR抑制剂”包括(但不限于)
(a)比若凡尼(brivanib)、茵太丹尼(intedanib)、E-7080、帕纳替尼(ponatinib)、SU-6668和AZD-4547,
(b)WO 2009/141386中公开的化合物和
(c)WO 2006/000420中公开的化合物(包括3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲单磷酸盐,BGJ398)。BGJ398是抑制FGFR 1-3(IC50介于3nM和7nM之间)的泛FGFR激酶抑制剂。
本发明药物组合中的双重KIT抑制剂和FGFR抑制剂包括至少一种选自下组的RTK抑制剂化合物:式I化合物或其互变异构体、式II化合物或其互变异构体、式III化合物或其互变异构体、所述化合物的药学上可接受的盐、所述互变异构体的药学上可接受的盐、或其混合物。
双重KIT抑制剂和FGFR抑制剂化合物可选自式I化合物、该化合物的互变异构体、该化合物的盐、所述互变异构体的盐、或其混合物,其中式I化合物具有下式:
其中:
R1、R2、R3及R4可相同或不同,且独立地选自H,Cl,Br,F,I,-OR10基团,-NR11R12基团,取代或未取代的伯烷基、仲烷基或叔烷基,取代或未取代的芳基,取代或未取代的烯基,取代或未取代的炔基,取代或未取代的杂环基,或取代或未取代的杂环基烷基;
R5、R6、R7及R8可相同或不同,且独立地选自H,Cl,Br,F,I,-OR13基团,-NR14R15基团,-SR11基团;取代或未取代的伯烷基、仲烷基或叔烷基;取代或未取代的芳基,取代或未取代的烯基,取代或未取代的炔基,取代或未取代的杂环基,或取代或未取代的杂环基烷基,取代或未取代的烷氧基烷基,取代或未取代的芳氧基烷基,或取代或未取代的杂环基氧基烷基;
R10及R13可相同或不同,且独立地选自取代或未取代烷基,取代或未取代的芳基,取代或未取代的杂环基,取代或未取代的杂环基烷基,取代或未取代的烷氧基烷基,取代或未取代的芳氧基烷基,或取代或未取代的杂环基氧基烷基;
R11及R14可相同或不同,且独立地选自取代或未取代的烷基,取代或未取代的芳基,或取代或未取代的杂环基;
R12及R15可相同或不同,且独立地选自取代或未取代的烷基,取代或未取代的芳基,或取代或未取代的杂环基;且
R16选自取代或未取代的烷基,取代或未取代的芳基,或取代或未取代的杂环基。
双重KIT抑制剂和FGFR抑制剂化合物也可以选自式II化合物或其互变异构体,该化合物的药学上可接受的盐,该互变异构体的药学上可接受的盐或其混合物,其中式II化合物具有下式:
其中:
R7是取代或未取代的杂环基。在一些实施方式中,R7是取代或未取代的杂环基,选自取代或未取代的哌啶基、哌嗪基或吗啉基。在其他实施方式中,R7是取代或未取代的N-烷基哌嗪基。在其他实施方式中,R7是取代或未取代的N-烷基哌嗪基,且N-烷基哌嗪基的烷基包含1至4个碳原子。
双重KIT抑制剂和FGFR抑制剂化合物也可以选自式III化合物或其互变异构体、该化合物的药学上可接受的盐、该互变异构体的药学上可接受的盐或其混合物,其中式III化合物具有下式:
式III化合物包括4-氨基-5-氟-3-[5-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮(化合物A)和(4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)(多韦替尼)。
在一个优选的实施方式中,本发明的药物组合包括至少一种式I化合物或其互变异构体、式II化合物或其互变异构体、式III化合物或其互变异构体、所述化合物的药学上可接受的盐、所述互变异构体的药学上可接受的盐、或其混合物,其是化合物A。
