TW201909918A - BET抑制劑及Bcl-2抑制劑之組合療法 - Google Patents
BET抑制劑及Bcl-2抑制劑之組合療法 Download PDFInfo
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- TW201909918A TW201909918A TW107125639A TW107125639A TW201909918A TW 201909918 A TW201909918 A TW 201909918A TW 107125639 A TW107125639 A TW 107125639A TW 107125639 A TW107125639 A TW 107125639A TW 201909918 A TW201909918 A TW 201909918A
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- inhibitor
- bcl
- bet
- inhibitors
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Abstract
本發明係有關於多發性骨髓瘤利用BET抑制劑及Bcl-2抑制劑之組合療法。
Description
本發明係有關於特別是多發性骨髓瘤利用BET抑制劑及Bcl-2抑制劑之組合療法。
多發性骨髓瘤(MM)為致衰弱惡性病，其為範圍自未發現顯著性(MGUS)之單株球蛋白症至漿細胞白血病之一系列疾病的一部分。首先描述於1848年，MM的特徵在於惡性漿細胞之增殖及後續單株異型蛋白質(M蛋白質)過多。
MM之呈現可在無征狀至有嚴重症狀的範圍中，其中併發症需要緊急治療。全身疾病包括出血、感染及腎衰竭；可能發生病理性骨折及脊髓受壓。
表觀遺傳調節異常在促成多種血液科惡性疾病中發現之異常基因表現模式方面起至關重要作用。因為許多表觀遺傳更改可逆，故此等因素作為潛在的抗腫瘤標靶而引起相當大的注意力。具有大量臨床關注之一個特定標靶為蛋白質之溴結構域(bromodomain)及額外末端(BET)家族，其包括BRD2、BRD3、BRD4及睪丸特異性BRDT。溴結構域(BRD)為對結合至乙醯化基元(包括染色體內之乙醯化組蛋白)具有高親和力的蛋白質結構域。蛋白質之BET家族結合至乙醯化染色體並調節基因轉錄。
選擇性抑制BET蛋白質與乙醯化染色體之間的相互作用在急性白血病、淋巴瘤及多發性骨髓瘤(MM)之臨床前模型中產生明顯活性。靶向BET蛋白質可特異性地靶向致癌基因及對疾病發展及進展重要之基因的轉錄。
Bcl-2蛋白質在許多疾病中，特別是在癌症、白血病、免疫及自身免疫疾病中發揮作用。據稱，Bcl-2蛋白質與以下有關：膀胱癌、腦癌、乳癌、骨髓癌、宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴母細胞白血病、濾泡性淋巴瘤、T細胞或B細胞源淋巴惡性病、黑素瘤、骨髓性白血病、骨髓瘤、口癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌、脾癌。Bcl-2蛋白質之過度表現與各種癌症及免疫系統之病症中對化療耐藥性、臨床後果、疾病進程、總體預後或其一組合相關。
出人意料地發現，BET抑制劑與Bcl-2抑制劑之組合展示顯著增強的抗多發性骨髓瘤功效，引起明顯的腫瘤消退。出人意料地，利用此組合之腫瘤消退超過添加劑，亦即，優於由兩個組分中之每一者分別誘導之累積抗腫瘤功效。
