CN102781238A - Tivozanib和坦罗莫司的组合 - Google Patents
Tivozanib和坦罗莫司的组合 Download PDFInfo
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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Abstract
本发明公开了一种治疗肿瘤患者的方法。该方法包括对患者联合给药：(a)每天1.5mg剂量的tivozanib；和(b)每周25mg剂量的坦罗莫司。在本发明的一些实施方式中，tivozanib是按照每天一个剂量的重复时间表给药三周，接下来一周不给药tivozanib。该公开的方法尤其适用于肾细胞癌的治疗。
Description
相关申请的交叉引用
本申请的权利要求要求2010年8月13日提交的美国专利申请号12/856,414，和2009年11月13日提交的美国临时专利申请号61/261,252的优先权和权益；每个申请的全部内容通过引用在此纳入。
技术领域
本发明的技术领域为药物，肿瘤学，酪氨酸激酶抑制剂，VEGF受体抑制剂，mTOR抑制剂，和制药。
背景技术
Tivozanib(也被称为AV-951和KRN951)是一种有效的和选择性的VEGF受体1、2和3的小分子抑制剂。Tivozanib展现出对于所有三种受体皮摩尔的抑制活性，以及其在临窗前模型中展现出抗肿瘤活性(Nakamura等，2006，CancerRes.66：9134-9142)。Tivozanib在一个272名患者的2期临床试验取得了阳性暂时结果(Bhargava等，2009，ASCO Annual Meeting Proceedings，第27卷，第15s期，摘要号5032)。与tivozanib在1期和2期临床试验中治疗相关的最常见的副作用是高血压和发声困难。
雷帕霉素的哺乳动物靶点，通常认为是mTOR(也被称为FRAP，RAFT1和RAP1)，其是一种充当活化的PI3K下游的激酶。已知的mTOR的多个特异性抑制剂包括雷帕霉素，坦罗莫司，依维莫司和OSI-027。在近几年中，坦罗莫司(TORISEL
；也被称为CCI-779)和依维莫司(AFINITOR
；也被称为RAD-001)作为肾细胞癌的单一疗法已经收到FDA上市许可。作为一种单一疗法，坦罗莫司代表性的在每周时间表中通过经脉输注给药。坦罗莫司的副作用严重，包括严重的过敏反应、黑或血色的大便、小腿疼痛、胸腔疼痛、咳嗽、小便困难或疼痛、不规律心跳、发烧、寒战、呼吸问题、严重的头痛、严重的胃疼或腹泻、粘膜溃疡、严重的疲劳或虚弱、手、脚或踝肿大、以及高血糖症状。
使用任何药物，最佳剂量包括平衡想要的治疗作用和不想要的副作用，也就是说，药物毒性。为获得有可接受的副作用特征的治疗作用的剂量范围被称为治疗窗。当两种药物组合使用时，对于治疗窗的情况会变得复杂和不可预知。两种药物的治疗作用可以是不加成的、加成的或增效的。类似地，不想要的副作用，也就是说，药物毒性，可以是不加成的、加成的或增效的。
尽管现有技术包括关于含有VEGF酪氨酸激酶抑制剂和mTOR抑制剂组合疗法的理论优势的提示，但是VEGF酪氨酸激酶抑制剂和坦罗莫司组合(combination)还是有问题的，因为毒性的合并。迄今，没有发现VEGF酪氨酸激酶抑制剂与坦罗莫司的组合在药物的各自个体最大耐受剂量(MTDs)中的临床耐受。例如，在2007年，Patnaik等报道了索拉非尼和坦罗莫司的组合导致了“在足量的索拉非尼下严重的粘膜与皮肤毒性”(Patnaik等，ASCO AnnualMeeting Proceedings Part I，第25卷，第18S期(6月20日增刊)，2007：3512)。在2009年，Patel等，报道了在第一组群(cohort)进行决定舒尼替尼和坦罗莫司组合治疗晚期肾细胞癌的MTDs试验的患者中的三分之二的患者的剂量限制毒性(Patel等，2009，Clinical Genitourinary Cancer 7：24-27)。基于这项研究，Patel等总结出：“伴随使用每周15mg的IV坦罗莫司和每天口服25mg的舒尼替尼(4周给药，2周不给药)是不被推荐的。”在一篇2009年的评论文章中，Sosman等陈述了坦罗莫司与索拉非尼组合需要减少剂量，以及坦罗莫司与舒尼替尼“一起给予是不安全的”(Sosman等，2009，Cancer 115：2368-2375，在第2371页)。
