TW202304459A - 包含fgfr抑制劑及nectin-4靶向劑之組合療法 - Google Patents
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Abstract
本揭示案係關於藉由組合投與作為成纖維細胞生長因子受體(FGFR)抑制劑之化合物與恩諾單抗(enfortumab vedotin)來治療癌症之方法。
Description
本揭示案係關於藉由組合投與作為成纖維細胞生長因子受體(FGFR)抑制劑之化合物與作為靶向Nectin-4的抗體-藥物結合物之恩諾單抗(enfortumab vedotin)來治療癌症之方法。
成纖維細胞生長因子受體(FGFR)係結合至成纖維細胞生長因子(FGF)配位體之受體酪胺酸激酶。四種FGFR蛋白(FGFR1-4)能夠結合配位體且參與包括組織發育、血管生成、傷口癒合及代謝調控在內之多種生理學過程之調控。在配位體結合時,此等受體經歷二聚化及磷酸化,導致蛋白激酶活性之刺激及多種細胞內對接蛋白之募集。此等相互作用促進一系列對於細胞生長、增殖及存活至關重要之包括Ras-MAPK、AKT-PI3K及磷脂酶C在內的細胞內信號傳導路徑之活化(於Eswarakumar等人,Cytokine & Growth Factor Reviews,2005中概述)。
經由FGF配位體或FGFR之過表現或FGFR中之活化突變引起的此路徑之異常活化可導致腫瘤發展、進展及抵抗習用癌症療法。在人類癌症中,已描述導致配位體獨立受體活化之基因改變,包括基因擴增、染色體易位及體細胞突變。對數千個腫瘤樣本之大規模DNA測序已表明,FGFR路徑之組分係人類癌症中最常發生突變的。許多此等活化突變與導致骨骼發育不良症候群之生殖系突變一致。人類疾病中導致異常配位體依賴性信號傳導之機制包括FGF過表現,及產生具有更混亂配位體結合能力之受體的FGFR剪接變化(於Knights及Cook Pharmacology & Therapeutics,2010;Turner及Grose,Nature Reviews Cancer,2010中概述)。因此,靶向FGFR之抑制劑的開發可適用於具有提高之FGF或FGFR活性之疾病的臨床治療。
其中牽涉FGF/FGFR之癌症類型包括但不限於:癌瘤(例如,膽管癌、腺癌)、膀胱、乳房、子宮頸、結腸直腸、子宮內膜、胃、頭頸、腎、肝、肺、卵巢、前列腺);造血系統惡性腫瘤(例如,多發性骨髓瘤、慢性淋巴球性淋巴瘤、成人T細胞白血病、急性骨髓性白血病、非霍奇金氏淋巴瘤(non-Hodgkin lymphoma)、骨髓增生性贅瘤及華氏巨球蛋白血症);及其他贅瘤(例如,神經膠母細胞瘤及肉瘤、黑色素瘤及橫紋肌肉瘤)。除了在致癌性贅瘤中之作用以外,FGFR活化亦已牽涉於包括但不限於軟骨發育不全及顱縫線封閉過早症候群之骨骼及軟骨細胞病症中。
目前正在開發用於治療癌症之FGFR抑制劑。例如,培米替尼(pemigatinib)或3-(2,6-二氟-3,5-二甲氧基苯基)-1-乙基-8-(嗎啉-4-基甲基)-1,3,4,7-四氫-2H-吡咯并[3',2':5,6]吡啶并[4,3-d]嘧啶-2-酮及其他FGFR之小分子抑制劑報導於例如美國專利第9,611,267號及美國公開案:第2012/0165305號;第2014/0045814號;第2013/0338134號;第2014/0171405號;第2014/0315902號;第2016/0115164號;第2016/0244448號;第2016/0244449號;第2016/0244450號;第2019/0337948號及第2020/0002338號中。
仍然需要使用FGFR抑制劑與其他治療劑組合之新型癌症治療方案。本揭示案係針對此需要及其他需要。
本申請案進一步提供治療患者之癌症之方法,其包含向該患者投與培米替尼或其醫藥學上可接受之鹽及恩諾單抗。
本申請案亦提供了培米替尼或其醫藥學上可接受之鹽及恩諾單抗在製備用於治療癌症之藥劑中之用途。
本申請案進一步提供了用於任一本文所述方法中之培米替尼或其醫藥學上可接受之鹽及恩諾單抗。
本申請案尤其提供一種治療患者之癌症之方法,其包含與恩諾單抗組合投與培米替尼,該培米替尼係具有如下結構之3-(2,6-二氟-3,5-二甲氧基苯基)-1-乙基-8-(嗎啉-4-基甲基)-1,3,4,7-四氫-2H-吡咯并[3',2':5,6]吡啶并[4,3-d]嘧啶-2-酮:
培米替尼。
培米替尼描述於美國專利第9,611,267號中,其全部內容以引用之方式併入本文中。培米替尼進一步描述於美國公開案:第2019/0337948號及第2020/0002338號中,其全部內容以引用之方式併入本文中。培米替尼可稱為「pemi」。如本文所述之培米替尼可抑制FGFR酶之活性。例如,藉由將抑制量的培米替尼投與給細胞、個體或患者,培米替尼可用於抑制細胞或需要抑制FGFR酶的個體或患者中之該酶之活性。作為FGFR抑制劑,培米替尼可用於治療與FGFR酶或FGFR配位體之異常表現或活性相關之各種疾病。抑制FGFR之化合物將可用於提供預防腫瘤生長或誘導腫瘤細胞凋亡之手段,具體而言係藉由血管生成抑制達成。本文揭示之方法可用於治療或預防諸如癌症等增殖性病症。具體而言,具有受體酪胺酸激酶活化突變體或受體酪胺酸激酶上調之腫瘤可能對本文描述之方法特別敏感。
恩諾單抗係一種抗體-藥物結合物,其經美國食品藥物管理局批准用於治療先前接受過PD-1或PD-L1抑制劑及含鉑化療的成年患者之表現Nectin-4的癌症,包括尿路上皮癌(例如,膀胱癌)。恩諾單抗係Nectin-4定向抗體及微管抑制劑之結合物。具體地,恩諾單抗係一種Nectin-4定向抗體-藥物結合物,其包含與單甲基奧瑞他汀(auristatin) E結合之完整人類抗Nectin-4 IgG1 κ單株抗體(AGS-22C3),該單甲基奧瑞他汀E係一種小分子微管破壞劑。結合發生在包含抗體之鏈間二硫鍵之半胱胺酸殘基上。恩諾單抗亦稱為「恩諾單抗-ejfv」及「PADCEV」。
本文提供了一種治療患者之癌症之方法,其包含向該患者投與:
(i) 培米替尼或其醫藥學上可接受之鹽;及
(ii) 恩諾單抗。
本文提供了一種治療患者之癌症之方法,其包含向該患者投與:
(i) 培米替尼;及
(ii) 恩諾單抗。
在一些實施例中,癌症係膀胱癌。
在一些實施例中,癌症係泌尿生殖系統癌症(例如,泌尿生殖系統腫瘤)。
體內研究表明,在某些劑量下,培米替尼及恩諾單抗之組合在治療膀胱癌中具有協同作用(實例C)。
在一些實施例中,培米替尼或其醫藥學上可接受之鹽及恩諾單抗同時或依序投與給患者。在一些實施例中,培米替尼或其醫藥學上可接受之鹽及恩諾單抗同時投與給患者。在一些實施例中,培米替尼或其醫藥學上可接受之鹽及恩諾單抗依序投與給患者。
培米替尼及其醫藥學上可接受之鹽可藉由多種方法投與給個體,例如有需要之個體,例如人類個體。對於許多應用,投與途徑係經口。在一些實施例中,培米替尼或其醫藥學上可接受之鹽以醫藥組成物形式投與。
在一些實施例中,培米替尼經口投與。在一些實施例中,培米替尼每天一次投與。
在一些實施例中,培米替尼以約1 mg至約50 mg之日劑量投與。在一些實施例中,培米替尼以約1 mg至約20 mg之日劑量投與。在一些實施例中,培米替尼以約1 mg至約15 mg之日劑量投與。在一些實施例中,培米替尼以約1 mg至約10 mg之日劑量投與。在一些實施例中,培米替尼以約1 mg至約5 mg之日劑量投與。在一些實施例中,培米替尼以約5 mg至約20 mg之日劑量投與。在一些實施例中,培米替尼以約5 mg至約10 mg之日劑量投與。在一些實施例中,培米替尼以約10 mg至約15 mg之日劑量投與。在一些實施例中,培米替尼以約4.5 mg之日劑量投與。在一些實施例中,培米替尼以約9 mg之日劑量投與。在一些實施例中,培米替尼以約13.5 mg之日劑量投與。
在一些實施例中,培米替尼以約20 mg或更低之日劑量投與。在一些實施例中,培米替尼以約15 mg或更低之日劑量投與。在一些實施例中,培米替尼以約13.5 mg或更低之日劑量投與。在一些實施例中,培米替尼以約10 mg或更低之日劑量投與。在一些實施例中,培米替尼以約9 mg或更低之日劑量投與。在一些實施例中,培米替尼以約8 mg或更低之日劑量投與。在一些實施例中,培米替尼以約7 mg或更低之日劑量投與。在一些實施例中,培米替尼以約6 mg或更低之日劑量投與。在一些實施例中,培米替尼以約5 mg或更低之日劑量投與。在一些實施例中,培米替尼以約4 mg或更低之日劑量投與。在一些實施例中,培米替尼以約3 mg或更低之日劑量投與。在一些實施例中,培米替尼以約2 mg或更低之日劑量投與。在一些實施例中,培米替尼以約1 mg或更低之日劑量投與。
在一些實施例中,培米替尼以錠劑形式投與。在一些實施例中,錠劑包含約0.5 mg至約10 mg培米替尼。在一些實施例中,錠劑包含約0.5 mg至約5 mg培米替尼。在一些實施例中,錠劑包含約2 mg、約4.5 mg、約9 mg、約13.5 mg或約18 mg培米替尼。在一些實施例中,錠劑包含約0.5 mg培米替尼。在一些實施例中,錠劑包含約2 mg培米替尼。在一些實施例中,錠劑包含約4.5 mg培米替尼。在一些實施例中,錠劑包含約9 mg培米替尼。在一些實施例中,錠劑包含約13.5 mg培米替尼。在一些實施例中,錠劑包含約18 mg培米替尼。
在一些實施例中,培米替尼以連續給藥方案每天一次投與。在一些實施例中,培米替尼以21天給藥方案投與,其中21天給藥方案包含:
(a) 第一期,其中培米替尼每天一次投與,持續14天;及
(b) 第二期,其中培米替尼未投與,持續7天。
在一些實施例中,培米替尼以連續21天給藥方案投與,
其中21天給藥方案包括:
(a) 第一期,其中培米替尼每天一次投與,持續14天;及
(b) 第二期,其中培米替尼未投與,持續7天。
在一些實施例中,恩諾單抗靜脈內投與。在一些實施例中,恩諾單抗以約0.5 mg/kg至約5.0 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約0.5 mg/kg至約2.0 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約0.5 mg/kg至約1.5 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約0.5 mg/kg至約1.25 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約1.0 mg/kg至約5.0 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約1.0 mg/kg至約2.0 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,恩諾單抗以約1.0 mg/kg至約1.5 mg/kg之劑量以靜脈內輸注形式投與。在一些實施例中,對於體重為100 kg或以上之患者,恩諾單抗以靜脈內輸注形式投與至多125 mg。在一些實施例中,對於體重為100 kg或以上之患者,恩諾單抗以靜脈內輸注形式投與至多100 mg。在一些實施例中,對於體重為100 kg或以上之患者,恩諾單抗以靜脈內輸注形式投與至多75 mg。在一些實施例中,對於體重為100 kg或以上之患者,恩諾單抗以約1.25 mg/kg之劑量以靜脈內輸注形式投與至多125 mg。在一些實施例中,恩諾單抗以約1.25 mg/kg之劑量以靜脈內輸注形式投與。
