TW202023568A - 用於治療癌症之組合療法 - Google Patents
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Abstract
本文揭露了治療癌症之方法，該方法包括對有需要的受試者給予有效量的藥物組成物，該藥物組成物包含多個AZD2811奈米顆粒和維奈托克。
Description
雖然在惡性血液病的治療方面取得了很大進展，但是仍有許多患有此類癌症的患者帶著不可治癒的疾病而生活。患有急性髓細胞性白血病（AML）的那些患者的治療選擇有限，且5年存活率約為25%，其中超過60歲的患者對治療反應差，中位存活期少於12個月。因此，重要的是繼續為患有不可治癒的癌症的患者尋找新的治療。
在一些實施方式中，揭露了一種治療癌症之方法，所述方法包括對有需要的受試者給予有效量的藥物組成物，所述藥物組成物包含多個AZD2811奈米顆粒和有效量的維奈托克（venetoclax）。
在一些實施方式中，揭露了包含多個AZD2811奈米顆粒的藥物組成物在癌症治療中的用途，其中所述治療包括分開、順序或同時給予維奈托克。
在一些實施方式中，揭露了維奈托克在癌症治療中的用途，其中所述治療包括分開、順序或同時給予包含多個AZD2811奈米顆粒的藥物組成物。
在一些實施方式中，揭露了套組（kit），該套組包含：第一藥物組成物，所述第一藥物組成物包含多個AZD2811奈米顆粒和藥學上可接受的載體；和包含維奈托克的第二藥物組成物，以及使用說明書。
在一些實施方式中，揭露了一種治療癌症之方法，所述方法包括對有需要的受試者給予有效量的藥物組成物，所述藥物組成物包含多個AZD2811奈米顆粒和有效量的維奈托克。
語言「AZD2811奈米顆粒」包括包含以下的奈米顆粒：極光（Aurora）激酶B抑制劑2-(3-((7-(3-(乙基(2-羥乙基)胺基)丙氧基)喹唑啉-4-基)胺基)-1H-吡唑-5-基)-N-(3-氟苯基)乙醯胺（也稱為AZD1152 hqpa）、約7至約15重量百分比的撲酸、和二嵌段聚(乳)酸-聚(乙)二醇共聚物；其中二嵌段聚(乳)酸-聚(乙)二醇共聚物具有數目平均分子量為約16 kDa的聚(乳酸)嵌段和數目平均分子量為約5 kDa的聚(乙)二醇嵌段；其中聚(乙)二醇嵌段包含約10至30重量百分比的治療性奈米顆粒。AZD2811奈米顆粒的製備公開於國際申請公開案號WO 2015/036792中。
維奈托克（也稱為ABT-199）係一種BCL-2抑制劑，其被批准用於治療患有慢性淋巴細胞性白血病（CLL）或小淋巴細胞淋巴瘤（SLL）的患者（其具有或不具有17p缺失，之前接受過至少一次治療）。維奈托克具有以下結構，並在國際申請公開案號2010/138588中作為實例5公開：
。
在一些實施方式中，維奈托克經口服給予。在一些實施方式中，維奈托克以包含10 mg、50 mg或100 mg維奈托克的口服藥物組成物給予。在一些實施方式中，維奈托克以20 mg劑量每日給予一次，持續7天，之後是在4周內每週上升的給藥方案，直至每日劑量400 mg。
語言「治療」（「treat」、「treating」和「treatment」）包括降低或抑制受試者中與極光激酶B、BCL-2或癌症相關的酶或蛋白活性，改善受試者癌症的一種或多種症狀，或者減緩或推遲受試者中癌症的進展。語言「治療」（「treat」、「treating」和「treatment」）還包括減少或抑制在受試者中腫瘤的生長或癌性細胞的增殖。
語言「抑制」（「inhibit」、「inhibition」或「inhibiting」）包括生物活性或過程的基線活性的降低。