因此，本發明尤其係關於： 適用作藥劑之BET抑制劑及Bcl-2抑制劑； 用於治療多發性骨髓瘤之BET抑制劑及Bcl-2抑制劑； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其中BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)、INCB-054329、INCB-057643、GSK525762、GS-5829、CPI-0610、Birabresib、PLX51107、ABBV-075、BI 894999、FT-1101、ZEN-3694、GSK-2820151或BMS-986158； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其中BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其中Bcl-2抑制劑為維奈托克(venetoclax)、納維克拉斯(navitoclax)、奧巴克拉(obatoclax)、S-055746或PNT-2258； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其中Bcl-2抑制劑為維奈托克； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其包含一或多種另外的其他細胞毒性劑、化學治療劑或抗癌劑； 根據本發明之供使用之BET抑制劑及Bcl-2抑制劑，其包含增強該等試劑之效果的電離輻射； 一種醫藥組合物，其包含BET抑制劑及Bcl-2抑制劑及一或多種醫藥學上可接受之賦形劑； 一種醫藥組合物，其包含用於治療多發性骨髓瘤之BET抑制劑及Bcl-2抑制劑及其一或多種醫藥學上可接受之鹽； BET抑制劑及Bcl-2抑制劑之用途，其用於製造供多發性骨髓瘤治療用之藥劑。 BET抑制劑及Bcl-2抑制劑之用途，其用於治療多發性骨髓瘤； 一種治療多發性骨髓瘤之方法，其包含向有需要之患者投與BET抑制劑及Bcl-2抑制劑； 一種套組，其包含BET抑制劑及Bcl-2抑制劑，用於同時、單獨或依序投與該BET抑制劑及Bcl-2抑制劑； 一種根據本發明之套組，其用於治療多發性骨髓瘤； 一種根據本發明之醫藥組合物、用途、方法或套組，其中BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)、INCB-054329、INCB-057643、GSK525762、GS-5829、CPI-0610、Birabresib、PLX51107、ABBV-075、BI 894999、FT-1101、ZEN-3694、GSK-2820151或BMS-986158； 根據本發明之醫藥組合物、用途、方法或套組，其中BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)； 根據本發明之醫藥組合物、用途、方法或套組，其中Bcl-2抑制劑為維奈托克、納維克拉斯、奧巴克拉、S-055746或PNT-2258；及 根據本發明之醫藥組合物、用途、方法或套組，其中Bcl-2抑制劑為維奈托克。
因此，根據本發明之供使用之BET抑制劑及Bcl-2抑制劑以組合方式投與(或共投與)。
因此，本發明係關於根據本發明之供以組合方式使用之BET抑制劑及Bcl-2抑制劑。
因此，本發明係關於供以組合方式用作藥劑，特別是供以組合方式治療多發性骨髓瘤用之BET抑制劑及Bcl-2抑制劑。
在一個實施例中，BET抑制劑為選自WO 2011/143669中所描述之化合物的化合物。生產該等BET抑制劑之方法亦揭示於WO 2011/143669中。
最佳地，BET抑制劑為與下式中一樣之2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺或其鹽。WO 2011/143669之實例JQ35描述其製備方法。
較佳BET抑制劑係以下式描繪：
以上BET抑制劑亦被稱作RG6146、JQ35或TEN-010。