在一些實施例中,恩諾單抗以連續給藥方案每週一次投與。
在一些實施例中,在一些實施例中,恩諾單抗以28天給藥方案投與,其中28天給藥方案包括:
(a) 第一期,其中恩諾單抗每週一次投與,持續21天;
(b) 第二期,其中恩諾單抗未投與,持續7天。
在一些實施例中,恩諾單抗以28天給藥方案投與,其中28天給藥方案包括在28天期之第1、8及15天投與恩諾單抗。
本文揭示之方法可用於治療癌症。示例癌症包括膀胱癌、乳癌(例如,激素R陽性、三陰性)、子宮頸癌、結腸直腸癌、小腸癌、結腸癌、直腸癌、肛門癌、子宮內膜癌、胃癌(gastric cancer)(例如,胃腸道間質瘤)、頭頸癌(例如,喉癌、下咽癌、鼻咽癌、口咽癌、唇癌及口腔癌、鱗狀頭頸癌)、腎癌(例如,腎細胞癌、尿路上皮癌、肉瘤、威爾姆氏腫瘤(Wilms tumor))、肝癌(例如,肝細胞癌、膽管細胞癌、肝血管肉瘤、肝母細胞瘤)、肺癌(例如,腺癌、小細胞肺癌及非小細胞肺癌、小細胞及非小細胞癌、支氣管癌、支氣管腺瘤、胸膜肺母細胞瘤)、卵巢癌、前列腺癌、睪丸癌、子宮癌、外陰癌、食道癌、膽囊癌、胰臟癌(例如外分泌性胰臟癌) 、胃癌(stomach cancer)、甲狀腺癌、甲狀旁腺癌、神經內分泌癌(例如,嗜鉻細胞瘤、默克爾細胞癌(Merkel cell cancer)、神經內分泌癌)、皮膚癌(例如,鱗狀細胞癌、卡波西氏肉瘤(Kaposi sarcoma)、默克爾細胞皮膚癌)及腦癌(例如,星細胞瘤、髓母細胞瘤、室管膜瘤、神經外胚層瘤、松果體瘤)。
其他示例癌症包括造血系統惡性腫瘤,諸如白血病或淋巴瘤、 多發性骨髓瘤、慢性淋巴球性淋巴瘤、成人T細胞白血病、B細胞淋巴瘤、皮膚T細胞淋巴瘤、急性骨髓性白血病、霍奇金氏淋巴瘤或非霍奇金氏淋巴瘤、骨髓增生性贅瘤(例如,8p11骨髓增生性症候群、真性紅血球增多症、原發性血小板增多症及原發性骨髓纖維化)、骨髓增生異常症候群、慢性嗜酸性球白血病、華氏巨球蛋白血症、毛細胞淋巴瘤、慢性骨髓性淋巴瘤、急性淋巴母細胞淋巴瘤、AIDS相關淋巴瘤及伯基特淋巴瘤(Burkitt's lymphoma)。
在某些實施例中,本文提供了一種治療有需要之患者之髓樣/淋巴樣贅瘤之方法。在某些實施例中,髓樣/淋巴樣贅瘤係8p11骨髓增生性症候群。如本文所用,術語「8p11骨髓增生性症候群」(EMS)係指與嗜酸性球增多及FGFR1異常相關之髓樣/淋巴樣贅瘤或伴有FGFR1重排之髓樣/淋巴樣贅瘤(MLN)。Jackson,Courtney C.等人
Human Pathology,2010,
41,461-476概述了8P11骨髓增生性症候群。在某些實施例中,髓樣/淋巴樣贅瘤表現出8p11易位。在某些實施例中,8p11易位與FGFR1之活化相關。在某些實施例中,患者對髓樣/淋巴樣贅瘤(例如,8p11骨髓增生性症候群)之至少一種先前治療失敗。在一些實施例中,先前治療係手術或放射療法。在一些實施例中,患者俱有肝炎病史。在一些實施例中,肝炎係慢性B型肝炎或C型肝炎。在一些實施例中,患者沒有肝炎病史。
在某些實施例中,癌症係膀胱癌(例如,尿路上皮癌、鱗狀細胞癌、腺癌)。在某些實施例中,膀胱癌係膀胱癌之管腔乳頭狀亞型。在某些實施例中,膀胱癌之特徵在於FGFR3突變,例如FGFR3融合。FGFR3融合之實例包括但不限於FGFR3-TACC3、FGFR3-BAIAP2L1、FGFR3-AES、FGFR3-ELAVL3、FGFR3-JAKMIP1、FGFR3-TNIP2及FGFR3-WHSC1,如De Luca 等人
Int. J. Mol. Sci.2020,21(8):6856 第1-18頁所述。
在一些實施例中,癌症係泌尿生殖系統癌症(例如,泌尿生殖系統腫瘤)。泌尿生殖系統癌症包括但不限於膀胱癌、腎癌、睪丸癌及前列腺癌。在一些實施例中,泌尿生殖系統癌症之特徵在於FGF/FGFR基因改變的腫瘤。在某些實施例中,泌尿生殖系統癌症之特徵在於FGFR3突變,例如FGFR3融合。FGFR3融合之實例包括但不限於FGFR3-TACC3、FGFR3-BAIAP2L1、FGFR3-AES、FGFR3-ELAVL3、FGFR3-JAKMIP1、FGFR3-TNIP2及FGFR3-WHSC1,如De Luca 等人
Int. J. Mol. Sci.2020,21(8):6856 第1-18頁所述。
在某些實施例中,癌症係膠質母細胞瘤或肺癌,其中膠質母細胞瘤或肺癌之特徵在於FGFR3突變,例如FGFR3融合。FGFR3融合之實例包括但不限於FGFR3-TACC3、FGFR3-BAIAP2L1、FGFR3-AES、FGFR3-ELAVL3、FGFR3-JAKMIP1、FGFR3-TNIP2及FGFR3-WHSC1,如De Luca 等人
Int. J. Mol. Sci.2020,21(8):6856 第1-18頁所述。
在某些實施例中,肝癌係膽管細胞癌(例如,肝內、肝門或肝門周圍、肝外遠端)。如本文所用,膽管細胞癌與膽管癌(cholangiocarcinoma)或膽管癌(bile duct cancer)相同。在某些實施例中,膽管癌係晚期或轉移性膽管癌。在某些實施例中,膽管癌係不可手術切除的。在某些實施例中,膽管癌係肝內的。在某些實施例中,膽管癌係肝外的。在某些實施例中,膽管癌表現出FGFR2酪胺酸激酶融合,其定義了獨特的分子亞型,如Arai,Yasuhito,等人
Hepatology,2014,
59,1427-1434中所述。在一些實施例中,膽管癌之特徵在於FGF/FGFR基因改變的腫瘤。在一些實施例中,腫瘤表現出FGFR2融合。FGFR2融合可為易位、間質缺失或染色體倒位。在一些實施例中,FGFR2融合係FGFR2易位。FGFR2易位可選自包括但不限於FGFR2-BICC1、FGFR2-AHCYL1、FGFR2-MACF1、FGFR2內含子17重排之群。在一些實施例中,腫瘤表現出除FGFR2易位之外的FGF/FGFR改變。在一些實施例中,膽管癌未表現出FGF/FGFR基因改變的腫瘤。
可用本文提供之方法治療之其他癌症包括眼部腫瘤、膠質母細胞瘤、黑色素瘤、橫紋肌肉瘤、淋巴肉瘤、平滑肌肉瘤、尿路上皮癌(例如,輸尿管、尿道、膀胱、臍尿管)及骨肉瘤。
本揭示案之方法亦可用於治療轉移性癌症,特別為表現PD-Ll之轉移性癌症。
在一些實施例中,使用本揭示案之方法可治療之疾病及適應症包括但不限於血液學癌症、透鏡癌、肉瘤、肺癌、胃腸道癌、泌尿生殖道癌、肝癌、骨癌、神經系統癌、婦科癌症及皮膚癌。
示範性血液學癌症包括淋巴瘤及白血病,諸如急性淋巴母細胞白血病(ALL)、急性骨髓性白血病(AML)、急性前骨髓細胞白血病(APL)、慢性淋巴球性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、慢性骨髓性白血病(CML)、瀰漫性大B細胞淋巴瘤(DLBCL)、套細胞淋巴瘤(MCL)、邊緣區淋巴瘤(MZL)、非霍奇金氏淋巴瘤(包括復發性或難治性NHL)、濾泡性淋巴瘤(FL)、霍奇金氏淋巴瘤、淋巴母細胞淋巴瘤、骨髓增生性疾病(例如原發性骨髓纖維化(PMF)、真性紅血球增多症(PV)、原發性血小板增多症(ET))、骨髓增生異常症候群(MDS)、T細胞急性淋巴母細胞淋巴瘤(T-ALL)、多發性骨髓瘤、皮膚T細胞淋巴瘤、外周T細胞淋巴瘤、華氏巨球蛋白血症、毛細胞淋巴瘤、慢性骨髓性淋巴瘤及伯基特淋巴瘤。
示範性肉瘤包括軟骨肉瘤、尤因氏肉瘤、骨肉瘤、橫紋肌肉瘤(rhabdomyosarcoma)、血管肉瘤、纖維肉瘤、脂肪肉瘤、黏液瘤、橫紋肌瘤、橫紋肌肉瘤、纖維瘤、脂肪瘤、錯構瘤及畸胎瘤。
示範性肺癌包括非小細胞肺癌(NSCLC)、小細胞肺癌、支氣管癌(鱗狀細胞、未分化之小細胞、未分化之大細胞、腺癌)、肺泡(小支氣管)癌、支氣管腺瘤、軟骨錯構瘤及間皮瘤。
示範性胃腸道癌包括食管癌(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌、淋巴瘤、平滑肌肉瘤)、胰臟癌(導管腺癌、胰島素瘤、升糖素瘤、胃泌素瘤、類癌腫瘤、VIP瘤)、小腸癌(腺癌、淋巴瘤、類癌腫瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神經纖維瘤、纖維瘤)、大腸癌(腺癌、管狀腺瘤、絨毛狀腺瘤、錯構瘤、平滑肌瘤)、結腸直腸癌、膽管癌。
示範性泌尿生殖道癌包括腎癌(腺癌、威爾姆氏腫瘤[腎母細胞瘤]、腎細胞癌)、膀胱及尿道癌(鱗狀細胞癌、移行細胞癌、腺癌、尿路上皮癌)、前列腺癌(腺癌、肉瘤)及睪丸癌(精原細胞瘤、畸胎瘤、胚胎性癌、畸形癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣瘤、脂肪瘤)。
示範性肝癌包括肝細胞瘤(肝細胞癌)、膽管上皮癌、肝母細胞瘤、血管肉瘤、肝細胞腺瘤及血管瘤。
示範性骨癌包括(例如)骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維性組織細胞瘤、軟骨肉瘤、尤因氏肉瘤、惡性淋巴瘤(網狀細胞肉瘤)、多發性骨髓瘤、惡性巨細胞瘤脊索瘤、骨軟骨瘤(骨軟骨性外生骨疣)、良性軟骨瘤、軟骨母細胞瘤、軟骨黏液纖維瘤、骨樣骨瘤及巨細胞腫瘤
示範性神經系統癌症包括頭骨癌(骨瘤、血管瘤、肉芽腫、黃色瘤、變形性骨炎)、腦膜癌(腦脊髓膜瘤、腦膜肉瘤、神經膠瘤病)、腦癌(星細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、生殖細胞瘤(松果體瘤)、神經膠質母細胞瘤、多形性神經膠質母細胞瘤、寡樹突神經膠質瘤、神經鞘瘤、視網膜母細胞瘤、先天性腫瘤)及脊髓癌(神經纖維瘤、腦膜瘤、神經膠質瘤、肉瘤)以及神經母細胞瘤、Lhermitte-Duclos病、中樞神經系統(CNS)贅瘤、原發性CNS淋巴瘤及脊髓軸腫瘤。
示範性婦科癌症包括子宮癌(子宮內膜癌)、子宮頸癌(子宮頸癌、前腫瘤子宮頸發育不良)、卵巢癌(卵巢癌(漿液囊腫腺癌、黏液性囊腺癌、未分類癌)、粒層-泡膜細胞腫瘤、賽爾托利-萊迪希氏細胞腫瘤(Sertoli-Leydig cell tumor)、無性細胞瘤、惡性畸胎瘤)、陰門癌(鱗狀細胞癌、上皮內癌、腺癌、纖維肉瘤、黑色素瘤)、陰道癌(透明細胞癌、鱗狀細胞癌、葡萄狀肉瘤(胚胎型橫紋肌肉瘤))及輸卵管癌(癌)。
示範性皮膚癌包括黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、默克爾細胞皮膚癌、發育不良性痣、脂肪瘤、血管瘤、皮膚纖維瘤及瘢瘤。
示範性頭頸癌包括膠質母細胞瘤、黑色素瘤、橫紋肌肉瘤、淋巴肉瘤、骨肉瘤、鱗狀細胞癌、腺癌、口腔癌、喉癌、鼻咽癌、鼻癌及鼻旁癌、甲狀腺癌及甲狀旁腺癌。