在另一优选的实施方式中,本发明的药物组合包括至少一种式I化合物或其互变异构体、式II化合物或其互变异构体、式III化合物或其互变异构体、所述化合物的药学上可接受的盐、所述互变异构体的药学上可接受的盐、或其混合物,其是多韦替尼。
式I的双重KIT抑制剂和FGFR抑制剂化合物或其互变异构体、式II化合物或其互变异构体、式III化合物或其互变异构体、所述该化合物的药学上可接受的盐、所述互变异构体的药学上可接受的盐、或其混合物,其配方和制备方法描述于(例如)WO2002/222598、WO2003/087095、WO2005/046589、WO2006/127926、WO2006/124413、WO2007/064719、WO2009/115562和WO2012/001074中,并以全文引用的方式并入本文中。
本发明的化合物可以游离形式或药学上可接受的盐的形式施用。
除非另有说明,本文中所用“药学上可接受的盐”包括无机碱盐、有机碱盐、无机酸盐、有机酸盐、或碱性或酸性氨基酸盐。对于无机碱盐,本发明包括(例如)钠或钾等碱金属盐;例如钙和镁或铝等碱土金属盐;和铵盐。对于有机碱盐,本发明包括(例如)三甲胺盐、三乙胺盐、嘧啶盐、甲基吡啶盐、乙醇胺盐、二乙醇胺盐和三乙醇胺盐。对于无机酸盐,本发明包括(例如)盐酸盐、氢硼酸盐、硝酸盐、硫酸盐和磷酸盐。对于有机酸,本发明包括(例如)甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、酒石酸盐、马来酸盐、乳酸盐、柠檬酸盐、琥珀酸盐、苹果酸盐、甲磺酸盐、苯磺酸盐和对甲苯磺酸盐。对于碱性氨基酸盐,本发明包括(例如)精氨酸盐、赖氨酸盐和鸟氨酸盐。酸性氨基酸包括(例如)天冬氨酸和谷氨酸。
式I化合物的单乳酸盐以各种多晶型物形式(包括(例如)一水合物形式和无水形式)存在。当同一物质组成(包括其一水合物和溶剂合物)以不同的晶格排列结晶,产生热力学和物理性质不同的特定的结晶形式,则产生多晶型物。
适于本发明的化合物A和多韦替尼的其他药学上可接受的盐包括例如WO 2005/04658中所公开的盐。
在一个实施方式中,多韦替尼以每日约0.001mg/kg体重/天至约100mg/kg体重/天范围内的有效剂量,以单剂量或分剂量向适合个体施用,优选以约1mg/kg/天至约35mg/kg/天以单剂量或分剂量施用。对于一个70kg的人而言,这将总计达到约0.07g/天至2.45g/天,优选约0.05至1.0g/天。
本发明的以下方面尤其重要:
(1)治疗人类患者的GIST的方法,其包含向有需要的人类患者施用有效针对GIST的剂量的(a)c-kit抑制剂和KIT抑制剂或(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂或其各自的药学上可接受的盐的组合,特别地,其中c-kit抑制剂选自伊马替尼、尼罗替尼和马赛替尼或其各自药学上可接受的盐。
(2)治疗人类患者的GIST的方法,其包含向有需要的人类患者施用有效针对GIST的剂量,其中GIST在伊马替尼疗法之后或在伊马替尼和舒尼替尼疗法之后恶化。
(3)用于治疗GIST的组合,其包含(a)c-kit抑制剂和(b)FGFR抑制剂或其各自药学上可接受的盐。
出于本发明的目的,包含(a)c-kit抑制剂和(b)FGFR抑制剂的组合优选选自
(1)伊马替尼或其药学上可接受的盐和化合物A或其药学上可接受的盐,
(2)伊马替尼或其药学上可接受的盐和多韦替尼或其药学上可接受的盐。
通过通用名或商品名识别的活性试剂的结构可从标准纲要“The MerckIndex”的实际版本或从数据库(例如Patents International(例如IMS WorldPublications))获得。其相应内容以引用方式并入本文中。
除非另有所述,否则c-kit抑制剂、双重KIT抑制剂和FGFR抑制剂以及FGFR抑制剂以包含该抑制剂的用于治疗增殖性病症的产品的产品信息中所指定的剂量使用,或(尤其)如没有该产品信息就,则以在剂量寻找实验中确定的剂量使用。