在一個實施例中，Bcl-2抑制劑為選自WO 2010/138588中所描述之化合物的化合物。生產該等Bcl-2抑制劑之方法亦揭示於WO 2010/138588中。
最佳地，Bcl-2抑制劑為與下式中一樣的4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氫-2H-哌喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其鹽。WO 2010/138588之實例5描述用於製備該Bcl-2抑制劑之方法。
較佳Bcl-2抑制劑係以下式描繪：
以上Bcl-2抑制劑又名ABT-199、GDC-0199或維奈托克。
根據本發明之術語「BET抑制劑」係指防止IC50
為約0.001 μM至約2 μM之BET蛋白質的活性的試劑。
根據本發明之術語「Bcl-2抑制劑」係指防止IC50
為約0.001 μM至約2 μM之Bcl-2蛋白質的活性的試劑。
「鹽」係指呈醫藥學上可接受之鹽形式之化合物之鹽。此類鹽可藉由以下各鹽例示：鹼金屬(鉀、鈉及其類似鹼金屬)鹽、鹼土金屬(鈣、鎂及其類似鹼土金屬)鹽、銨鹽、醫藥學上可接受之有機胺(四甲銨、三乙胺、甲胺、二甲胺、環戊胺、苯甲胺、苯乙胺、哌啶、單乙醇胺、二乙醇胺、參(羥甲基)胺基甲烷、離胺酸、精胺酸、N-甲基-D-還原葡糖胺及其類似胺)鹽及酸加成鹽(無機酸鹽(鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽及其類似鹽)及有機酸鹽(乙酸鹽、三氟乙酸鹽、乳酸鹽、酒石酸鹽、乙二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、苯甲酸鹽、檸檬酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙磺酸鹽、葡萄糖醛酸鹽、葡糖酸鹽及其類似鹽))。
「IC50
」係指特定化合物抑制50%之特定量測活性所需要之濃度。
術語「組合」、「共投與(co-administration/co-administering)」係指以一種或若干種調配投與根據本發明之BET抑制劑及Bcl-2抑制劑。共投與可為同時的或按任一次序依序的，其中較佳在兩種(或所有)活性劑同時發揮其生物活性時存在一時間段。BET抑制劑及Bcl-2抑制劑可經同時或依序共投與。當依序共投與治療劑時，該劑量可例如在同一天以三次單獨投與方式投與，或該等試劑中之一者可在第1天投與且第二及第三種試劑可在第2天至第7天，較佳在第2天至第4天共投與。因此，在一個實施例中，術語「依序」意謂在第一組分給藥後7天內或在或第一組分給藥後4天內；且術語「同時」」意謂相同時間或在同一天。關於BET抑制劑及Bcl-2抑制劑及之維持劑量之術語「共投與」意謂，若治療週期適合於兩種藥物，則維持劑量可同時(例如每一週)共投與。或者，該等組分中之一者(Bcl-2抑制劑或BET抑制劑)可例如每隔一天至每隔兩天投與且第二種組分可每週投與。或在一天內或數天依序共投與維持劑量。
不言而喻，以「治療有效量」(或簡單地「有效量」)向患者投與抑制劑，該量為將引發研究人員、獸醫、醫學醫生或其他臨床醫生所探尋之組織、系統、動物或人類之生物或醫學反應的各別化合物或組合之量。
BET抑制及Bcl-2抑制劑之共投與量及共投與時序將取決於正治療之患者之類型(物種、性別、年齡、體重等)及病狀及正治療之疾病或病狀的嚴重程度。
BET抑制劑較佳經皮下投與。
BET抑制劑較佳以約0.3 mg/kg/d與約0.65 mg/kg/d之間的劑量投與。
BET抑制劑較佳係每3週每日投與，持續14個連續日(亦即，2週給藥，1週休息)。
BET抑制劑較佳以約0.3 mg/kg/d與約0.65 mg/kg/d之間的劑量皮下投與。
BET抑制劑較佳係每3週以約0.3 mg/kg/d與約0.65 mg/kg/d之間的劑量經皮下投與，持續14個連續日(亦即，2週給藥，1週休息)。