在一些實施例中,本揭示案提供了一種用於治療有需要之患者之肝細胞癌之方法。在一些實施例中,本揭示案提供了一種用於治療有需要之患者之橫紋肌肉瘤、食道癌、乳癌或頭頸癌之方法。
本文所述之方法涉及治療癌症,例如實體瘤。
在一些實施例中,實體瘤選自皮膚癌、肺癌、淋巴瘤、肉瘤、膀胱癌、輸尿管癌、尿道癌及臍尿管癌、胃癌、子宮頸癌、肝癌、乳癌、腎癌、鱗狀細胞癌、結腸直腸癌、子宮內膜癌、肛門癌,以及具有高微衛星不穩定性(MSI-H)、錯配修復缺陷(dMMR)及/或DNA聚合酶ε外切核酸酶結構域突變陽性疾病之腫瘤。
在一些實施例中,實體瘤選自膽管癌、黑色素瘤、非小細胞肺癌、小細胞肺癌、霍奇金氏淋巴瘤、尿路上皮癌、胃癌、肝細胞癌、默克爾細胞癌、三陰性乳癌、腎細胞癌、頭頸鱗狀細胞癌及結腸直腸癌。
在一些實施例中,實體瘤選自肉瘤、頭頸癌、黑色素瘤及非小細胞肺癌。在一些實施例中,實體瘤係肉瘤。在一些實施例中,實體瘤係頭頸癌。在一些實施例中,實體瘤係黑色素瘤。在一些實施例中,實體瘤係非小細胞肺癌。
如本文所用,可互換使用之術語「個體」、或「患者」係指任何動物,包括哺乳動物,較佳地小鼠、大鼠、其他囓齒動物、兔、犬、貓、豬、牛、綿羊、馬或靈長類動物,且最佳地為人類。
如本文所用,片語「治療有效量」係指在組織、系統、動物、個體或人類中引起由研究者、獸醫、醫生或其他臨床醫師所尋求之生物學或醫學反應的活性化合物或醫藥劑之量。
如本文所用,術語「治療(「treating」或「treatment」)」係指以下項中之一或多者:(1)抑制疾病;例如,抑制正經歷或表現出該疾病、疾患或病症之病理或症狀之個體的疾病、疾患或病症(亦即,阻止病理及/或症狀進一步發展);及(2)減輕疾病;例如,減輕正經歷或表現出該疾病、疾患或病症之病理或症狀之個體的疾病、疾患或病症(亦即逆轉該病理及/或症狀),諸如降低疾病之嚴重性。在一些實施例中,術語「治療」係指抑制或減輕疾病。
如本文所用,術語「共同投與」或「併行投與」係指同時或幾乎同時投與培米替尼及一或多種其他藥物(例如,恩諾單抗)。例如,培米替尼可例如在同一天、一週內或一個月內作為一或多種其他藥物投與。在一些實施例中,一或多種其他藥物在培米替尼的投與之間投與。
如本文所用,術語「療法」係指投與適用於治療癌症之化合物。例如,療法可指投與培米替尼用於治療癌症。
如本文所用,且除非另有說明,術語「約」在與數值或數值範圍結合使用時,表示該數值或數值範圍可偏離熟習此項技術者認為合理的程度。具體而言,術語「約」在本上下文中使用時表示數值或數值範圍可變化所引用數值或數值範圍之5%、4%、3%、2%、1%、0.9%、0.8%、0.7%、 0.6%、0.5%、0.4%、0.3%、0.2%或0.1%。
如本文所用,術語「細胞」係指
體外、
離體或
體內細胞。在一些實施例中,
離體細胞可為從諸如哺乳動物之生物體切除的組織樣品之一部分。在一些實施例中,
體外細胞可為細胞培養物中之細胞。在一些實施例中,
體內細胞係生活在諸如哺乳動物之生物體中之細胞。
如本文所用,術語「接觸」係指在體外系統或體內系統中使指定部分組合在一起 。例如,使FGFR酶與培米替尼「接觸」包括將本文所述之化合物投與具有FGFR之個體或患者,例如人類,以及例如,將培米替尼引入包含含有FGFR酶之細胞或純化製劑之樣品中。
片語「醫藥學上可接受之」在本文中用以指在合理醫學判斷範圍內適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症且與合理益處/風險比相稱之彼等化合物、材料、組成物及/或劑型。
如本文所用,片語「醫藥學上可接受之載劑或賦形劑」係指醫藥學上可接受之材料、組成物或媒劑,諸如液體或固體填充劑、稀釋劑、溶劑或包封材料。賦形劑或載劑通常係安全的、無毒的且在生物學上或其他方面都係所要的,並且包括獸醫用途及人類醫藥學用途可接受之賦形劑或載劑。在一實施例中,每種組分係如本文定義的「醫藥學上可接受的」。參見例如,
Remington : The Science and Practice of Pharmacy ,第21 版
;Lippincott Williams & Wilkins:Philadelphia,Pa.,2005;
Handbook of Pharmaceutical Excipients ,第 6 版;Rowe等人編輯;The Pharmaceutical Press and the American Pharmaceutical Association:2009;
Handbook of Pharmaceutical Additives ,第 3 版;Ash及Ash編輯;Gower Publishing Company:2007;
Pharmaceutical Preformulation and Formulation ,第 2 版;Gibson編輯;CRC Press LLC:Boca Raton,Fla.,2009。
在一些實施例中,培米替尼之醫藥學上可接受之鹽用於本文所述之方法及組合療法中。美國公開案第2019/0337948號中描述了培米替尼之鹽形式。
培米替尼之固體形式(例如,結晶形式)亦可用於本文所述之方法及組合療法中。美國公開案第2020/0002338號中描述了培米替尼之固體形式及製備培米替尼之固體形式之方法。
應瞭解,為清晰起見,在單獨實施例之上下文中闡述之本發明之某些特徵亦可在單一實施例中組合提供(而實施例意欲被組合,就如同以多重依賴形式編寫一樣)。相反,本發明為簡便起見而闡述於單一實施例之上下文中之各種特徵亦可單獨地或以任何適宜亞組合提供。
與其他劑之組合療法
示範性其他治療劑如下所述。
I. 癌症療法
癌細胞生長及存活可受多種信號傳導路徑之功能異常之影響。因此,將不同酶/蛋白質/受體抑制劑組合起來治療此等疾患係有用的,此等不同酶/蛋白質/受體抑制劑在其調節活性之靶中表現出不同偏好。靶向一種以上信號傳導途徑(或一種以上參與給定信號傳導途徑之生物分子)可降低細胞群體中出現藥物抗性之可能性,及/或降低治療之毒性。
一或多種其他醫藥劑,諸如化學治療劑、抗發炎劑、類固醇、免疫抑制劑、免疫腫瘤治療劑(immune-oncology agent)、代謝酶抑制劑、趨化介素受體抑制劑及磷酸酶抑制劑,以及靶向療法,諸如Bcr-Abl、Flt-3、EGFR、HER2、JAK、c-MET、VEGFR、PDGFR、c-Kit、IGF-1R、RAF、FAK、CDK2及CDK4/6激酶抑制劑(諸如WO 2006/056399中所述之彼等抑制劑),可與本揭示案之治療方法及方案組合用於治療癌症及實體瘤。其他劑諸如治療性抗體可與本揭示案之治療方法及方案組合用於治療癌症及實體瘤。該一或多種其他醫藥劑可同時或依序投與給患者。
如本文揭示之治療方法可與一或多種其他酶/蛋白/受體抑制劑療法組合用於治療疾病,諸如癌症及本文所述之其他疾病或病症。例如,本揭示案之治療方法及方案可與以下激酶之一或多種抑制劑組合用於治療癌症:Akt1、Akt2、Akt3、BCL2、CDK2、CDK4/6、TGF- βR、PKA、PKG、PKC、CaM-激酶、磷酸化酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IDH2、IGF-1R、IR-R、PDGFαR、PDGFβR、PI3K (α、β、γ、δ、及多種或選擇性)、CSF1R、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、PARP、Ron、Sea、TRKA、TRKB、TRKC、TAM 激酶(Axl、Mer、Tyro3)、FLT3、VEGFR/Flt2、Flt4、EphA1、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK及B-Raf。可與本揭示案之治療方法及方案組合用於治療癌症之抑制劑的非限制性實例包括FGFR抑制劑(FGFR1、FGFR2、FGFR3或FGFR4,例如,INCB62079)、EGFR抑制劑(亦稱為ErB-1或HER-1;例如,厄洛替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、奧希替尼(orsimertinib)、西妥昔單抗(cetuximab)、奈昔木單抗(necitumumab)或帕尼單抗(panitumumab))、VEGFR抑制劑或路徑阻斷劑(例如貝伐珠單抗(bevacizumab)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉菲尼(sorafenib)、阿西替尼(axitinib)、瑞格菲尼(regorafenib)、普納替尼(ponatinib)、卡博替尼(cabozantinib)、凡德他尼、雷莫蘆單抗(ramucirumab)、樂伐替尼(lenvatinib)、ziv-阿柏西普(ziv-aflibercept))、PARP抑制劑(例如,奧拉帕尼(olaparib)、魯卡帕尼(rucaparib)、維利帕尼(veliparib)或尼拉帕尼(niraparib))、JAK抑制劑(JAK1及/或JAK2,
例如,魯索替尼(ruxolitinib)、
巴瑞替尼 (baricitinib) 、伊他替尼 (itacitinib) (INCB39110)、LSD1抑制劑(例如,INCB59872及INCB60003)、TDO抑制劑、PI3K-δ抑制劑(例如,INCB50465及INCB50797)、PI3K-γ抑制劑(諸如PI3K-γ選擇性抑制劑)、Pim抑制劑(例如,INCB53914)、CSF1R抑制劑、TAM受體酪胺酸激酶(Tyro-3、Axl及Mer)、腺苷受體拮抗劑(例如,A2a/A2b受體拮抗劑)、HPK1抑制劑、趨化介素受體抑制劑(例如,CCR2或CCR5抑制劑)、SHP1/2磷酸酶抑制劑、組織蛋白去乙醯酶抑制劑(HDAC) (諸如HDAC8抑制劑)、血管生成抑制劑、介白素受體抑制劑、溴及額外末端家族成員抑制劑(例如,溴結構域抑制劑或BET抑制劑,諸如INCB54329及INCB57643)、c-MET抑制劑(例如,卡馬替尼(capmatinib))、抗CD19抗體(例如,他法替他單抗(tafasitamab))、ALK2抑制劑(例如,INCB00928);或其組合。
在一些實施例中,本文所述之治療方法與PI3Kδ抑制劑之投與組合。在一些實施例中,本文所述之治療方法與JAK抑制劑之投與組合。在一些實施例中,本文所述之治療方法與JAK1或JAK2抑制劑(例如,巴瑞替尼或魯索替尼)之投與組合。在一些實施例中,本文所述之治療方法與JAK1抑制劑之投與組合。在一些實施例中,本文所述之治療方法與對JAK2具有選擇性之JAK1抑制劑之投與組合。
於組合療法中投與之示例抗體包括但不限於曲妥珠單抗(trastuzumab)(
例如,抗HER2)、蘭尼單抗(ranibizumab) (
例如,抗VEGF-A)、貝伐珠單抗(AVASTIN
TM,
例如,抗VEGF)、帕尼單抗(
例如,抗EGFR)、西妥昔單抗(
例如,抗EGFR)、瑞圖宣(rituxan) (
例如,抗CD20)及針對c-MET之抗體。