人类患者中的适宜的临床研究是(例如)在患有在伊马替尼一线疗法之后恶化的GIST的患者中进行的开放标记的非随机研究。这些研究证明,与单独使用治疗方案的一种组分相比,所主张的治疗方法尤其优越。可通过这些研究(例如RFS或无进展生存期-PFS)的结果,或通过由本领域技术人员已知的研究设计的改变来直接确定对GIST的有益效果。
实施例
以下实施例阐述上述发明,但不以任何方式限制本发明的范围。相关领域的技术人员已知的其他测试模型也可以确定所主张的发明的有益效果。
实施例1-原发性GIST中的FGF受体1(FGFR1)和FGF2表达
细胞系和培养物
自Brigham and Women’s Hospital,Boston,MA获得GIST882、GIST48和GIST430细胞系。由在编码K642E突变体KIT蛋白的KIT外显子13中具有纯合错义突变的未经治疗的人类GIST建立GIST882(Tuveson DA,Willis NA等,Oncogene 2001;20:5054-5058)。由对伊马替尼治疗有初期临床反应之后恶化的GIST建立GIST48和GIST430(Bauer S,Yu LK,Demetri GD,Fletcher JA.CancerRes 2006;66:9153-9161)。GIST48具有原发纯合外显子11错义突变(V560D)和继发杂合外显子17错义突变(D820A)。GIST430具有原发杂合外显子11框内缺失和继发杂合外显子13错义突变(V564A)。自日本高知医学院(KochiMedical School,Kochi)获得GIST-T1。GIST-T1是由在KIT外显子11中具有57个碱基杂合缺失的转移性人类GIST建立(Taguchi T,Sonobe H,Toyonaga S等,Lab Invest 2002;82:663-665)。
在补充有15%FBS及1%L-谷氨酸的RPMI-1640(ATCC目录编号30-2001)中培养GIST882细胞,在补充有15%FBS、0.5%Mito+(BD Bioscience目录编号355006)、1%BPE(BD Bioscience/Fisher目录编号354123)和1%L-谷氨酸的F10(Gibco/Invitrogen目录编号11550-043)中培养GIST48细胞,在补充有15%FBS和1%L-谷氨酸的IMEM(Gibco/Invitrogen目录编号12440-053)中培养GIST430细胞,且在补充有10%FBS的DMEM(Gibco/Invitrogen目录编号11965)中培养GIST-T1细胞。
细胞活力检测
将伊马替尼和多韦替尼溶解于DMSO中成为10mM储液,且随后用培养基稀释,从而制得一系列不同浓度(μM)(0、0.02、0.05、0.16、0.49、1.48、4.44、13.3和40)的工作溶液。在治疗之前向96孔细胞培养板的每一孔中接种悬浮于80μl培养基中的10,000个细胞,并使其生长24小时。向每一孔中添加10μl 60μg/mL肝素(Sigma目录编号H3149),然后向这些板的每一孔中添加10μl 50μg/mL FGF2(R&D目录编号233-FB/CF)或培养基。向各孔中添加10μl每一上述化合物稀释液和10μl培养基直至最终体积为120μl,从而代表所有成对组合以及单一药剂。在添加化合物之后,在37℃下于5%CO2培育箱中将细胞培育72小时。使用CellTiter-Glo发光细胞活力检测法(Promega目录编号G755B)和Victor4读板器(Perkin Elmer)来测量细胞增殖。如其他处所述来测定协同性得分值及CI70计算值(Lehar J,Krueger AS等,Nat Biotechnol 2009;27:659-666)。