BET抑制劑較佳為RG6146。
BET抑制劑(特別是RG6146)之投與可中斷至多3週，亦即，1、2或3週。
Bcl-2抑制劑較佳經口投與。
Bcl-2抑制劑較佳以約400 mg/d至約800 mg/d之間的劑量投與。
Bcl-2抑制劑較佳以約400 mg/d與約800 mg/d之間的劑量經口投與。
Bcl-2抑制劑較佳每天投與(亦即每日)。其被稱作連續投與。
Bcl-2抑制劑較佳每天以約400 mg/d與約800 mg/d之間的劑量經口投與。
Bcl-2抑制劑較佳為維奈托克。
BET抑制劑及Bcl-2抑制劑之投與週期較佳在同一天開始。
取決於疾病之類型及嚴重強度，可投與以下量：約0.3 mg/kg/d至約0.65 mg/kg/d之BET抑制劑，較佳RG6146；約400 mg/d至約800 mg/d之Bcl-2抑制劑，較佳維奈托克。
特定有利組合為：每3週每天投與約0.3 mg/kg/d至約0.65 mg/kg/d之BET抑制劑，較佳RG6146，持續14個連續日(亦即，2週給藥，1週休息)；連續(亦即每天)投與約400 mg/d至約800 mg/d之Bcl-2抑制劑，較佳維奈托克。
另外的特定有利組合為：每3週每天經皮下投與約0.3 mg/kg/d至約0.65 mg/kg/d之BET抑制劑，較佳RG6146，持續14個連續日(亦即，2週給藥，1週休息)；連續(亦即每天)及經口投與約400 mg/d至約800 mg/d之Bcl-2抑制劑，較佳維奈托克。
在以上給藥方案中，BET抑制劑(特別是RG6146)之投與可中斷至多3週，亦即，1、2或3週。
在以上給藥方案中，Bcl-2抑制劑(特別是維奈托克)之投與可中斷至多3週，亦即，1、2或3週。
所推薦之劑量可在進一步共投與化學治療劑時變化。
本發明適用於預防或減少患有多發性骨髓瘤之此類患者之癌轉移或進一步傳播。本發明適用於增加此類患者之生存期持續時間、增加此類患者之無進展生存期、增加反應之持續時間、產生統計顯著且臨床上有意義的經治療患者之改良，如藉由生存期持續時間、無進展生存期、反應率或反應持續時間所量測。在一較佳實施例中，本發明適用於提高患者群組中之反應率。
在本發明之上下文中，可使用另外的其他細胞毒性劑、化學治療劑或抗癌劑或增強此類試劑(例如細胞介素)之效果之化合物或電離輻射。此類分子適合地以對預期目的有效之量存在於組合中。
此類另外的試劑包括例如：烷基化劑或具有烷化作用之試劑，諸如環磷醯胺(CTX；例如cytoxan®)、苯丁酸氮芥(CHL；例如leukeran®)、順鉑(CisP；例如platinol®)、白消安(例如，myleran®)、美法侖(melphalan)、卡莫司汀(carmustine；BCNU)、鏈佐黴素、曲他胺(TEM)、絲裂黴素C及其類似物；抗代謝物，諸如甲胺喋呤(MTX)、依託泊苷(etoposide)(VP16；例如vepesid®)、6-巰基嘌呤(6MP)、6-硫鳥嘌呤(6TG)、阿糖胞苷(Ara-C)、5-氟尿嘧啶(5-FU)、卡培他濱(capecitabine)(例如，Xeloda®)、達卡巴嗪(dacarbazine；DTIC)及其類似物；抗生素，諸如放線菌素D、小紅莓(DXR；例如adriamycin®)、道諾黴素(daunorubicin)(柔紅黴素(daunomycin))、博萊黴素(bleomycin)、光神黴素及其類似物；生物鹼，諸如長春花生物鹼(諸如長春新鹼(VCR)、長春鹼)及其類似物；及其他抗腫瘤試劑，諸如太平洋紫杉醇(例如，taxol®)及太平洋紫杉醇衍生物、細胞生長抑制劑、糖皮質激素(諸如地塞米松(dexamethasone，DEX；例如decadron®)及皮質類固醇(諸如潑尼松))、核苷酶抑制劑(諸如羥基尿素)、胺基酸消耗酶類(諸如天冬醯胺酶)、甲醯四氫葉酸及其他葉酸衍生物及類似的不同抗腫瘤試劑。