发明内容
本发明部分基于人类临床数据，其论证了tivozanib，一种VEGF酪氨酸激酶抑制剂，和坦罗莫司可以在人类癌症患者安全地组合，每种药物给予它们之前确定的最大耐受剂量。这个发现是令人惊讶的，因为之前的研究表明VEGF酪氨酸激酶抑制剂不能安全的与坦罗莫司联合给药。本发明提供了一种治疗人类肿瘤患者的方法，包括对患者联合给药：(a)每天1.5mg剂量的tivozanib；和(b)每周25mg剂量的坦罗莫司。在本发明的一些实施方式中，tivozanib是按照每天一个剂量的重复时间表给药三周，接下来一周不给药tivozanib。在本发明优选实施方式中，肿瘤为肾细胞癌。
发明详述
本发明涉及方法(i)减小肿瘤生长和(ii)增加遭受固体肿瘤癌例如肾细胞癌、结直肠瘤、和神经内分泌瘤患者的功效和存活率。已经公开的方法基于组合疗法，其中VEGF酪氨酸激酶抑制剂tivozanib与mTOR抑制剂坦罗莫司联合给药。已经公开的方法令人惊奇的在它们各自MTD下使用tivozanib和坦罗莫司，尽管之前的研究发现其它VEGF酪氨酸激酶抑制剂与坦罗莫司组合是不能临床耐受的。
I.定义
为了方便起见，将在说明书、实施例、以及附加的权利要求中的一些术语收集在这个部分。
这里使用的，“组合疗法，”表示联合给药tivozanib和坦罗莫司，其具体的剂量方案部分用于提供这些治疗剂的联合作用得到的有益效果。这些治疗剂代表性地组合是在一个定义的时间段(例如，周或月)下进行的。组合疗法包括在并行的方式下给予治疗剂，例如，治疗剂可以在相同或不同的时间给药和可以以相同的途径或不同的途径给药。每种治疗剂的并行给药可以通过适当的途径实现。例如，tivozanib可以口服给药同时坦罗莫司是静脉给药。
这里使用的，“药学上可接受的”或“药理学上可接受的”表示当适当的向动物或人给药时，分子实体和组合物不会产生不利的、过敏的或其他不良反应。术语，“药学上可接受的载体”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗和吸收延缓剂之类的。这些介质和试剂用于药学活性物质的用途在现有技术中是熟知的。除了任何常规的介质或试剂与活性成分不相容的范围外，其在治疗组合物中的应用是可预期的。补充的活性成分也可以纳入组合物中。
这里使用的，“tivozanib”表示N-{2-氯-4-[(6，7-二甲氧基-4-喹啉基)氧基]-苯基}-N’-(5-甲基-3-异噁唑基)脲以及具有如下化学结构：
包括其药学上可接受的盐、酯、或多晶型物。例如，参考美国专利号6,821,987；7166,722；和7,211,587，每个专利通过引入它们的全文在此纳入。在一些实施方式中，tivozanib为N-{2-氯-4-[(6，7-二甲氧基-4-喹啉基)氧基]-苯基}-N’-(5-甲基-3-异噁唑基)脲或盐酸盐的水合物。在一些实施方式中，tivozanib为N-{2-氯-4-[(6，7-二甲氧基-4-喹啉基)氧基]-苯基}-N’-(5-甲基-3-异噁唑基)脲单盐酸盐一水合物。
这里使用的，“坦罗莫司”表示42-(3-羟基-2-(羟甲基)-2-甲基丙酸)雷帕霉素，其具有如下结构：
例如，参考美国专利号5,362,718，其通过引入它们的全文在此纳入。坦罗莫司(TORISEL
)也被称为CCI-779。TORISEL是惠氏制药市售的。
II.本发明的方法
tivozanib和坦罗莫司的并行给药可以通过单独的制剂，也就是说，tivozanib制剂和坦罗莫司制剂并行给药。相对于本发明而言，单独制剂的给药是“并行的”，如果它们给药的时机是tivozanib和坦罗莫司的药理活性在时间上重叠，由此对患者发挥联合抗肿瘤作用。在本发明的上下文中，并行给药，也就是说，组合疗法，不需要两种药物同时给药，也不需要通过相同的给药途径给药，也不不需要在同一时间在患者身体中存在。Tivozanib和坦罗莫司的药理活性短暂重叠依靠的因素包括(相对于这两种药物中的每一种)：给药剂量、频率和时机，半衰期，和药物代谢动力学。