蛋白印迹(Western blotting)
根据制造商所阐述的程序使用RIPA缓冲液(Cell Signaling Technology目录编号9806)自细胞单层制备蛋白质溶解产物。检测磷酸-KIT(目录编号3073S)、总KIT(目录编号3308)、磷酸-AKT S473(目录编号4058)、总AKT(目录编号9272)、磷酸-ERK(目录编号9101)、总ERK(目录编号9107)和磷酸-FRS2(目录编号3864)的抗体购自Cell Signaling Technology。GAPDH的抗体(目录编号MAB374)购自Millipore且抗-FRS2(H-91)(目录编号sc-8318)购自SantaCruz。使用LI-COR Odyssey红外成像系统检测结合的抗体。
结果
Novartis OncExpress数据库含有通过Affymetrix Human Genome U133A或U133Plus 2.0阵列描述的关于30,094例原发性肿瘤(包括110种GIST样品)的内部和公开存储的表达数据。在包含于此数据集的41种肿瘤类型中,除已知GIST-特异性基因(例如KIT、ETV1及PRKCQ)外,FGF2及其受体FGFR1也在GIST中展示最高平均表达水平(图1),这表示FGFR途径在GIST中可以是存活途径。也发现FGF2在原发性GIST中在蛋白质水平上过表达(图2)。FGFR1而不是FGF2在GIST细胞系中过表达。然而,在添加多种浓度的外源性FGF2时会激活FGFR信号传导途径(图3)。伊马替尼和多韦替尼的KIT抑制也通过GIST细胞系中的蛋白印迹来测量(图4)。
GIST-T1和GIST882对通过由尼罗替尼治疗达成的KIT抑制敏感(图5和6,上图)。然而,这两种细胞系显示在存在添加的FGF2的情况下对KIT抑制较不敏感且GI50值偏移10倍以上(图5和6,上图),这表示FGFR信号传导一旦激活即可作为存活途径。因此,组合KIT抑制剂和有效的FGFR抑制剂应该增强GIST细胞系中的生长抑制。
除是双重KIT抑制剂和FGFR抑制剂外,多韦替尼也是有口服活性、有效且有选择性的FGFR抑制剂。当在存在添加的FGF2的情况下利用多韦替尼治疗GIST-T1和GIST882时,最大抑制恢复到与不存在FGF2的情况下相当的程度,这表示多韦替尼作为双重KIT和FGFR抑制剂抑制KIT途径和FGFR途径二者(图5和6,下图)。为测定单一药剂和组合了FGFR抑制剂多韦替尼和KIT抑制剂伊马替尼(CGP057148B)的组合对GIST细胞生长抑制的效果,比较了经各剂量范围的每一单独化合物和成对组合处理3天的细胞增殖反应。作为单一药剂,伊马替尼在不存在FGF2的情况下有效抑制GIST-T1和GIST882生长(图7)。在存在添加的FGF2的情况下,这两种细胞系对伊马替尼治疗较不敏感(图7),这与图5和6中展示的结果类似。无论是否存在添加的FGF2,多韦替尼都有效抑制GIST-T1和GIST882,这与图5和6中展示的发现一致(图7)。多韦替尼和KIT抑制剂(伊马替尼)的组合在存在FGF2的情况下在GIST细胞中产生弱组合效应,这是因为多韦替尼能够抑制KIT途径和FGFR途径。然而,在GIST-T1、GIST882和GIST48中伊马替尼是比多韦替尼更有效的KIT抑制剂(图4),这表示组合伊马替尼和多韦替尼仍然可具有临床益处。组合效果在图7中展示,其是通过测定产生70%生长抑制时的剂量位移的70%抑制效应下的组合指数(CI70)和测定在整个剂量矩阵中所观察的整体协同性的协同性得分值来确定(Lehar J,Krueger AS,al.Nat Biotechnol 2009;27:659-666)。