以下試劑亦可用作另外的試劑：氨磷汀(arnifostine) (例如，ethyol®)、放線菌素、氮芥(氮芥子氣)、鏈脲菌素、環磷醯胺、洛莫司汀(lomustine) (CCNU)、小紅莓脂體(例如，doxil®)、吉西他濱(gemcitabine) (例如，gemzar®)、道諾黴素脂體(例如，daunoxome®)、丙卡巴肼(procarbazine)、絲裂黴素、多烯紫杉醇(docetaxel)(例如，taxotere®)、阿地白介素(aldesleukin)、卡鉑(carboplatin)、奧賽力鉑(oxaliplatin)、克拉屈濱(cladribine)、喜樹鹼(camptothecin)、CPT 11(伊立替康(irinotecan))、10-羥基7-乙基-喜樹鹼(SN38)、氟尿苷、氟達拉濱(fludarabine)、異環磷醯胺、艾達黴素(idarubicin)、美司鈉(mesna)、干擾素β、干擾素α、米托蒽醌(mitoxantrone)、拓朴替康(topotecan)、亮丙瑞林(leuprolide)、甲地孕酮(megestrol)、美法侖(melphalan)、巰基嘌呤、普卡黴素(plicamycin)、米托坦(mitotane)、培門冬酶(pegaspargase)、噴司他丁(pentostatin)、哌泊溴烷(pipobroman)、普卡黴素、他莫昔芬(tamoxifen)、替尼泊甙(teniposide)、睾內酯(testolactone)、硫鳥嘌呤、噻替派(thiotepa)、尿嘧啶芥(uracil mustard)、長春瑞濱(vinorelbine)或苯丁酸氮芥(chlorambucil)。
上文所描述之細胞毒性劑及抗癌劑以及如蛋白激酶抑制劑之抗增生標靶特異性抗癌藥物在化學治療方案中之使用一般較好地在癌症療法技術中表徵，且其在本文中之使用受相同考慮因素影響以便作出一些調整來監測耐受性及效果且控制投與途徑及劑量。舉例而言，細胞毒素劑之實際劑量可視使用組織培養方法所測定之患者培養細胞反應而變化。一般而言，劑量與在不存在額外的其他試劑下之用量相比將減少。
有效細胞毒性劑之典型劑量可在製造商所推薦之範圍內，且若由活體外反應或動物模型中之反應所指示，則該等典型劑量可減少至多約1個數量級之濃度或量。因此，實際劑量將視醫師之判斷、患者之病狀及基於初始經培養之惡性細胞或經組織培養之組織樣本的活體外反應或在適當動物模型中所觀測到的反應之治療性方法之效果而定。
在本發明的上下文，可進行有效量之電離輻射及/或可使用放射性藥品。輻射之來源可在經治療患者之外部或內部。當來源在患者外部時，療法被稱為外部輻射療法(EBRT)。當輻射之來源在患者內部時，治療被稱為近接療法(BT)。用於本發明之上下文之放射性原子可選自以下群組，其包括但不限於：鐳、釔-90、銫-137、銥-192、鋂-241、金-198、鈷-57、銅-67、鎝-99、碘-123、碘-131及銦-111。亦有可能用此類放射性同位素標記抗體。
輻射療法為控制不可切除或不可手術之腫瘤及/或腫瘤轉移之標準治療。當輻射療法已與化學療法組合時，已觀測到改良之結果。輻射療法係基於傳遞至標靶區域之高劑量輻射將使得腫瘤組織與正常組織中之生殖細胞死亡的原理。一般根據輻射吸收劑量(Gy)、時間及分離來定義輻射給藥方案且必須由腫瘤學家謹慎定義。患者所接受之輻射的量將視各種考慮因素而定，但兩個最重要的因素為腫瘤相對於身體內其他關鍵結構或器官之位置及腫瘤已擴散之程度。經受輻射療法之患者的典型治療過程將為經1週至6週時段之治療時程，以10 Gy與80 Gy之間的總劑量，以約1.8 Gy至2.0 Gy之單次每日部分(一週五天)投與患者。在本發明之一較佳實施例中，當用本發明之組合治療及輻射治療人類患者體內之腫瘤時，存在協同作用。換言之，當與輻射組合，視情況與額外的化學治療劑或抗癌劑組合時，藉助於包含本發明組合之試劑抑制腫瘤生長得以增強。輔助輻射療法之參數包含在例如WO 99/60023中。