tivozanib在人体中的半衰期是在3.8-4.7天的范围内。Tivozanib在慢性给药后在血清中积聚，达到基于它的半衰期可被预期的程度。血清水平在大约2-3周后达到稳定状态。
坦罗莫司在人体中的半衰期大约为17小时。坦罗莫司不会出现多于基于它的半衰期所预期的积聚。但是，坦罗莫司的主要代谢物，也就是说，西罗莫司(雷帕霉素)具有mTOR活性，具有约三倍于母体化合物的半衰期。因此，坦罗莫司被认为在坦罗莫司被清除后发挥生理作用。
当tivozanib和坦罗莫司根据本发明并行给药，tivozanib的剂量为每天1.5mg。在本发明的一些实施方式中，tivozanib是按照每天一粒胶囊的重复时间表(例如，含有1.5mg tivozanib的单个剂量)给药三周，接下来一周不给药(也就是说，3周给药，1周不给药)。在此预期的是1.5mg剂量的tivozanib可以是单个胶囊或片剂或一个或多个胶囊或片剂。
当tivozanib和坦罗莫司根据本发明并行给药，坦罗莫司的剂量为每周25mg。在本发明的一些实施方式中，药理学上当量剂量的西罗莫司(雷帕霉素)会代替坦罗莫司。
当tivozanib和坦罗莫司根据本发明并行给药，药物组合可以通过单一制剂或单独的制剂给药。在本发明的一些实施方式中，tivozanib通过口服片剂或胶囊给药，以及坦罗莫司作为静脉内(IV)输注给药。在本发明的优选实施方式中，tivozanib是按照每天一个1.5mg的胶囊的重复时间表给药三周，接下来一周不给药，同时通过IV输注每周一次给药25mg的坦罗莫司。
本发明的方法适于治疗各种类型的固体肿瘤，例如，肾细胞癌、结直肠瘤和神经内分泌瘤。本发明尤其适用于肾细胞癌的治疗。
具体实施方式
本发明通过下列实施例进一步说明。下列实施例被提供仅用于说明用途，并且它并不以任何方式解释为限制本发明的范围或内容。
tivozanib和坦罗莫司的组合产品(combination)在1期临床试验中试验。那些没有接受在先的VEGF-靶向疗法或那些在在先的VEGF-靶向疗法中应答失败的晚期肾细胞癌(具有清晰的细胞组分)人类患者为登记的候选人。每位患者接受口服tivozanib(3周给药，1周不给药)和静脉内输注坦罗莫司(每周一次)。在前的试验中，tivozanib的安全性确定为1.5mg/天的剂量，其给药四周紧接着暂停两周(4周给药，2周不给药)，或给药三周紧接着暂停一周(3周给药，1周不给药)。坦罗莫司核准的剂量为25mg每周一次。在这项1期研究中以下列的剂量水平进行评价：
| 剂量水平 | Tivozanib剂量 | 坦罗莫司剂量 |
| 1 | 0.5mg/天 | 15mg/周 |
| 2 | 1.0mg/天 | 15mg/周 |
| 3 | 1.5mg/天 | 15mg/周 |
| 4-MTD组群 | 1.5mg/天 | 25mg/周 |
16名患者参加这项研究：16名男性和0名女性，中位数年龄62岁(43-70岁的范围)，卡诺夫斯基能力状态(KPS)100％(11名患者)，90％(4名患者)或80％(2名患者)。12名患者(75％)接受过在先的VEGF靶向疗法。治疗的中位数持续时间为16.8周(0.7-51.4周的范围)。基于初步的数据，在所有的剂量水平上观察到至少有20％的患者的治疗相关的不良事件为：口腔炎/粘膜炎(38％)、血小板减少(31％)、腹泻(31％)、疲劳/虚弱(19％)、高血压(19％)、皮疹(10％)、恶心(19％)和呕吐(19％)。未观察到剂量限制毒性以及4级毒性。在该1期临床试验中，组合的MTD为1.5mg/天的tivozanib和25mg/周的坦罗莫司。可利用的数据表明两种药物之间缺乏任何显著的药物代谢动力学作用。两位患者具有确切的部分应答。五位患者在至少20周中具有稳定的病情。
这次人类临床研究支持如下结论。
(1)晚期肾细胞癌的人类患者对tivozanib与坦罗莫司的组合具有好的耐受。
(2)tivozanib是第一个与坦罗莫司联用的VEGF酪氨酸激酶抑制剂，双方都以足量联用：1.5mg/天的tivozanib和25mg/周的坦罗莫司。
(3)tivozanib与坦罗莫司的组合显示了对具有晚期肾癌患者，包括那些先前经可用于该疾病的市售药物治疗失败的患者具有令人鼓舞的临床活性。
以引入方式纳入
