CN112533605A - 用于治疗癌症的组合疗法 - Google Patents
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Abstract
本文披露了治疗癌症的方法，该方法包括对有需要的受试者施用有效量的药物组合物，该药物组合物包含多个AZD2811纳米颗粒和有效量的5‑阿扎胞苷。
Description
相关申请
本申请根据35 U.S.C.§119(e)要求2018年7月30日提交的美国临时专利申请号62/711,753和2018年9月5日提交的美国临时专利申请号62/727,152的优先权权益。前述申请的内容通过引用以其全部内容并入本文。
背景技术
虽然在恶性血液病的治疗方面取得了很大进展，但是仍有许多患有此类癌症的患者带着不可治愈的疾病而生活。患有急性髓细胞性白血病(AML)的那些患者的治疗选择有限，且5年存活率约为25％，其中超过60岁的患者对治疗反应差，中位存活期少于12个月。因此，重要的是继续为患有不可治愈的癌症的患者寻找新的治疗。
发明内容
在一些实施例中，披露了一种治疗癌症的方法，所述方法包括对有需要的受试者施用有效量的药物组合物，所述药物组合物包含多个AZD2811纳米颗粒和有效量的5-阿扎胞苷。
在一些实施例中，披露了包含多个AZD2811纳米颗粒的药物组合物在癌症治疗中的用途，其中所述治疗包括分开、顺序或同时施用5-阿扎胞苷。
在一些实施例中，披露了5-阿扎胞苷在癌症治疗中的用途，其中所述治疗包括分开、顺序或同时施用包含多个AZD2811纳米颗粒的药物组合物。
在一些实施例中，披露了试剂盒，所述试剂盒包含：第一药物组合物，所述第一药物组合物包含多个AZD2811纳米颗粒和药学上可接受的载体；和第二药物组合物，所述第二药物组合物包含5-阿扎胞苷和药学上可接受的载体。
附图说明
图1例示了在AML的KG1a异种移植鼠模型中单独的AZD2811、单独的5-阿扎胞苷、以及AZD2811和5-阿扎胞苷的组合随时间的肿瘤体积的减小。
图2例示了在AML的HL-60异种移植鼠模型中单独的AZD2811、单独的5-阿扎胞苷、以及AZD2811和5-阿扎胞苷的组合随时间的肿瘤体积的减小。
图3例示了用单独的5-阿扎胞苷或用AZD2811和5-阿扎胞苷的组合处理的小鼠的存活比例。
具体实施方式
在一些实施例中，披露了一种治疗癌症的方法，所述方法包括对有需要的受试者施用有效量的药物组合物，所述药物组合物包含多个AZD2811纳米颗粒和有效量的5-阿扎胞苷。
语言“AZD2811纳米颗粒”包括包含以下的纳米颗粒：极光(Aurora)激酶B抑制剂2-(3-((7-(3-(乙基(2-羟乙基)氨基)丙氧基)喹唑啉-4-基)氨基)-1H-吡唑-5-基)-N-(3-氟苯基)乙酰胺(也称为AZD1152hqpa)、约7至约15重量百分比的扑酸、和二嵌段聚(乳)酸-聚(乙)二醇共聚物；其中二嵌段聚(乳)酸-聚(乙)二醇共聚物具有数均分子量为约16kDa的聚(乳酸)嵌段和数均分子量为约5kDa的聚(乙)二醇嵌段；其中聚(乙)二醇嵌段包含约10至30重量百分比的治疗性纳米颗粒。AZD2811纳米颗粒的制备公开于国际申请公开号WO 2015/036792中。在一些实施例中，将AZD2811纳米颗粒静脉内施用。在一些实施例中，AZD2811纳米颗粒以多达约600mg AZD2811(例如多达约100mg、多达约200mg、多达约300mg、多达约400mg、多达约500mg或多达约600mg AZD2811)的剂量施用。在一些实施例中，AZD2811纳米颗粒将在约2小时、约3小时或约4小时内静脉内施用。在一些实施例中，将AZD2811纳米颗粒在为期28天的周期的第1天和第4天施用。
术语“5-阿扎胞苷”包括具有以下结构的化合物：
称为4-氨基-1-(β-D-呋喃核糖基)-1，3，5-三嗪-2(1H)-酮或拉达卡霉素(ladakamycin)。5-阿扎胞苷被认为经由两种机制具有抗肿瘤活性-在低剂量下，通过抑制DNA甲基转移酶，引起DNA的低甲基化；和在高剂量下，通过掺入DNA和RNA通过其对骨髓中的异常造血细胞的直接细胞毒性，导致细胞死亡。在一些实施例中，所述方法包括对受试者施用包含5-阿扎胞苷和甘露醇的药物组合物。在一些实施例中，所述药物组合物包含1∶1重量比的5-阿扎胞苷和甘露醇(例如，各100mg的5-阿扎胞苷和甘露醇)。在一些实施例中，将5-阿扎胞苷皮下施用。在一些实施例中，将5-阿扎胞苷静脉内施用。在一些实施例中，5-阿扎胞苷以75mg/m2每天施用达7天，然后每四周进行重复周期，增加100mg/m2。在一些实施例中，在为期28天的周期的第1天至第7天以75mg/m2剂量施用5-阿扎胞苷。在一些实施例中，在为期28天的周期的第1天至第5天和第8天及第9天以75mg/m2剂量施用5-阿扎胞苷。
语言“治疗”(“treat”、“treating”和“treatment”)包括降低或抑制受试者中与极光激酶B、DNA甲基转移酶或癌症相关的酶或蛋白活性，改善受试者癌症的一种或多种症状，或者减缓或推迟受试者中癌症的进展。表述“治疗”(“treat”、“treating”和“treatment”)还包括减少或抑制受试者中肿瘤的生长或癌性细胞的增殖。