如本文所使用，「醫藥學上可接受之載劑」或「醫藥學上可接受之賦形劑」意欲包括與醫藥投與相容之任何及所有材料(包括溶劑、分散介質、包衣、抗菌劑及抗真菌劑、等滲及吸收延遲劑)，及與醫藥投與相容之其他材料及化合物。除非任何習知介質或試劑與活性化合物不相容，否則涵蓋其在本發明之組合物中之使用。亦可在組合物中併入補充活性化合物。
醫藥組合物可藉由用醫藥學上可接受的無機或有機載劑或賦形劑加工根據本發明之BET抑制劑及Bcl-2抑制劑而獲得。舉例而言，乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽及其類似者可用作錠劑、包衣錠劑、糖衣藥丸及硬質明膠膠囊之此類載劑。舉例而言，軟質明膠膠囊之適合載劑為植物油、蠟、脂肪、半固體及液體多元醇及其類似者。然而，視活性物質之性質而定，在軟質明膠膠囊之情況下通常不需要載劑。產生溶液及糖漿之適合載劑為例如水、多元醇、甘油、植物油及其類似者。舉例而言，栓劑之合適載劑為天然或硬化油、蠟、脂肪、半液體或液體多元醇及其類似者。
此外，醫藥組合物可含有防腐劑、增溶劑、穩定劑、濕潤劑、乳化劑、甜味劑、著色劑、調味劑、用於改變滲透壓之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦可含有其他治療上有價值之物質。
BET抑制劑及Bcl-2抑制劑呈單獨或組合形式之醫藥組合物可僅係藉由將具有所需純度的抗體與任選醫藥學上可接受之載劑、賦形劑或穩定劑(Remington's Pharmaceutical Sciences第16版, Osol, A.編(1980))混合而製備成凍乾調配物或水溶液形式以供儲存。可接受載劑、賦形劑或穩定劑在所採用劑量及濃度下對接受者無毒，且包括：緩衝劑，諸如磷酸鹽、檸檬酸鹽及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑(諸如氯化十八烷基二甲基苯甲銨；氯化六羥季銨；苯紮氯銨；苄索氯銨、苯酚、丁醇或苯甲醇；對羥基苯甲酸烷基酯，諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯；兒茶酚；間苯二酚；環己醇；3-戊醇；及m-甲酚)；低分子量(低於約10個殘基)多肽；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯啶酮；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸；單糖、雙糖及其他碳水化合物，包括葡萄糖、甘露糖或糊精；螯合劑，諸如EDTA；糖，諸如蔗糖、甘露醇、海藻糖或山梨醇；成鹽相對離子，諸如鈉；金屬複合物(例如Zn-蛋白複合物)；及/或非離子界面活性劑，諸如TWEENTM
、PLURONICSTM
或聚乙二醇(PEG)。
BET抑制劑及Bcl-2抑制劑之醫藥組合物包括適合於經口、經鼻、經局部(包括頰內及舌下)、經直腸、經陰道及/或非經腸投與之彼等者。組合物可適宜地以單位劑型呈現且可藉由藥劑學技術中熟知之任何方法來製備。可與載劑材料組合以產生單個劑型之活性成份的量將視經治療之宿主以及特定的投與模式而變化。可與載劑材料組合以產生單一劑型之活性成份的量將大體為Bcl-2抑制劑或BET抑制劑產生治療效果之量。一般而言，此量(以百分比計)將在約1%至約90%活性成分，較佳約5%至約70%，最佳約10%至約30%之範圍內。製備此等組合物之方法包括使Bcl-2抑制劑或BET抑制劑與載劑及視情況選用之一或多種附屬成分結合之步驟。一般而言，可藉由使Bcl-2抑制劑及BET抑制劑與液體載劑或細粉狀固體載劑或兩者均勻且緊密地結合及隨後(若需要)使產物成形來製備醫藥組合物。適用於經口投與之醫藥組合物可呈膠囊、扁囊劑、丸劑、錠劑、口含錠(使用調味基質，通常為蔗糖及阿拉伯膠或黃蓍)、散劑、顆粒之形式，或水性或非水性液體中之溶液或懸浮液形式，或水包油或油包水液體乳劑形式，或酏劑或糖漿形式，或片劑(使用惰性基質，諸如明膠及甘油，或蔗糖及阿拉伯膠)及/或漱口劑形式及其類似形式，各含有預定量之Bcl-2抑制劑及BET抑制劑作為活性成分。Bcl-2抑制劑及BET抑制劑亦可以藥團、舐劑或糊劑形式投與。