以下劑中之一或多者可與本揭示案之治療方法組合投與給患者且提供為非限制性清單:細胞生長抑制劑、順鉑(cisplatin)、多柔比星(doxorubicin)、剋癌易(taxotere)、紫杉醇(taxol)、依託泊苷(etoposide)、伊立替康(irinotecan)、抗癌妥(camptosar)、托泊替康(topotecan)、太平洋紫杉醇(paclitaxel)、多西他賽(docetaxel)、埃博黴素(epothilone)、他莫昔芬(tamoxifen)、5-氟尿嘧啶(5-fluorouracil)、胺甲喋呤(methotrexate)、替莫唑胺(temozolomide)、環磷醯胺(cyclophosphamide)、SCH 66336、R115777、L778,123、BMS 214662、IRESSA
TM(吉非替尼)、TARCEVA
TM(厄洛替尼)、針對EGFR內含子之抗體、ara-C、阿德力黴素(adriamycin)、癌得星(cytoxan)、吉西他濱(gemcitabine)、尿嘧啶氮芥(uracil mustard)、甲川氯(chlormethine)、異環磷醯胺(ifosfamide)、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、哌泊溴烷(pipobroman)、三乙烯三聚氰胺(triethylenemelamine)、三乙烯硫代磷胺(triethylenethiophosphoramine)、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、鏈脲黴素(streptozocin)、達卡巴嗪(dacarbazine)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-巰嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱(fludarabine phosphate)、奧沙利鉑(oxaliplatin)、雷可瓦寧(leucovirin)、ELOXATIN™ (奧沙利鉑)、噴司他汀(pentostatine)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、博來黴素(bleomycin)、放線菌素D (dactinomycin)、道諾黴素(daunorubicin)、多柔比星、表柔比星(epirubicin)、伊達比星(idarubicin)、光輝黴素(mithramycin)、去氧助間型黴素(deoxycoformycin)、絲裂黴素-C (mitomycin-C)、L-天冬醯胺酶、替尼泊苷17.α.-乙炔雌二醇(teniposide 17.alpha.-ethinylestradiol)、己烯雄酚(diethylstilbestrol)、睪固酮(testosterone)、普賴松(Prednisone)、氟甲睪酮(Fluoxymesterone)、丙酸屈他雄酮(Dromostanolone propionate)、睪內酯(testolactone)、乙酸甲地孕酮(megestrolacetate)、甲基普賴蘇濃(methylprednisolone)、甲基睪固酮、普賴蘇濃、曲安奈德(triamcinolone)、氯烯雌醚(chlorotrianisene)、羥助孕酮(hydroxyprogesterone)、胺魯米特(aminoglutethimide)、雌氮芥(estramustine)、乙酸甲羥助孕酮(medroxyprogesteroneacetate)、亮丙瑞林(leuprolide)、氟他胺(flutamide)、托瑞米芬(toremifene)、戈舍瑞林(goserelin)、卡鉑(carboplatin)、羥基脲(hydroxyurea)、安吖啶(amsacrine)、丙卡巴肼(procarbazine)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、左旋咪唑(levamisole)、納瓦濱(navelbene)、阿那曲唑(anastrazole)、來曲唑(letrazole)、卡培他濱(capecitabine)、瑞羅杉芬(reloxafine)、屈洛昔芬(droloxafine)、六甲基三聚氰胺(hexamethylmelamine)、癌思停(avastin)、HERCEPTIN
TM(曲妥珠單抗)、BEXXAR
TM(托西莫單抗(tositumomab))、VELCADE
TM(硼替佐米(bortezomib))、ZEVALIN
TM(替伊莫單抗(ibritumomab tiuxetan))、 TRISENOX
TM(三氧化砷)、XELODA
TM(卡培他濱)、長春瑞濱(vinorelbine)、卟菲爾鈉(porfimer)、ERBITUX
TM(西妥昔單抗)、噻替派(thiotepa)、六甲蜜胺(altretamine)、美法侖、曲妥珠單抗、來曲唑、氟維司群(fulvestrant)、依西美坦(exemestane)、異環磷醯胺、利妥昔單抗(rituximab)、C225 (西妥昔單抗)、坎帕斯(Campath) (阿倫單抗(alemtuzumab))、氯法拉濱(clofarabine)、克拉屈濱(cladribine)、阿非迪黴素(aphidicolon)、瑞圖宣、舒尼替尼、達沙替尼(dasatinib)、替紮西他濱(tezacitabine)、Sml1、氟達拉濱、噴司他汀、曲阿平(triapine)、地多西(didox)、曲米西(trimidox)、阿米西(amidox)、3-AP及MDL-101,731。
本揭示案之治療方法及方案可進一步與其他治療癌症之方法,例如藉由化學療法、放射療法、腫瘤靶向療法、輔助療法、免疫療法或手術組合使用。免疫療法之實例包括細胞介素治療(例如,干擾素、GM-CSF、G-CSF、IL-2)、CRS-207免疫療法、癌症疫苗、單株抗體、雙特異性或多特異性抗體、抗體藥物結合物、過繼性T細胞轉移、Toll受體促效劑、RIG-I促效劑、溶瘤性病毒療法及免疫調節小分子(包括沙利度胺(thalidomide)或JAK1/2抑制劑、PI3Kδ抑制劑及諸如此類)。化合物可與一或多種抗癌藥物(諸如化學治療劑)組合投與。化學治療劑之實例包括以下項中之任一者:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿侖單抗、阿利維A酸(alitretinoin)、別嘌呤醇(allopurinol)、六甲蜜胺、阿那曲唑(anastrozole)、三氧化二砷(arsenic trioxide)、天冬醯胺酸酶(asparaginase)、阿紮胞苷(azacitidine)、貝伐珠單抗、貝沙羅汀(bexarotene)、巴瑞替尼、博萊黴素、硼替佐米、靜脈劑型白消安(busulfan intravenous)、經口劑型白消安(busulfan oral)、卡普睪酮(calusterone)、卡培他濱、卡鉑、卡莫司汀、西妥昔單抗、苯丁酸氮芥、順鉑、克拉屈濱、氯法拉濱、環磷醯胺、阿糖胞苷、達卡巴嗪、放線菌素D、達肝素鈉(dalteparin sodium)、達沙替尼、道諾黴素、地西他濱(decitabine)、地尼白介素(denileukin)、地尼白介素-毒素連接物(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他賽、多柔比星、丙酸屈他雄酮、依庫珠單抗(eculizumab)、艾卡哚司他(epacadostat)、表柔比星、厄洛替尼、雌氮芥、磷酸依託泊苷、依託泊苷、依西美坦、檸檬酸芬太尼(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷、氟達拉濱、氟尿嘧啶、氟維司群、吉非替尼、吉西他濱、吉妥珠單抗奧佐米星(gemtuzumab ozogamicin)、乙酸戈舍瑞林、乙酸組胺瑞林(histrelin acetate)、替伊莫單抗、伊達比星、異環磷醯胺、甲磺酸伊馬替尼(imatinib mesylate)、干擾素α 2a (interferon alfa 2a)、伊立替康、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、來那度胺(lenalidomide)、來曲唑(letrozole)、甲醯四氫葉酸(leucovorin)、乙酸亮丙瑞林、左旋咪唑、洛莫司汀、氮芥(meclorethamine)、乙酸甲地孕酮、美法侖、巰基嘌呤(mercaptopurine)、胺甲喋呤、甲氧沙林(methoxsalen)、絲裂黴素C、米托坦、米托蒽醌、苯丙酸南諾龍(nandrolone phenpropionate)、奈拉濱(nelarabine)、諾菲單抗(nofetumomab)、奧沙利鉑、太平洋紫杉醇、帕米膦酸鹽(pamidronate)、帕尼單抗、培門冬酶(pegaspargase)、聚乙二醇非格司亭(pegfilgrastim)、培美曲塞二鈉(pemetrexed disodium)、噴司他丁、哌泊溴烷、普卡黴素(plicamycin)、丙卡巴肼、奎納克林(quinacrine)、拉布立酶(rasburicase)、利妥昔單抗、魯索替尼、索拉非尼、鏈脲黴素、舒尼替尼、蘋果酸舒尼替尼、他莫昔芬、替莫唑胺、替尼泊苷、睪內酯、沙利度胺、硫鳥嘌呤(thioguanine)、噻替派、托泊替康、托瑞米芬、托西莫單抗、曲妥珠單抗、維甲酸(tretinoin)、尿嘧啶氮芥、戊柔比星(valrubicin)、長春鹼、長春新鹼、長春瑞濱、伏立諾他(vorinostat)及唑來膦酸鹽(zoledronate)。
化學治療劑之其他實例包括蛋白體抑制劑(例如硼替佐米)、沙利度胺、瑞復美(revlimid)及DNA損傷劑,諸如美法崙、多柔比星、環磷醯胺、長春新鹼、依託泊苷、卡莫司汀及諸如此類。
示例類固醇包括皮質類固醇,諸如地塞米松(dexamethasone)或普賴松。
示例Bcr-Abl抑制劑包括甲磺酸伊馬替尼(GLEEVAC™)、尼羅替尼(nilotinib)、達沙替尼、博舒替尼(bosutinib)及普納替尼及醫藥學上可接受之鹽。其他示例適宜Bcr-Abl抑制劑包括美國專利第5,521,184號、WO 04/005281及美國第60/578,491號中所揭示之屬類及種類之化合物及其醫藥學上可接受之鹽。
示例適宜Flt-3抑制劑包括米哚妥林(midostaurin)、來他替尼(lestaurtinib)、利尼伐尼(linifanib)、舒尼替尼、馬來酸舒尼替尼、索拉菲尼、奎紮替尼(quizartinib)、克萊拉尼(crenolanib)、帕利替尼(pacritinib)、坦度替尼(tandutinib)、PLX3397及ASP2215以及其醫藥學上可接受之鹽。其他示例適宜Flt-3抑制劑包括如WO 03/037347、WO 03/099771及WO 04/046120中所揭示之化合物及其醫藥學上可接受之鹽。