伊马替尼和多韦替尼的组合即使在存在FGF2的情况下也能在GIST细胞系中展示协同性(图7)。已在来自患者的GIST882(表达K642E突变体KIT)、GIST430(表达ex11del/V654A KIT)和GIST-T1(表达ex11del KIT)细胞系中评估多韦替尼和伊马替尼的单一药剂及组合两种形式的效果。当组合评估伊马替尼和多韦替尼的抗增殖性效果时,观察到生长抑制大于在GIST882和GIST430细胞系中通过伊马替尼或多韦替尼单一药剂治疗所达到的抑制百分比。
表1
协同性是以“加权”协同性得分值S(其中S≤1表示少许加和性或无协同性,或者S>1表示具有少许协同性,且S>2表示具有明显协同性)或以组合指数CI(其中CI=1表示剂量加和性,CI<0.5表示“真正”协同性(2×剂量位移),CI<0.3表示“有用”协同性(3×位移),且CI<0.1表示“强”协同性(10×位移))来量化。以粗体形式表示明显协同性评价。
实施例2:在之前伊马替尼和舒尼替尼疗法中失败的胃肠道基质瘤(GIST)患者中进行的伊马替尼和双重KIT抑制剂及FGFR抑制剂多韦替尼的组合的单组剂量寻找Ib期研究
入组标准:
1.男性或女性患者≥18岁
2.WHO体能状态(PS)为0-2
3.不可切除或转移性GIST获得组织学确诊的诊断
4.可用组织标本:
·剂量递增群:患者必须具有可在研究过程期间输送的可用于存档的肿瘤组织
·剂量扩增群:患者必须具有可在研究过程期间输送的可用于存档的肿瘤组织,且必须同意新鲜的治疗前活组织检查。
5.此前用于治疗不可切除或转移性GIST的伊马替尼随后舒尼替尼的疗法失败。注意用于以下两期试验的特定标准:
·剂量递增群:患者在先前的伊马替尼疗法中失败且然后在舒尼替尼疗法中失败。治疗失败可归因于治疗(伊马替尼和舒尼替尼二者)中的疾病恶化或对疗法(舒尼替尼)的不耐受。
·剂量扩增群:患者必须在伊马替尼和舒尼替尼二者后具有记载的疾病恶化。此外,患者的先前疗法不可超过二线疗法(即在使用伊马替尼治疗之后使用舒尼替尼治疗)。
Claims (9)
1.一种用于治疗GIST的药物组合,其包含(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂,或其各自药学上可接受的盐。
2.根据权利要求1的药物组合,其中该c-kit抑制剂选自伊马替尼、尼罗替尼和马赛替尼,或其各自药学上可接受的盐。
3.根据权利要求2的药物组合,其中该双重KIT抑制剂和FGFR抑制剂是4-氨基-5-氟-3-[5-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮或其药学上可接受的盐或互变异构体。
4.在人类患者中治疗GIST的方法,其包含向有此需要的人类患者施用有效针对GIST的剂量的(a)c-kit抑制剂和(b)双重KIT抑制剂和FGFR抑制剂或FGFR抑制剂或其各自药学上可接受的盐的组合。
5.根据权利要求4的方法,其中该c-kit抑制剂选自伊马替尼、尼罗替尼和马赛替尼,或其各自药学上可接受的盐。
6.根据权利要求4或5中的方法,其中该双重KIT抑制剂和FGFR抑制剂是4-氨基-5-氟-3-[5-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮或其药学上可接受的盐或互变异构体。
7.根据权利要求4或5中的方法,其中GIST在伊马替尼疗法之后恶化。
8.根据权利要求4或5中的方法,其中GIST在伊马替尼和舒尼替尼疗法之后恶化。
9.根据权利要求5的方法,其中伊马替尼以介于300mg和600mg之间的每日剂量被使用。
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US20150202203A1 (en) | 2015-07-23 |
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