在本發明之另外的實施例中，BET抑制劑及Bcl-2抑制劑經調配成一種或兩種單獨醫藥組合物。
亦可例如藉由凝聚技術或藉由種族聚合將活性成份包覆於所製備之微囊中，例如羥基甲基纖維素或明膠微囊及聚-(甲基丙烯酸甲酯)微囊分別包覆於膠狀藥物輸送系統(例如脂質體、白蛋白微球體、微乳劑、奈米顆粒及奈米囊劑)中或於巨乳液中。此類技術揭示於Remington's Pharmaceutical Sciences,第16版, Osol, A. (編) (1980)中。
可製備持續釋放型製劑。持續釋放型製劑之適合實例包括含有抗體之固體疏水性聚合物之半滲透基質，該等基質呈成形製品形式，例如膜或微膠囊。持續釋放型基質之實例包括聚酯、水凝膠(例如，聚(2-羥基乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚乳酸交酯(US 3,773,919)、L-麩胺酸與γ-乙基-L-麩胺酸之共聚物、不可降解乙烯-乙酸乙烯酯、諸如LUPRON DEPOTTM
(由乳酸-乙醇酸共聚物及亮丙瑞林乙酸鹽構成之可注射微球體)之可降解乳酸-乙醇酸共聚物及聚-D-(-)-3-羥基丁酸。
用於活體內投藥之調配物必須為無菌的。此容易藉由無菌過濾膜過濾來完成。
以下實例及圖式經提供以說明本發明且不具有限制特性。
實例 實例 1 ： 活體內抗腫瘤功效
評估BET抑制劑RG6146結合Bcl-2抑制劑(維奈托克(GDC-0199))對KMS-12BM MM異種移植物之活體內抗腫瘤功效。
測試劑
提供來自Roche, Basel, Switzerland之BET抑制劑RG6146作為粉劑且在使用之前將其再懸浮。Bcl-2抑制劑(維奈托克)由Genentech, South San Francisco, USA提供且在使用之前調配。
細胞株及培養條件
原始KMS-12BM人類多發性骨髓瘤細胞株(MM)購自ATCC (Manassas, VA, USA)。藉由TAP CompacT CellBase細胞培養機器人根據方案進行腫瘤細胞擴增以供移植。在37℃下於水飽和氛圍中，在5% CO2
下於RPMI 1640培養基、FCS 10%及2 mM L麩醯胺酸中常規培養腫瘤細胞株。用胰蛋白酶/EDTA 1×分裂兩次/週及用於移植之通道3進行培養物傳遞(culture passage)。
動 物
根據提交之準則以每天12小時光照/12小時黑暗之循環將在到達時年齡為5至7週之雌性CIEA NOG小鼠(Taconic)維持在無特定病原體條件下。實驗研究方案由當地政府審查且批准。動物在到達之後維持在動物設施中一週以使其適應新環境且進行觀測。在常規基礎上進行連續健康監測。減肥食物及經高壓處理水隨意提供。
監測
每日控制動物之臨床症狀且偵測不良作用。監測整個實驗，記錄動物之體重。
動物之處理
在隨機分組之後，當中值腫瘤尺寸為約170 mm3
時開始進行動物處理。每天一次(QD)在第14至25天經ip投與媒劑。在第14至25天以單一試劑及以組合形式進行30 mg/kg之BET抑制劑RG6146 ip處理。最後，在第14至25天將Bcl-2抑制劑(維奈托克)作為單一試劑及以組合形式以100 mg/kg經口給予。
抗腫瘤功效