示例適宜RAF抑制劑包括達拉菲尼(dabrafenib)、索拉菲尼及威羅菲尼(vemurafenib)以及其醫藥學上可接受之鹽。其他示例適宜RAF抑制劑包括如WO 00/09495及WO 05/028444中所揭示之化合物及其醫藥學上可接受之鹽。
示例適宜FAK抑制劑包括VS-4718、VS-5095、VS-6062、VS-6063、BI853520及GSK2256098以及其醫藥學上可接受之鹽。其他示例適宜FAK抑制劑包括如WO 04/080980、WO 04/056786、WO 03/024967、WO 01/064655、WO 00/053595及WO 01/014402中所揭示之化合物及其醫藥學上可接受之鹽。
示例適宜CDK4/6抑制劑包括帕博西尼(palbociclib)、瑞博西尼(ribociclib)、曲拉西尼(trilaciclib)、萊拉西尼(lerociclib)及阿貝西尼(abemaciclib)及其醫藥學上可接受之鹽。其他示例適宜CDK4/6抑制劑包括如WO 09/085185、WO 12/129344、WO 11/101409、WO 03/062236、WO 10/075074及WO 12/061156中所揭示之化合物及其醫藥學上可接受之鹽。
本揭示案之治療方法及方案可進一步與一或多種其他激酶抑制劑(包括伊馬替尼)組合使用,尤其用於治療對伊馬替尼或其他激酶抑制劑具有抗性之患者。
在一些實施例中,本揭示案之治療方法可與化學治療劑組合用於治療癌症,且與對單獨化學治療劑之反應相比,可改良治療反應,而其毒性效應不惡化。在一些實施例中,本揭示案之治療方法可與本文提供之化學治療劑組合使用。例如,用於治療多發性骨髓瘤之其他醫藥劑可包括但不限於美法侖、美法侖加普賴松[MP]、多柔比星、地塞米松及Velcade (硼替佐米)。用於治療多發性骨髓瘤之其他劑包括Bcr-Abl、Flt-3、RAF及FAK激酶抑制劑。在一些實施例中,該劑係烷基化劑、蛋白酶體抑制劑、皮質類固醇或免疫調節劑。烷化劑之實例包括環磷醯胺(CY)、美法崙(MEL)及苯達莫司汀(bendamustine)。在一些實施例中,蛋白酶體抑制劑係卡非佐米(carfilzomib)。在一些實施例中,皮質類固醇係地塞米松(DEX)。在一些實施例中,免疫調節劑係來那度胺(LEN)或泊馬度胺(pomalidomide) (POM)。加和或協同效應係組合本揭示案之治療方法與其他劑之期望結果。
本揭示案之治療方法可與結合至人PD-1或人PD-L1之抗體或其抗原結合片段組合。
在一些實施例中,皮質類固醇(諸如地塞米松)與本揭示案之治療方法組合投與給患者,其中地塞米松間歇投與而非連續投與。
本文所述之治療方法可與另一種免疫原性劑,諸如癌細胞、經純化腫瘤抗原(包括重組蛋白、肽及碳水化合物分子)、細胞、及經編碼免疫刺激細胞介素之基因轉型之細胞組合。可使用之腫瘤疫苗之非限制性實例包括黑色素瘤抗原之肽,諸如gp100、MAGE抗原、Trp-2、MARTI及/或酪胺酸酶之肽、或經轉型以表現細胞介素GM-CSF之腫瘤細胞。
本文所述之治療方法可與疫苗接種方案組合使用以用於治療癌症。在一些實施例中,轉導腫瘤細胞以表現GM-CSF。在一些實施例中,腫瘤疫苗包括來自牽涉於人類癌症之病毒之蛋白,此等病毒諸如人乳頭瘤病毒(HPV)、肝炎病毒(HBV及HCV)及卡波西氏疱疹肉瘤病毒(KHSV)。在一些實施例中,本揭示案之治療方法及方案可與腫瘤特異性抗原諸如自腫瘤組織本身分離之熱休克蛋白組合使用。在一些實施例中,本文所述治療方法可與樹突狀細胞免疫組合以活化有效抗腫瘤反應。
本揭示案之治療方法可與將表現Feα或Feγ受體之效應細胞靶向腫瘤細胞的雙特異性大環肽組合使用。本揭示案之治療方法亦可與活化宿主免疫反應性之大環肽組合。
在一些其他實施例中,本揭示案之治療方法與其他治療劑在骨髓移植或幹細胞移植之前、期間及/或之後投與給患者組合。本揭示案之治療方法及方案可與骨髓移植組合使用以用於治療多種造血源性腫瘤。
當向患者投與多於一種醫藥劑時,如前述實施例中之任一者所述,它們可同時、單獨、依序或組合投與(
例如,對於多於兩種劑)。
安全且有效投與大部分此等化學治療劑之方法為熟習此項技術者已知。另外,其投與闡述於標準文獻中。例如,許多化學治療劑之投與闡述於「Physicians' Desk Reference」 (PDR,例如1996版,Medical Economics Company,Montvale,NJ)中,其揭示內容如同所闡述以全文引用之方式併入本文中。
II. 免疫檢查點療法
本文所述之治療方法可與一或多種免疫檢查點抑制劑組合使用以治療疾病,諸如癌症或感染。示範性免疫檢查點抑制劑包括針對免疫檢查點分子(諸如CBL-B、CD20、CD28、CD40、CD70、CD122、CD96、CD73、CD47、CDK2、GITR、CSF1R、JAK、PI3K δ、PI3K γ、TAM、精胺酸酶、HPK1、CD137 (亦稱作4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、TLR (TLR7/8)、TIGIT、CD112R、VISTA、PD-1、PD-L1及PD-L2)之抑制劑。在一些實施例中,免疫檢查點分子係選自CD27、CD28、CD40、ICOS、OX40、GITR及CD137之刺激性檢查點分子。在一些實施例中,免疫檢查點分子係選自A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3、TIGIT及VISTA之抑制性檢查點分子。在一些實施例中,本文提供之化合物可與一或多種選自以下之劑組合使用:KIR抑制劑、TIGIT抑制劑、LAIR1抑制劑、CD160抑制劑、2B4抑制劑及TGFR β抑制劑。
在一些實施例中,本文提供之鹽治療方法可與免疫檢查點分子例如OX40、CD27、GITR及CD137 (亦稱為4-1BB)之一或多種促效劑組合使用。
在一些實施例中,免疫檢查點分子之抑制劑係抗PD1抗體、抗PD-L1抗體或抗CTLA-4抗體。
在一些實施例中,免疫檢查點分子之抑制劑係PD-1或PD-L1之抑制劑,例如抗PD-1或抗PD-L1單株抗體。在一些實施例中,抗PD-1或抗PD-L1抗體係尼沃魯單抗(nivolumab)、派姆單抗(pembrolizumab)、阿替珠單抗(atezolizumab)、德瓦魯單抗(durvalumab)、阿維魯單抗(avelumab)、塞米匹利單抗(cemiplimab)、阿替珠單抗、阿維魯單抗、替雷利珠單抗(tislelizumab)、斯巴達珠單抗(spartalizumab) (PDR001)、塞曲利單抗(cetrelimab) (JNJ-63723283)、特瑞普利單抗(toripalimab) (JS001)、卡瑞利珠單抗(camrelizumab) (SHR-1210)、信迪利單抗(sintilimab) (IBI308)、AB122 (GLS-010)、AMP-224、AMP-514/MEDI-0680、BMS936559、JTX-4014、BGB-108、SHR-1210、MEDI4736、FAZ053、BCD-100、KN035、CS1001、BAT1306、LZM009、AK105、HLX10、SHR-1316、CBT-502 (TQB2450)、A167 (KL-A167)、STI-A101 (ZKAB001)、CK-301、BGB-A333、MSB-2311、HLX20、TSR-042或LY3300054。在一些實施例中,PD-1或PD-L1之抑制劑係美國專利第7,488,802號、第7,943,743號、第8,008,449號、第8,168,757號、第8,217,149號或第10,308,644號;美國公開案第2017/0145025號、第2017/0174671號、第2017/0174679號、第2017/0320875號、第2017/0342060號、第2017/0362253號、第2018/0016260號、第2018/0057486號、第2018/0177784號、第2018/0177870號、第2018/0179179號、第2018/0179201號、第2018/0179202號、第2018/0273519號、第2019/0040082號、第2019/0062345號、第2019/0071439號、第2019/0127467號、第2019/0144439號、第2019/0202824號、第2019/0225601號、第2019/0300524號或第2019/0345170號;PCT公開案第WO 03042402號、第WO 2008156712號、第WO 2010089411號、第WO 2010036959號、第WO 2011066342號、第WO 2011159877號、第WO 2011082400號或第WO 2011161699號中揭示之PD-1或PD-L1之抑制劑,該等專利各自以全文引用之方式併入本文中。在一些實施例中,PD-L1之抑制劑係INCB086550。
在一些實施例中,抗體係抗PD-1抗體,例如抗PD-1單株抗體。在一些實施例中,抗PD-1抗體係尼沃魯單抗、瑞替凡利單抗(retifanlimab)、派姆單抗、塞米匹利單抗、斯巴達珠單抗、卡瑞利珠單抗、塞曲利單抗、特瑞普利單抗、信迪利單抗、AB122、AMP-224、JTX-4014、BGB-108、BCD-100、BAT1306、LZM009 、AK105、HLX10或TSR-042。在一些實施例中,抗PD-1抗體係尼沃魯單抗、派姆單抗、塞米匹利單抗、斯巴達珠單抗、卡瑞利珠單抗、塞曲利單抗、特瑞普利單抗或信迪利單抗。在一些實施例中,抗PD-1抗體係派姆單抗。在一些實施例中,抗PD-1抗體係尼沃魯單抗。在一些實施例中,抗PD-1單株抗體係瑞替凡利單抗。在一些實施例中,抗PD-1抗體係塞米匹利單抗。在一些實施例中,抗PD-1抗體係斯巴達珠單抗。在一些實施例中,抗PD-1抗體係卡瑞利珠單抗。在一些實施例中,抗PD-1抗體係塞曲利單抗。在一些實施例中,抗PD-1抗體係特瑞普利單抗。在一些實施例中,抗PD-1抗體係信迪利單抗。在一些實施例中,抗PD-1抗體係AB122。在一些實施例中,抗PD-1抗體係AMP-224。在一些實施例中,抗PD-1抗體係JTX-4014。在一些實施例中,抗PD-1抗體係BGB-108。在一些實施例中,抗PD-1抗體係BCD-100。在一些實施例中,抗PD-1抗體係BAT1306。在一些實施例中,抗PD-1抗體係LZM009。在一些實施例中,抗PD-1抗體係AK105。在一些實施例中,抗PD-1抗體係HLX10。在一些實施例中,抗PD-1抗體係TSR-042。在一些實施例中,抗PD-1單株抗體係尼沃魯單抗或派姆單抗。在一些實施例中,抗PD1抗體係SHR-1210。其他抗癌劑包括抗體治療劑,諸如4-1BB (例如,烏瑞魯單抗(urelumab)、烏托米單抗(utomilumab))。在一些實施例中,免疫檢查點分子之抑制劑係PD-L1之抑制劑,例如抗PD-L1單株抗體。在一些實施例中,抗PD-L1單株抗體係阿替珠單抗、阿維魯單抗、德瓦魯單抗、替雷利珠單抗、BMS-935559、MEDI4736、阿替珠單抗(MPDL3280A;亦稱為RG7446)、阿維魯單抗(MSB0010718C)、FAZ053、KN035、CS1001、SHR-1316、CBT-502、A167、STI-A101、CK-301、BGB-A333、MSB-2311、HLX20或LY3300054。在一些實施例中,抗PD-L1抗體係阿替珠單抗、阿維魯單抗、德瓦魯單抗或替雷利珠單抗。在一些實施例中,抗PD-L1抗體係阿替珠單抗。在一些實施例中,抗PD-L1抗體係阿維魯單抗。在一些實施例中,抗PD-L1抗體係德瓦魯單抗。在一些實施例中,抗PD-L1抗體係替雷利珠單抗。在一些實施例中,抗PD-L1抗體係BMS-935559。在一些實施例中,抗PD-L1抗體係MEDI4736。在一些實施例中,抗PD-L1抗體係FAZ053。在一些實施例中,抗PD-L1抗體係KN035。在一些實施例中,抗PD-L1抗體係CS1001。在一些實施例中,抗PD-L1抗體係SHR-1316。在一些實施例中,抗PD-L1抗體係CBT-502。在一些實施例中,抗PD-L1抗體係A167。在一些實施例中,抗PD-L1抗體係STI-A101。在一些實施例中,抗PD-L1抗體係CK-301。在一些實施例中,抗PD-L1抗體係BGB-A333。在一些實施例中,抗PD-L1抗體係MSB-2311。在一些實施例中,抗PD-L1抗體係HLX20。在一些實施例中,抗PD-L1抗體係LY3300054。