術語「癌症」包括但不限於惡性血液病，例如急性髓細胞性白血病（AML）、MDS、CMML、多發性骨髓瘤、套細胞淋巴瘤（MCL）、慢性淋巴細胞性白血病（CLL）、彌漫性大B細胞淋巴瘤（DLBCL）、伯基特淋巴瘤、濾泡性淋巴瘤和小淋巴細胞性淋巴瘤（SLL）。在一些實施方式中，所述癌症係易感於極光激酶B抑制劑（例如AZD2811奈米顆粒）的癌症。在一些實施方式中，所述癌症係易感於BCL-2抑制劑（例如維奈托克）的癌症。
術語「受試者」包括暖血哺乳類動物，例如靈長類、狗、貓、兔、大鼠和小鼠。在一些實施方式中，該受試者係靈長類，例如，人類。在一些實施方式中，該受試者患有癌症。在一些實施方式中，該受試者需要治療（例如，該受試者將在生物學或醫學上從治療獲益）。
語言「藥物組成物」包括以下組成物，所述組成物包含多個AZD2811奈米顆粒和藥學上可接受的賦形劑、載體或稀釋劑。語言「藥學上可接受的賦形劑、載體或稀釋劑」包括化合物、材料、組成物、和/或劑型，它們在可靠的醫療判斷的範圍內，適合用於與人類和動物的組織接觸而不產生過度毒性、刺激、過敏反應、或其他問題或併發症，如藉由熟悉該項技術者所確定的。藥物組成物可以是以下形式：一種或多種水性或非水性無毒腸胃外可接受的緩衝系統、稀釋劑、增溶劑、共溶劑或載體中的無菌可注射溶液。無菌可注射製劑也可以是在非水性稀釋劑、載體或共溶劑中的無菌可注射水性或油性懸浮液或懸浮液，其可以根據已知程序利用一種或多種合適的分散劑或潤濕劑和懸浮劑配製。藥物組成物可以是用於靜脈推注/輸注的溶液，或者用緩衝劑系統用或不用其他賦形劑重構的凍幹系統（單獨的或與賦形劑一起）。凍乾的冷凍乾燥材料可以由非水性溶劑或水性溶劑製備。劑型也可以是進一步稀釋用於後續輸注的濃縮物。
術語「有效量」包括包含AZD2811奈米顆粒的藥物組成物的量和/或維奈托克的量，所述量將引起受試者中的生物或醫學反應，例如，與極光激酶B、BCL-2或癌症相關的酶或蛋白質活性的降低或抑制；改善癌症症狀；或者減緩或推遲癌症的進展。在一些實施方式中，語言「有效量」包括包含AZD2811奈米顆粒和/或維奈托克的藥物組成物的以下量，所述量對於至少部分地減輕、抑制和/或改善受試者的癌症，或抑制極光激酶B、BCL-2，和/或減少或抑制受試者的腫瘤的生長或癌性細胞的增殖係有效的。
在一些實施方式中，揭露了套組，該套組包含：第一藥物組成物，所述第一藥物組成物包含多個AZD2811奈米顆粒和藥學上可接受的載體；和包含維奈托克的第二藥物組成物，以及使用說明書。實例 實例 1 ：選擇性 AURKB 抑制劑 AZD2811 與維奈托克組合在急性髓細胞性白血病的臨床前模型中的功效
KGa1 ：
將在50%基質膠中的2 x 107
個KG1a AML細胞皮下植入成年雌性SCID小鼠的左側。根據第7天的腫瘤體積將小鼠隨機分成8組，平均腫瘤體積為0.2 cm3
，並開始所有給藥。AZD2811奈米顆粒每週給藥一次，以任一100 mg/kg靜脈內輸注20-30秒（100 mg/kg係與維奈托克（ABT-199）100 mg/kg組合的最大耐受劑量；維奈托克以100 mg/kg每天口服給予）。所有藥物給藥持續3周的週期。
HL-60 ：
將在50%基質膠中的1 x 107
個HL-60 AML細胞皮下植入成年雌性SCID小鼠的左側。根據第7天的腫瘤體積將小鼠隨機分成8組，平均腫瘤體積為0.2 cm3
，並開始所有給藥。AZD2811奈米顆粒每週給藥一次，以任一50 mg/kg、25 mg/kg、12.5 mg/kg和6.25 mg/kg靜脈內輸注20-30秒（100mg/kg係與維奈托克（ABT-199）100 mg/kg組合的最大耐受劑量；維奈托克以100 mg/kg每天口服給予）。所有藥物給藥持續3周的週期。對於兩種模型，單個操作者每週測量腫瘤兩次，並且藉由隨機化籠進行所有給藥以最小化系統偏差。對於MOLM-13原位模型，將1 x 106