在此引用的每篇专利文件和学术文章的全部公开实际上是以引入方式纳入的。
等价物
本发明除去其本质特性外可以包含在其它明确的形式中。前述的实施方式因此是被认为是例证性的而不是对在此描述的本发明的限制。本发明的范围通过附加权利要求而不是通过前述说明书进行指示，以及与权利要求等同的解释和范围的所有变化都被认为是包含在此的。
权利要求为：
Claims (10)
1.一种治疗患者中肿瘤的方法，包括对患者联合给药：(a)每天1.5mg剂量的tivozanib；和(b)每周25mg剂量的坦罗莫司。
2.权利要求1的方法，其中tivozanib是按照每天一个剂量的重复时间表给药三周，接下来一周不给药tivozanib。
3.权利要求1的方法，其中肿瘤选自下组：肾细胞癌，结直肠瘤，和神经内分泌瘤。
4.权利要求1的方法，其中肿瘤为肾细胞癌。
5.权利要求1-4任一项的方法，其中tivozanib为N-{2-氯-4-[(6，7-二甲氧基-4-喹啉基)氧基]-苯基}-N’-(5-甲基-3-异噁唑基)-脲单盐酸盐一水合物。
6.tivozanib和坦罗莫司的组合，用于通过每天给药1.5mg的tivozanib和每周给药25mg的坦罗莫司治疗肿瘤。
7.权利要求6的tivozanib和坦罗莫司的组合，其中tivozanib是按照每天一个剂量的重复时间表给药三周，接下来一周不给药tivozanib。
8.权利要求6或7的tivozanib和坦罗莫司的组合，其中肿瘤选自下组：肾细胞癌，结直肠瘤，和神经内分泌瘤。
9.权利要求6或7的tivozanib和坦罗莫司的组合，其中肿瘤为肾细胞癌。
10.权利要求6-9任一项的tivozanib和坦罗莫司的组合，其中tivozanib为N-{2-氯-4-[(6，7-二甲氧基-4-喹啉基)氧基]-苯基}-N’-(5-甲基-3-异噁唑基)脲单盐酸盐一水合物。
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| PCT/US2010/056372 WO2011060162A1 (en) | 2009-11-13 | 2010-11-11 | Tivozanib and temsirolimus in combination |
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| US20070105887A1 (en) * | 2005-11-04 | 2007-05-10 | Wyeth | Antineoplastic combinations of temsirolimus and sunitinib malate |
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| AVEO PHARMACEUTICALS: "A Phase 1b, Open-Label, Dose-Finding Study to Evaluate the Safety of AV-951 in Combination With Temsirolimus in Subjects With Metastatic Renal Cell Carcinoma", 《CLINICALTRIALS.GOV ARCHIVE[ONLINE]》 * |
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| EP2498606A1 (en) | 2012-09-19 |
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| JP2013510866A (ja) | 2013-03-28 |
| MX2012005497A (es) | 2012-07-03 |
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| KR20120104574A (ko) | 2012-09-21 |
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Application publication date: 20121114 |