表述“抑制”(“inhibit”、“inhibition”或“inhibiting”)包括生物活性或过程的基线活性的降低。
术语“癌症”包括但不限于恶性血液病，例如急性髓细胞性白血病(AML)、骨髓增生异常综合征(MDS)和慢性髓单核细胞性白血病(CMML)。在一些实施例中，所述癌症包括易感于用激光激酶B抑制剂(例如AZD2811纳米颗粒)治疗的癌症。在一些实施例中，所述癌症包括易感于用DNA甲基转移酶抑制剂(例如5-阿扎胞苷)治疗的癌症。
语言“药物组合物”包括以下组合物，其包含多个AZD2811纳米颗粒和药学上可接受的赋形剂、载体或稀释剂。语言“药学上可接受的赋形剂、载体或稀释剂”包括化合物、材料、组合物、和/或剂型，它们在可靠的医疗判断的范围内，适合用于与人类和动物的组织接触而不产生过度毒性、刺激、过敏反应、或其他问题或并发症，如通过本领域技术人员所确定的。药物组合物可以是以下形式：一种或多种水性或非水性无毒肠胃外可接受的缓冲系统、稀释剂、增溶剂、共溶剂或载体中的无菌可注射溶液。无菌可注射制剂也可以是在非水性稀释剂、载体或共溶剂中的无菌可注射水性或油性悬浮液或悬浮液，其可以根据已知程序利用一种或多种合适的分散剂或润湿剂和悬浮剂配制。药物组合物可以是用于静脉推注/输注的溶液，或者用缓冲剂体系用或不用其他赋形剂重构的冻干体系(单独的或与赋形剂一起)。冻干的冷冻干燥材料可以由非水性溶剂或水性溶剂制备。剂型也可以是进一步稀释用于后续输注的浓缩物。
术语“受试者”包括暖血哺乳类动物，例如灵长类、狗、猫、兔、大鼠和小鼠。在一些实施例中，该受试者是灵长类，例如，人类。在一些实施例中，该受试者患有癌症。在一些实施例中，该受试者患有复发性AML。在一些实施例中，该受试者患有复发性高风险MDS。在一些实施例中，该受试者患有癌症且是治疗初试的
(例如，从未曾接受过癌症的治疗)。在一些实施例中，该受试者需要治疗(例如，该受试者将在生物学或医学上从治疗获益)。在一些实施例中，用止吐药物预治疗受试者。
术语“有效量”包括包含AZD2811纳米颗粒的药物组合物的量和/或5-阿扎胞苷的量，所述量将引起受试者中的生物或医学反应，例如，与激光激酶B、DNA甲基转移酶或癌症相关的酶或蛋白质活性的减少或抑制；改善癌症症状；或者减缓或推迟癌症的进展。在一些实施例中，语言“有效量”包括包含AZD2811纳米颗粒和/或5-阿扎胞苷的药物组合物的以下量，所述量对于至少部分地减轻、抑制和/或改善受试者的癌症，或抑制极光激酶B、DNA甲基转移酶，和/或减少或抑制受试者的肿瘤的生长或癌性细胞的增殖是有效的。
在一些实施例中，披露了试剂盒，所述试剂盒包含：第一药物组合物，所述第一药物组合物包含多个AZD2811纳米颗粒和药学上可接受的载体；和包含5-阿扎胞苷的第二药物组合物，以及使用说明书。
实例
实例1.选择性AURKB抑制剂AZD2811与5-阿扎胞苷组合在急性髓细胞性白血病的
临床前模型中的功效
KG1a：将在50％基质胶中的2×107个KG1a AML细胞皮下植入成年雌性SCID小鼠的左侧。将小鼠随机化成12组，并在移植后的第1天(D1)启动所有药物和所有组合的给药。AZD2811纳米颗粒每周给药一次，以100mg/kg静脉内输注20-30秒(100mg/kg是与5-阿扎胞苷1mg/kg组合的最大耐受剂量；通过腹膜内途径每天给药5-阿扎胞苷两次，持续3天，然后是无给药的4天休息)。所有药物给药持续3周的周期。单个操作者每周测量肿瘤两次，并且通过随机化笼进行所有给药以最小化系统偏差。当肿瘤达到1.5cm3时小鼠达到研究存活终点。
HL-60：将在50％基质胶中的1×107个HL-60AML细胞皮下植入成年雌性SCID小鼠的左侧。将小鼠随机化成12组，并在移植后的第7天分别启动所有药物和所有组合的给药。AZD2811纳米颗粒每周给药一次，以25mg/kg静脉内输注20-30秒(100mg/kg是与5-阿扎胞苷1mg/kg组合的最大耐受剂量；5-阿扎胞苷通过腹膜内途径每天给药两次，持续3天，然后是无给药的4天休息)。所有药物给药持续3周的周期。单个操作者每周测量肿瘤两次，并且通过随机化笼进行所有给药以最小化系统偏差。当肿瘤达到1.5cm3时小鼠达到研究存活终点。
结果：如图1和2所示，AZD2811纳米颗粒和5-阿扎胞苷单一疗法两者在KG1a模型中均适度有效，其中在HL-60中功效更高，并且在两种模型中，药剂的组合显示出显著更强的功效。如图3所示，在HL-60模型中，AZD2811和5-阿扎胞苷的组合相对于单独的5-阿扎胞苷给出统计学上显著的存活益处(p＜0.005；对数秩检验)。
Claims (9)
1.一种治疗癌症的方法，所述方法包括对有需要的受试者施用有效量的药物组合物，所述药物组合物包含多个AZD2811纳米颗粒和有效量的5-阿扎胞苷。
2.如权利要求1所述的方法，其中所述方法包括顺序地、分开地或同时地施用包含多个AZD2811纳米颗粒的药物组合物以及5-阿扎胞苷。
3.如权利要求1所述的方法，其中所述癌症是恶性血液病。
4.如权利要求3所述的方法，其中所述恶性血液病选自急性髓细胞性白血病(AML)、MDS和CMML。
5.包含多个AZD2811纳米颗粒的药物组合物在癌症治疗中的用途，其中所述治疗包括分开、顺序或同时施用5-阿扎胞苷。