個MOLM-13細胞注射到成年雌性NOG小鼠的尾靜脈中。3天後，將小鼠按體重隨機分成8組，並在次日開始治療。AZD2811奈米顆粒每週給藥一次，以25 mg/kg靜脈內輸注20-30秒（25 mg/kg係與維奈托克（ABT-199）100 mg/kg組合的最大耐受劑量；維奈托克以100 mg/kg每天口服給予）。藉由腹膜內途徑以0.5 mg/kg每天給予5-阿紮胞苷兩次，持續3天，然後是無給藥的4天休息；5-阿紮胞苷與100 mg/kg的維奈托克每天組合給予。所有藥物給藥持續2周的週期，研究終點由福利評分表（welfare scoring table）確定。
結果：
如圖1所示，AZD2811奈米顆粒和維奈托克（ABT-199）單一療法兩者在KG1a模型中均適度有效，並且與任一單獨藥劑相比，與維奈托克的組合顯示出顯著增強的組合功效。如圖2所示，AZD2811奈米顆粒和維奈托克（ABT-199）單一療法兩者在HL-60模型中均有活性，並且與任一單獨的藥劑相比，與維奈托克的組合顯示出顯著增強的組合功效，特別是在最低劑量的AZD2811的情況下。在圖3中，AZD2811和維奈托克的組合比護理標準方案維奈托克和5-阿紮胞苷提供了統計學上顯著的存活益處，而護理標準方案維奈托克和5-阿紮胞苷本身相比於單獨的維奈托克改善了存活。
無
[圖1]例示了用媒介物、單獨的AZD2811、單獨的維奈托克（ABT-199）、以及AZD2811和維奈托克（ABT-199）的組合處理的小鼠隨時間變化的KG1a腫瘤體積。
[圖2]例示了用媒介物、不同劑量的單獨的AZD2811、單獨的維奈托克（ABT-199）、以及不同劑量的AZD2811和維奈托克（ABT-199）的組合處理的小鼠隨時間變化的HL-60腫瘤體積。
[圖3]例示了在播散性AML異種移植物模型MOLM-13中將AZD2811與維奈托克（ABT-199）組合相對於維奈托克（ABT-199）與5-阿紮胞苷（5-azacitidine）的護理標準組合的統計學顯著（p = 0.01；對數秩檢驗）的存活益處。
無
Claims (9)
- 一種治療癌症之方法，所述方法包括對有需要的受試者給予有效量的藥物組成物，所述藥物組成物包含多個AZD2811奈米顆粒和有效量的維奈托克。
- 如申請專利範圍第1項所述之方法，其中所述方法包括順序地、分開地或同時地給予包含多個AZD2811奈米顆粒的藥物組成物以及維奈托克。
- 如申請專利範圍第1項所述之方法，其中所述癌症係血液學癌症。
- 如申請專利範圍第3項所述之方法，其中所述血液學癌症選自急性髓細胞性白血病（AML）、MDS、CMML、多發性骨髓瘤、套細胞淋巴瘤（MCL）、慢性淋巴細胞性白血病（CLL）、彌漫性大B細胞淋巴瘤（DLBCL）、伯基特淋巴瘤和濾泡性淋巴瘤。
- 包含多個AZD2811奈米顆粒的藥物組成物在癌症治療中的用途，其中所述治療包括分開、順序或同時給予維奈托克。
- 維奈托克在癌症治療中之用途，其中所述治療包括分開、順序或同時給予包含多個AZD2811奈米顆粒的藥物組成物。
- 如申請專利範圍第4或5項所述之用途，其中所述癌症係血液學癌症。
- 如申請專利範圍第7項所述之用途，其中所述血液學癌症選自急性髓細胞性白血病（AML）、MDS、CMML、多發性骨髓瘤、套細胞淋巴瘤（MCL）、慢性淋巴細胞性白血病（CLL）、彌漫性大B細胞淋巴瘤（DLBCL）、伯基特淋巴瘤和濾泡性淋巴瘤。
- 一種套組，所述套組包含： 第一藥物組成物，所述第一藥物組成物包含多個AZD2811奈米顆粒和藥學上可接受的載體；以及 第二藥物組成物，所述第二藥物組成物包含維奈托克和藥學上可接受的載體。
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