在一些實施例中,免疫檢查點分子之抑制劑係結合至PD-L1之小分子,或其醫藥學上可接受之鹽。在一些實施例中,免疫檢查點分子之抑制劑係結合至且內化PD-L1之小分子,或其醫藥學上可接受之鹽。在一些實施例中,免疫檢查點分子之抑制劑係選自US 2018/0179201、US 2018/0179197、US 2018/0179179、US 2018/0179202、US 2018/0177784、US 2018/0177870、美國第16/369,654號(2019年3月29日提交)及美國第62/688,164號中之化合物或其醫藥學上可接受之鹽,該等專利各自以全文引用之方式併入本文中。
在一些實施例中,免疫檢查點分子之抑制劑係KIR、TIGIT、LAIR1、CD160、2B4及TGFR β之抑制劑。
在一些實施例中,抑制劑係MCLA-145。
在一些實施例中,免疫檢查點分子之抑制劑係CTLA-4之抑制劑,例如抗CTLA-4抗體。在一些實施例中,抗CTLA-4抗體係伊匹單抗(ipilimumab)、曲美目單抗(tremelimumab)、AGEN1884或CP-675,206。
在一些實施例中,免疫檢查點分子之抑制劑係LAG3之抑制劑,例如抗LAG3抗體。在一些實施例中,抗LAG3抗體係BMS-986016、LAG525、INCAGN2385或依替莫德(eftilagimod) α (IMP321)。
在一些實施例中,免疫檢查點分子之抑制劑係CD73之抑制劑。在一些實施例中,CD73之抑制劑係奧來單抗(oleclumab)。
在一些實施例中,免疫檢查點分子之抑制劑係TIGIT之抑制劑。在一些實施例中,TIGIT之抑制劑係OMP-31M32。
在一些實施例中,免疫檢查點分子之抑制劑係VISTA之抑制劑。在一些實施例中,VISTA之抑制劑係JNJ-61610588或CA-170。
在一些實施例中,免疫檢查點分子之抑制劑係B7-H3之抑制劑。在一些實施例中,B7-H3之抑制劑係恩妥珠單抗(enoblituzumab)、MGD009或8H9。
在一些實施例中,免疫檢查點分子之抑制劑係KIR之抑制劑。在一些實施例中,KIR之抑制劑係利魯單抗(lirilumab)或IPH4102。
在一些實施例中,免疫檢查點分子之抑制劑係A2aR之抑制劑。在一些實施例中,A2aR之抑制劑係CPI-444。
在一些實施例中,免疫檢查點分子之抑制劑係TGF-β之抑制劑。在一些實施例中,TGF-β之抑制劑係曲貝德生(trabedersen)、加魯色替尼(galusertinib)或M7824。
在一些實施例中,免疫檢查點分子之抑制劑係PI3K-γ之抑制劑。在一些實施例中,PI3K-γ之抑制劑係IPI-549。
在一些實施例中,免疫檢查點分子之抑制劑係CD47之抑制劑。在一些實施例中,CD47之抑制劑係Hu5F9-G4或TTI-621。
在一些實施例中,免疫檢查點分子之抑制劑係CD73之抑制劑。在一些實施例中,CD73之抑制劑係MEDI9447。
在一些實施例中,免疫檢查點分子之抑制劑係CD70之抑制劑。在一些實施例中,CD70之抑制劑係庫薩土珠單抗(cusatuzumab)或BMS-936561。
在一些實施例中,免疫檢查點分子之抑制劑係TIM3之抑制劑,例如抗TIM3抗體。在一些實施例中,抗TIM3抗體係INCAGN2390、MBG453或TSR-022。
在一些實施例中,免疫檢查點分子之抑制劑係CD20之抑制劑,例如抗CD20抗體。在一些實施例中,抗CD20抗體係奧妥珠單抗(obinutuzumab)或利妥昔單抗。
在一些實施例中,免疫檢查點分子之促效劑係OX40、CD27、CD28、GITR、ICOS、CD40、TLR7/8及CD137 (亦稱為4-1BB)之促效劑。
在一些實施例中,CD137之促效劑為烏瑞魯單抗(urelumab)。在一些實施例中,CD137之促效劑係烏托米單抗。
在一些實施例中,免疫檢查點分子之促效劑係GITR之抑制劑。在一些實施例中,GITR之促效劑係TRX518、MK-4166、INCAGN1876、MK-1248、AMG228、BMS-986156、GWN323、MEDI1873或MEDI6469。在一些實施例中,免疫檢查點分子之促效劑係OX40之促效劑,例如OX40促效劑抗體或OX40L融合蛋白。在一些實施例中,抗OX40抗體係INCAGN01949、MEDI0562 (他瓦利單抗(tavolimab))、MOXR-0916、PF-04518600、GSK3174998、BMS-986178或9B12。在一些實施例中,OX40L融合蛋白係MEDI6383。
在一些實施例中,免疫檢查點分子之促效劑係CD40之促效劑。在一些實施例中,CD40之促效劑係CP-870893、ADC-1013、CDX-1140、SEA-CD40、RO7009789、JNJ-64457107、APX-005M或Chi Lob 7/4。
在一些實施例中,免疫檢查點分子之促效劑係ICOS之促效劑。在一些實施例中,ICOS之促效劑為GSK-3359609、JTX-2011或MEDI-570。
在一些實施例中,免疫檢查點分子之促效劑係CD28之促效劑。在一些實施例中,CD28之促效劑係西拉利珠單抗(theralizumab)。
在一些實施例中,免疫檢查點分子之促效劑係CD27之促效劑。在一些實施例中,CD27之促效劑係瓦利魯單抗(varlilumab)。
在一些實施例中,免疫檢查點分子之促效劑係TLR7/8之促效劑。在一些實施例中,TLR7/8之促效劑係MEDI9197。
本揭示案之化合物可與雙特異性抗體組合使用。在一些實施例中,雙特異性抗體之結構域之一靶向PD-1、PD-L1、CTLA-4、GITR、OX40、TIM3、LAG3、CD137、ICOS、CD3或TGFβ受體。在一些實施例中,雙特異性抗體結合至PD-1及PD-L1。在一些實施例中,結合至PD-1及PD-L1之雙特異性抗體係MCLA-136。在一些實施例中,雙特異性抗體結合至PD-L1及CTLA-4。在一些實施例中,結合至PD-L1及CTLA-4之雙特異性抗體係AK104。
在一些實施例中,本揭示案之化合物可與一或多種代謝酶抑制劑組合使用。在一些實施例中,代謝酶抑制劑係IDO1、TDO或精胺酸酶之抑制劑。IDO1抑制劑之實例包括艾卡哚司他、NLG919、BMS-986205、PF-06840003、IOM2983、RG-70099及LY338196。精胺酸酶抑制劑之抑制劑包括INCB1158。
如貫穿全文所提供,其他化合物、抑制劑、劑等可與本發明化合物以單一或連續劑型組合,或可以單獨劑型同時或依序投與。
醫藥調配物及劑型
當用作藥物時,本文所述之培米替尼可以醫藥組成物形式投與,此等醫藥組成物係指本文所述之培米替尼與至少一種醫藥學上可接受之載劑之組合。此等組成物可以醫藥技術中熟知之方式製備,且可藉由多種路徑投與,視需要局部治療抑或全身性治療及欲治療之區域而定。投與可為局部投與(包括眼部及黏膜投與,包括鼻內、陰道及直腸遞送)、肺部投與(例如藉由吸入或吹入粉末或氣溶膠,包括藉由噴霧器;氣管內、鼻內、表皮或透皮投與)、經眼、經口或非經腸投與。用於經眼遞送之方法可包括局部投與(滴眼劑)、結膜下、眼周或玻璃體內註射或藉由球囊導管或外科手術放置於結膜囊中之眼科插入物引入。非經腸投與包括靜脈內、動脈內、皮下、腹膜內或肌內註射或輸注;或顱內投與,例如鞘內或腦室內投與。非經腸投與可呈單次濃注劑量之形式,或可例如藉由連續灌注泵達成。用於局部投與之醫藥組成物及調配物可包括透皮貼劑、軟膏、洗劑、乳膏、凝膠、滴劑、栓劑、噴霧劑、液體及粉末。習知醫藥載劑、水性、粉末或油性基質、增稠劑及其類似物可為必需或可需的。
本揭示案亦包括醫藥組成物,其包含作為活性成分之培米替尼與一或多種醫藥學上可接受之載劑之組合。在製備本文所述之組成物時,活性成分通常與賦形劑混合、由賦形劑稀釋、或包封在呈例如膠囊、囊劑、紙或其他容器形式之此載劑內。當賦形劑充當稀釋劑時,其可為固體、半固體或液體材料,其用作活性成分之媒劑、載劑或介質。因此,組成物可為錠劑、丸劑、粉末、口含錠、小藥囊、扁囊劑、酏劑、懸浮液、乳液、溶液、糖漿、氣霧劑(作為固體或處於液體介質中)、含有例如多至10重量%活性化合物之軟膏、軟明膠膠囊及硬明膠膠囊、栓劑、無菌可注射溶液及無菌包裝粉末。
在製備調配物時,可以研磨活性化合物以提供適當粒子尺寸,之後將其與其他成分組合。若活性化合物基本上不溶,則可以將其研磨成小於200目之粒子尺寸。若活性化合物實質上可溶於水,則可藉由研磨來調節粒徑,以在調配物中提供實質上均勻之分佈,例如約40目。
適宜賦形劑之一些實例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、澱粉、阿拉伯膠、磷酸鈣、藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、糖漿及甲基纖維素。此等調配物可另外包括:潤滑劑,諸如滑石、硬脂酸鎂及礦物油;潤濕劑;乳化劑及懸浮劑;防腐劑,諸如羥基苯甲酸甲酯及羥基苯甲酸丙酯;甜味劑;及調味劑。可調配本文所述之組成物以便在藉由採用此項技術已知之程序向患者投與後提供活性成分之快速、持續或延遲釋放。
組成物可調配成單位劑型,每一劑量含有約4至約5 mg、或約4.5 mg之活性成分。在一些實施例中,單位劑型包含約9 mg活性成分。在一些實施例中,單位劑型包含約13.5 mg活性成分。術語「單位劑型」係指適宜作為人類個體及其他哺乳動物之單位劑量之物理上離散的單位,各單位包含預定量之經計算產生所要治療效果之活性物質以及適宜藥物賦形劑。