6.5-阿扎胞苷在癌症治疗中的用途，其中所述治疗包括分开、顺序或同时施用包含多个AZD2811纳米颗粒的药物组合物。
7.如权利要求5或6所述的用途，其中所述癌症是血液学癌症。
8.如权利要求7所述的用途，其中所述血液学癌症选自急性髓细胞性白血病(AML)、MDS和CMML。
9.一种试剂盒，所述试剂盒包含：
第一药物组合物，所述第一药物组合物包含多个AZD2811纳米颗粒和药学上可接受的载体；和
包含5-阿扎胞苷的第二药物组合物，以及使用说明书。
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| US62/727152 | 2018-09-05 | ||
| PCT/IB2019/056403 WO2020026102A1 (en) | 2018-07-30 | 2019-07-26 | Combination therapy for treating cancer |
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| US20060205685A1 (en) * | 2005-03-11 | 2006-09-14 | Pasit Phiasivongsa | Azacytosine analogs and derivatives |
| CN105555315A (zh) * | 2013-09-16 | 2016-05-04 | 阿斯利康(瑞典)有限公司 | 治疗性聚合物纳米颗粒及其制备和使用方法 |
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- 2019-07-26 JP JP2021504837A patent/JP2021533112A/ja active Pending
- 2019-07-26 MX MX2021001084A patent/MX2021001084A/es unknown
- 2019-07-26 WO PCT/IB2019/056403 patent/WO2020026102A1/en unknown
- 2019-07-26 MA MA053341A patent/MA53341A/fr unknown
- 2019-07-26 CA CA3106783A patent/CA3106783A1/en not_active Abandoned
- 2019-07-26 AU AU2019312904A patent/AU2019312904A1/en not_active Abandoned
- 2019-07-26 US US17/263,915 patent/US20210315898A1/en not_active Abandoned
- 2019-07-26 CN CN201980050538.4A patent/CN112533605A/zh active Pending
- 2019-07-26 EP EP19778638.7A patent/EP3829586A1/en not_active Withdrawn
- 2019-07-26 KR KR1020217005795A patent/KR20210039414A/ko unknown
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|---|---|---|---|---|
| US20060205685A1 (en) * | 2005-03-11 | 2006-09-14 | Pasit Phiasivongsa | Azacytosine analogs and derivatives |
| CN105555315A (zh) * | 2013-09-16 | 2016-05-04 | 阿斯利康(瑞典)有限公司 | 治疗性聚合物纳米颗粒及其制备和使用方法 |
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| Publication number | Publication date |
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| AU2019312904A1 (en) | 2021-03-11 |
| KR20210039414A (ko) | 2021-04-09 |
| JP2021533112A (ja) | 2021-12-02 |
| WO2020026102A1 (en) | 2020-02-06 |
| TW202019440A (zh) | 2020-06-01 |
| CA3106783A1 (en) | 2020-02-06 |
| US20210315898A1 (en) | 2021-10-14 |
| MA53341A (fr) | 2021-11-03 |
| EP3829586A1 (en) | 2021-06-09 |
| MX2021001084A (es) | 2021-05-12 |
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