用基質膠將KMS-12BM人類MM細胞s.c.接種至雌性CIEA-NOG小鼠上。在稍後14天將負載腫瘤小鼠隨機分組成所指示研究組並開始化合物處理。用媒劑對照，用30 mg/kg BET抑制劑RG6146或用100 mg/kg Bcl-2抑制劑(維奈托克)作為單一試劑或以其組合形式處理負載腫瘤動物。其結果是，作為單一試劑給予之所有化合物展現出對KMS-12BM異種移植物之顯著抗腫瘤功效。簡言之，相比對照，用BET抑制劑RG6146處理導致對KMS-12BM異種移植物之具有幾乎腫瘤停滯(94%腫瘤生長抑制)之較強顯著功效。與此相比，注意到在用Bcl-2抑制劑(維奈托克)處理後的較弱活性(49% TGI)，而在用包括BET抑制劑RG6164加Bcl-2抑制劑(維奈托克)之雙重組合組處理後達成優良功效。
更詳細地，雙重組合方法實質上誘發最後達到54%之腫瘤消退。相比各別單一試劑分組，關於KMS-12BM MM異種移植物之腫瘤消退的雙重組合分組之較強功效超過添加劑。
結果藉由下表1及圖1說明。表 1 ： BETi RG6146 及 Bcl - 2i 維奈托克之功效 ( 第 25 天 )
TCR：處理與對照比：pTCR：非參數腫瘤控制比；CI：信賴區間
圖1：與媒介物(vehicule)及單一療法相比，利用RG6146及維奈托克之雙重組合之療法的抗腫瘤功效(第14天至第25天)。
Claims (15)
- 一種組合，其包含適用作藥劑之BET抑制劑及Bcl-2抑制劑。
- 一種組合，其包含用於治療多發性骨髓瘤之BET抑制劑及Bcl-2抑制劑。
- 如請求項1或2之組合，其中該BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)。
- 如請求項1或2之組合，其中該Bcl-2抑制劑為維奈托克(venetoclax)。
- 如請求項1或2之組合，其進一步包含一或多種另外的其他細胞毒性劑、化學治療劑或抗癌劑。
- 一種醫藥組合物，其包含BET抑制劑及Bcl-2抑制劑及一或多種醫藥學上可接受之賦形劑。
- 如請求項6之醫藥組合物，其中該BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)。
- 如請求項6之醫藥組合物，其中該Bcl-2抑制劑為維奈托克(venetoclax)。
- 一種BET抑制劑及Bcl-2抑制劑之用途，其用於製造供多發性骨髓瘤治療用之藥劑。
- 如請求項9之用途，其中該BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)。
- 如請求項9之用途，其中該Bcl-2抑制劑為維奈托克。
- 一種套組，其包含BET抑制劑及Bcl-2抑制劑，用於同時、單獨或依序投與該BET抑制劑及Bcl-2抑制劑。
- 如請求項12之套組，其用於治療多發性骨髓瘤。
- 如請求項12之套組，其中該BET抑制劑為2-[(S)-4-(4-氯-苯基)-2,3,9-三甲基-6H-1-硫雜-5,7,8,9a-四氮雜-環戊[e]薁-6-基]-N-[3-(4-甲基-哌嗪-1-基)-丙基]-乙醯胺(RG6146)。
- 如請求項12之套組，其中該Bcl-2抑制劑為維奈托克。
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| WO2023108045A1 (en) * | 2021-12-10 | 2023-06-15 | Abbvie Inc. | Dosing regimens for use in treating relapsed and refractory multiple myeloma with venetoclax |
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| CN101568342A (zh) * | 2006-11-27 | 2009-10-28 | 阿雷斯贸易股份有限公司 | 多发性骨髓瘤的治疗 |
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