活性化合物可在寬劑量範圍內有效,且通常以醫藥學上有效之量投與。然而,應理解,實際投與之化合物之量通常由醫師根據相關情況確定,此等相關情況包括欲治療之疾患、選擇之投與路徑、投與之實際化合物、個體患者之年齡、體重及反應、患者症狀之嚴重性及其類似情況。
為了製備固體組成物諸如錠劑,將主要活性成分與醫藥賦形劑混合以形成含有培米替尼之均勻混合物的固體預調配組成物。當將此等預調配組成物稱作均勻時,活性成分通常均勻分散於組成物中,使得該組成物可容易地再分成同等有效單位劑型,諸如錠劑、丸劑及膠囊。然後將該固體預調配物細分為上文所述類型之含有例如0.1至約500 mg本揭示案之活性成分的單位劑型。
在一些實施例中,培米替尼經口投與。在一些實施例中,培米替尼每天一次投與。在一些實施例中,培米替尼以約5 mg至約20 mg之日劑量投與。在一些實施例中,培米替尼以約10 mg至約15 mg之日劑量投與。在一些實施例中,培米替尼以約13.5 mg之日劑量投與。在一些實施例中,培米替尼以錠劑形式投與。在一些實施例中,錠劑包含約0.5 mg至約10 mg培米替尼。在一些實施例中,錠劑包含約0.5 mg至約5 mg培米替尼。在一些實施例中,錠劑包含約2 mg、約4.5 mg、約9 mg、約13.5 mg或約18 mg培米替尼。在一些實施例中,錠劑包含約0.5 mg培米替尼。在一些實施例中,錠劑包含約2 mg培米替尼。在一些實施例中,錠劑包含約4.5 mg培米替尼。在一些實施例中,錠劑包含約9 mg培米替尼。在一些實施例中,錠劑包含約13.5 mg培米替尼。在一些實施例中,錠劑包含約18 mg培米替尼。
可以將本揭示案之錠劑或丸劑包衣或以其他方式混配以提供具有延長作用之優點的劑型。例如,錠劑或丸劑可包含內部劑量組分及外部劑量組分,後者呈位於前者之上之包膜形式。該兩種組分可由腸溶層分開,該腸溶層用於抵抗胃中之崩解且允許內部組分完整地進入十二指腸或延遲釋放。多種材料可用於此類腸溶層或包衣,此類材料包括多種聚合酸及聚合酸與諸如蟲膠、十六醇及乙酸纖維素之材料之混合物。
可摻入本文所述之培米替尼或組成物以經口投與或藉由注射投與之液體形式包括水性溶液、適當調味之糖漿、水性或油性懸浮液及具有食用油諸如棉籽油、芝麻油、椰子油或花生油之調味乳液、以及酏劑及類似醫藥媒劑。
用於吸入或吹入之組成物包括醫藥學上可接受之水性或有機溶劑或其混合物中之溶液及懸浮液,及粉末。液體或固體組成物可包含如上文所述之適宜的醫藥學上可接受之賦形劑。在一些實施例中,組成物藉由經口或經鼻呼吸途徑投與以產生局部或全身作用。可藉由使用惰性氣體將組成物霧化。霧化溶液可直接從霧化裝置呼吸,或者霧化裝置可連接至面罩帳幕或間歇正壓呼吸機。溶液、懸浮液或粉末組成物可從以適當方式遞送調配物之裝置經口或經鼻投與。
向患者投與之化合物或組成物之量將根據所投與之藥物、所投與之目的(諸如預防或療法)、患者之狀況、投與方式等而變化。在治療應用中,可以足以治癒或至少部分阻止疾病及其併發症之症狀的量向已經罹患疾病之患者投與組成物。有效劑量將取決於所治療之疾病狀況以及主治醫生根據諸如疾病之嚴重性、患者之年齡、體重及一般狀況等因素所作出之判斷。
向患者投與之組成物可呈上文所述之醫藥組成物之形式。這些組成物可藉由常規滅菌技術滅菌,或者可無菌過濾。可包裝水性溶液以按原樣使用或將其凍乾,將經凍乾製劑在投與前與無菌水性載劑組合。化合物製劑之pH值通常在3至11之間,更佳地5至9,最佳地7至8。應當理解,使用某些前述賦形劑、載劑或穩定劑將導致形成醫藥用鹽類。
培米替尼之治療劑量可根據例如治療所欲達成之特定用途、化合物之投與方式、患者之健康及狀況以及處方醫師之判斷而變化。培米替尼在醫藥組成物中之比率或濃度可根據許多因素而變化,此等因素包括劑量、化學特性(例如疏水性)及投與路徑。例如,培米替尼可提供於含有約0.1至約10重量/體積之化合物的水性生理緩沖溶液中,以用於非經腸投與。一些典型的劑量範圍為約1 µg/kg至約1 g/kg體重/天。在一些實施例中,劑量範圍為約0.01 mg/kg至約100 mg/kg體重/天。劑量可能取決於以下變量,諸如疾病或病症之類型及進展程度、特定患者之總體健康狀況、所選化合物之相對生物學功效、賦形劑之調配及其投與路徑。有效劑量可由源自
活體外或動物模型測試系統之劑量反應曲線中推斷出。
培米替尼還可與一或多種其他活性成分組合調配,此等活性成分可包括任何醫藥劑,諸如抗病毒劑、疫苗、抗體、免疫增強劑、免疫抑制劑、抗炎劑等。
本文所述之恩諾單抗可以醫藥組成物及至少一種醫藥學上可接受之賦形劑的形式投與。此等組成物可以醫藥技術中熟知之方式製備,且可藉由多種路徑投與,視需要局部治療抑或全身性治療及欲治療之區域而定。醫藥組成物可呈多種形式。此等形式包括,例如,液體、半固體及固體劑型,諸如液體溶液(例如,可注射及可輸注溶液)、分散體或懸浮液、錠劑、丸劑、粉末、脂質體及栓劑。較佳的形式可取決於預期的投與模式及治療應用。通常,本文所述之劑之組成物呈可注射或可輸注溶液之形式。
恩諾單抗可藉由多種方法投與。對於許多應用,投與途徑係以下之一:靜脈注射或輸注(IV)、皮下注射(SC)、腹膜內(IP)或肌內注射。亦可使用關節內遞送。亦可使用其他非經腸投與模式。此類模式之實例包括:動脈內、鞘內、囊內、眶內、心臟內、皮內、經氣管、皮下、關節內、囊下、蛛網膜下腔、脊髓內、以及硬膜外及胸骨內註射。
標記化合物
本揭示案之另一個方面係關於標記之培米替尼(放射性標記、螢光標記、同位素標記等),其不僅可用於成像技術,且可用於
體外及
體內測定。
本揭示案進一步包括同位素標記之培米替尼。「同位素」或「放射性標記之」化合物為培米替尼,其中一或多個原子經具有與通常在自然界中發現(亦即天然存在)之原子質量或質量數不同之原子質量或質量數的原子置換或取代。可摻入本揭示案之化合物中之適宜放射性核種包括但不限於
2H (對於氘亦寫為D)、
3H (對於氚亦寫為T)、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
18F、
35S、
36Cl、
82Br、
75Br、
76Br、
77Br、
123I、
124I、
125I及
131I。例如,本揭示案之化合物中之一或多個氫原子可由氘原子置換,可視情況地由氘原子取代。
培米替尼之一或多個組成原子可以天然或非天然豐度由原子之同位素置換或取代。在一些實施例中,培米替尼包括至少一個氘原子。例如,本文呈現之化合物中之一或多個氫原子可由氘置換或取代。在一些實施例中,化合物包括兩或更多個氘原子。在一些實施例中,化合物包括1-2個、1-3個、1-4個、1-5個或1-6個氘原子。在一些實施例中,化合物中之所有氫原子可由氘原子置換或取代。
將同位素納入有機化合物中之合成方法係此項技術中已知的(Deuterium Labeling in Organic Chemistry,Alan F. Thomas (New York,N.Y.,Appleton-Century-Crofts,1971;The Renaissance of H/D Exchange,Jens Atzrodt,Volker Derdau,Thorsten Fey及Jochen Zimmermann,Angew. Chem. Int. 2007版,7744-7765;James R. Hanson之The Organic Chemistry of Isotopic Labelling,Royal Society of Chemistry,2011)。經同位素標記之化合物可用於各種研究,諸如NMR光譜、代謝實驗及/或測定。
用較重同位素(諸如氘)取代可提供某些治療優點,此係由更高之代謝穩定性引起,例如
活體內半衰期延長或劑量需求降低,因此此在一些情況下可能係較佳的。(參見
例如A. Kerekes 等人
J. Med. Chem.2011,54,201-210;R. Xu 等人
J. Label Compd. Radiopharm.2015,58,308-312)。具體地,在一或多個代謝位點處之取代可提供一或多種治療優點。
應理解,「放射性標記之化合物」或「標記之化合物」係已摻入至少一種放射性核種之化合物。在一些實施例中,放射性核種選自由
3H及
14C組成之群。在一些實施例中,放射性核種選自由
11C、
18F、
75Br、
76Br及
77Br組成之群。
套組
本揭示案亦包括可用於例如治療癌症之套組,其包括一或多個容器,該一或多個容器含有包含治療有效量之培米替尼或其實施方案之任一者之醫藥組成物。此類套組可進一步包括一或多種不同的習知醫藥套組組件,
例如像具有一或多種醫藥學上可接受之載劑的容器、其他容器
等,如熟習此項技術者將容易清楚的。套組中亦可包括呈插頁或標籤形式之說明書,其指明欲投與之組分的量、投與指南、及/或混合此等組分之指南。
實例
將藉由具體實例更詳細地闡述本發明。以下實例係出於說明性目的而提供,且不意欲以任何方式限制本發明。熟習此項技術者將容易地認識到可改變或修改以產生基本上相同結果之各種非關鍵參數。
實例 A. RT112/84 及 UM-UC-14 體外增殖測定
在RT112/84及UM-UC-14膀胱癌細胞系中體外評定培米替尼加恩諾單抗(EV) (Padcev,Refdrug Inc.)對增殖之效應。簡而言之,將RT112/84及UM-UC-14細胞以1000個細胞/孔在96孔板上過夜。將培米替尼(劑量反應曲線從1至100 nM)單獨或與300、100或10 ng/mL EV組合添加到孔中。藉由Cell Titer glo (Promega)處理5天后在PHERAStar (BMG LABTECH)讀板器上測定活力。數據顯示,用培米替尼組合中間體及高劑量EV處理RT112/84細胞導致低劑量培米替尼之增殖減少。相比之下,用培米替尼組合EV處理UM-UC-14在高EV濃度下僅產生中等效應。
圖 1A係描繪用1至100 nM範圍內之不同濃度的培米替尼單獨或與300、100或10 ng/mL EV組合處理對RT112/84膀胱癌細胞系的細胞增殖之效應之圖。
圖 1B係描繪用1至100 nM範圍內之不同濃度的培米替尼單獨或與300、100或10 ng/mL EV組合處理對UM-UC-14膀胱癌細胞系的細胞增殖之效應之圖。
實例 B. 培米替尼對 Nectin-4 水平之 效應 RT112/84 體外 Nectin-4 受體密度
在RT112/84膀胱癌細胞系中體外評定培米替尼加恩諾單抗(「EV」) (Padcev,Refdrug Inc.)對Nectin-4受體密度之效應。簡而言之,將RT112/84細胞用100 nM培米替尼、100 nM EV或兩者之組合處理。然後通過流式細胞分析技術在具有Quantibrite藻紅蛋白(PE)珠(BD Biosciences貨號340495) 之LSRFortessa X-20儀器(BD Biosciences)上使用抗Nectin-4 PE結合抗體(RnD Systems貨號FAB2659)在治療後之不同時間點評定Nectin-4之受體密度(圖2A)。數據顯示,用 100 nM EV單獨或與100 nM培米替尼組合處理RT112/84細胞導致與靶內化相關之受體密度降低。相比之下,用100 nM培米替尼處理RT112/84細胞不會引起與靶內化相關之Nectin-4受體密度之變化。
圖 2A係描繪用(i) 100 nM培米替尼,(ii) 100 nM EV或(iii) 100 nM培米替尼及100 nM EV處理的RT112/84細胞中Nectin-4受體密度之圖。
RT112/84 體內 Nectin-4 受體密度
亦在6至8週齡NSG小鼠 (Jackson laboratories)之RT112/84膀胱癌異種移植模型(圖 2B)中在體內評定培米替尼加EV (Padcev,Refdrug Inc.)對Nectin-4受體密度之效應。將培米替尼於0.5%甲基纖維素中懸浮於5% N,N-二甲基乙醯胺(DMAC) + 50 mM檸檬酸鹽緩衝液中用於經口投與,且將EV懸浮於鹽水中用於靜脈內投與。簡而言之,在皮下接種懸浮於基質膠(Corning Life Sciences,Tewksbury,Mass)中之2x10
6RT112/84之前一天將小鼠左脇腹剃毛。在第16天,向小鼠給藥(i)媒劑;(ii) 0.3 mg/kg培米替尼;(iii) 1 mg/kg培米替尼;(iv) 3 mg/kg EV;(v) 0.3 mg/kg培米替尼及3 mg/kg EV;或(vi) 1 mg/kg培米替尼及3 mg/kg EV,且在投與後4小時收集腫瘤。然後將腫瘤處理成單細胞懸浮液,且通過流式細胞分析技術在具有Quantibrite藻紅蛋白(PE)珠(BD Biosciences貨號340495)之LSRFortessa X-20儀器(BD Biosciences)上使用抗Nectin-4 PE結合抗體(RnD Systems貨號FAB2659)評定Nectin-4之受體密度。數據顯示,用EV單獨或與培米替尼組合治療RT112/84荷瘤小鼠導致與靶內化相關之受體密度降低。相比之下,用培米替尼治療RT112/84荷瘤小鼠不會引起與靶內化相關之Nectin-4受體密度之變化。
圖 2B係描繪獲自投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤細胞中Nectin-4受體密度之圖。
RT112/84 體內 pERK 抑制
在6至8週齡NSG小鼠(Jackson laboratories)之RT112/84膀胱癌異種移植模型(圖3)中在體內評定培米替尼加EV (Padcev,Refdrug Inc.)對pERK抑制之效應。將培米替尼於0.5%甲基纖維素中懸浮於5% N,N-二甲基乙醯胺(DMAC) + 50 mM檸檬酸鹽緩衝液中用於經口投與,且將EV懸浮於鹽水中用於靜脈內投與。簡而言之,在皮下接種懸浮於基質膠(Corning Life Sciences,Tewksbury,Mass)中之2x10
6RT112/84之前一天將小鼠左脇腹剃毛。在第16天,向小鼠給藥(i)媒劑;(ii) 1 mg/kg培米替尼;(iii) 3 mg/kg EV;或(vi) 1 mg/kg培米替尼及3 mg/kg EV,且在投與後4小時收集腫瘤。然後處理腫瘤,並藉由MSD (Mesoscale)評定腫瘤裂解物之磷酸化ERK之水平。數據顯示,用培米替尼單獨或與EV組合治療RT112/84荷瘤小鼠導致ERK之磷酸化降低。相比之下,與媒劑治療之腫瘤相比,用EV單獨治療RT112/84荷瘤小鼠不會引起ERK磷酸化水平之變化。
圖 3係描繪獲自投與(i)媒劑,(ii) 1 mg/kg培米替尼,(iii) 3 mg/kg EV,或(iv) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤細胞中ERK之磷酸化之圖。
實例 C. 培米替尼與恩諾單抗之組合作用導致體內腫瘤生長控制增加 RT112/84 異種移植模型
在6至8週齡NSG小鼠(Jackson laboratories)之RT112/84膀胱癌(85061106,Sigma/ECACC,UK)異種移植模型(圖4)中評定組合培米替尼加EV (Padcev,Refdrug Inc.)之體內作用。將培米替尼於0.5%甲基纖維素中懸浮於5% N,N-二甲基乙醯胺(DMAC) + 50 mM檸檬酸鹽緩衝液中用於經口投與,且將EV懸浮於鹽水中用於靜脈內投與。簡而言之,在皮下接種懸浮於基質膠(Corning Life Sciences,Tewksbury,Mass)中之2x10
6RT112/84之前一天將小鼠左脇腹剃毛。在第7天,藉由遊標卡尺量測腫瘤尺寸,並藉由公式體積 = [L (長尺寸) x W2 (短尺寸)]/2估計體積。將小鼠隨機分為6組,每組10隻小鼠,平均體積大約(約200 mm
3)。在研究期間每週量測腫瘤3次。從第7天開始,向小鼠給藥(i)媒劑;(ii) 0.3 mg/kg培米替尼;(iii) 1 mg/kg培米替尼;(iv) 3 mg/kg EV;(v) 0.3 mg/kg培米替尼及3 mg/kg EV;或(vi) 1 mg/kg培米替尼及3 mg/kg EV。培米替尼每天經口投與一次(QD),持續10天,而EV每4天給藥一次(總共2劑)。數據顯示,當與對照媒劑組相比時,除培米替尼0.3 mg/kg外,所有治療均具有延遲腫瘤生長之治療作用。數據之Bliss獨立性(不受影響之部分)分析表明,當與各自之對照相比時,0.3 mg/kg培米替尼與3 mg/kg EV之組合產生腫瘤生長延遲之協同作用。
圖 4係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤體積之圖。
在單獨實驗中,將小鼠在第7天隨機分為9組,每組10隻小鼠,平均體積大約(約200 mm
3)。在療效研究期間(第21天)每週量測腫瘤3次。從第7天開始,向小鼠給藥(i)媒劑;(ii) 0.3 mg/kg培米替尼;(iii) 1 mg/kg培米替尼;(iv) 3 mg/kg EV;(v) 10 mg/kg EV;(vi) 0.3 mg/kg培米替尼及3 mg/kg EV;(vii) 0.3 mg/kg培米替尼及10 mg/kg EV;(viii) 1 mg/kg培米替尼及3 mg/kg EV;或(ix) 1 mg/kg培米替尼及10 mg/kg EV。培米替尼QD經口投與,持續10天,而EV每4天給藥一次(總共2劑)。數據顯示,高劑量EV可實現更大的腫瘤生長抑制,而與培米替尼組合無關,並且與低劑量3 mg/kg EV與高劑量1 mg/kg培米替尼組合之水平相似。此外,觀察小鼠以確定總體存活(圖6)。數據顯示,與對照或單組治療相比,高劑量EV與高劑量培米替尼組合在此等小鼠中產生更好的總體存活。
圖 5係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠之腫瘤體積之圖。
圖 6A係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠之整體存活之卡普蘭-麥爾圖。
圖 6B係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠於接種後100天之時段內之整體存活之卡普蘭-麥爾圖。
UM-UC-14 異種移植模型
亦在NSG小鼠之另一種癌症異種移植模型UM-UC-14 (08090509,Sigma/ECACC,UK)中評定組合培米替尼加EV之體內作用(圖7)。將培米替尼於0.5%甲基纖維素中懸浮於5% DMAC + 50 mM檸檬酸鹽緩衝液中用於經口投與,且將EV懸浮於1 x PBS中用於靜脈內投與。簡而言之,在皮下接種懸浮於基質膠(Corning Life Sciences,Tewksbury,Mass)中之5x10
6UM-UC-14之前一天將小鼠左脇腹剃毛。在第5天,藉由遊標卡尺量測腫瘤尺寸,並藉由公式體積 = [L (長尺寸) x W2 (短尺寸)]/2估計體積。將小鼠隨機分為6組,每組10隻小鼠,平均體積大約(約100 mm
3)。在研究期間每週量測腫瘤3次。從第5天開始,向小鼠給藥(i)媒劑;(ii) 0.3 mg/kg培米替尼;(iii) 1 mg/kg培米替尼;(iv) 3 mg/kg EV;(v) 0.3 mg/kg培米替尼及3 mg/kg EV;或(vi) 1 mg/kg培米替尼及3 mg/kg EV。培米替尼QD經口投與,持續10天,而EV每4天給藥一次(總共2劑)。數據顯示,當與對照媒劑組相比時,僅培米替尼1 mg/kg治療作為單一劑具有延遲腫瘤生長之治療作用,而培米替尼0.3 mg/kg及1 mg/kg與EV 3 mg/kg之兩種組合對延遲腫瘤生長具有顯著治療作用。數據之Bliss獨立性(不受影響之部分)分析表明,當與各自之對照相比時,0.3 mg/kg培米替尼與3 mg/kg EV之組合產生腫瘤生長延遲之協同作用。
圖 7係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之UM-UC-14荷瘤小鼠之腫瘤體積之圖。
除本文所述之彼等修改之外,本發明之各種修改亦將為熟習此項技術者根據以上描述顯而易知。此類修改亦意欲落入所附權利要求之範圍內。本申請案中所引用之每一參考文獻(包括所有專利、專利申請案及公開案)係以全文引用之方式併入本文中。
圖 1A係描繪對用1至100 nM範圍內之不同濃度的培米替尼單獨或與300、100或10 ng/mL EV組合處理之RT112/84膀胱癌細胞系的細胞增殖之效應之圖。
圖 1B係描繪對用1至100 nM範圍內之不同濃度的培米替尼單獨或與300、100或10 ng/mL EV組合處理之UM-UC-14膀胱癌細胞系的細胞增殖之效應之圖。
圖 2A係描繪用(i) 100 nM培米替尼,(ii) 100 nM恩諾單抗(EV)或(iii) 100 nM培米替尼及100 nM EV處理的RT112/84細胞中Nectin-4受體密度之圖。
圖 2B係描繪獲自投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤細胞中Nectin-4受體密度之圖。
圖 3係描繪獲自投與(i)媒劑,(ii) 1 mg/kg培米替尼,(iii) 3 mg/kg EV,或(iv) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤細胞中ERK之磷酸化之圖。
圖 4係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之RT112/84荷瘤小鼠之腫瘤體積之圖。
圖 5係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠之腫瘤體積之圖。
圖 6A係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠之整體存活之卡普蘭-麥爾(Kaplan-Meier)圖。
圖 6B係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 10 mg/kg EV,(vi) 0.3 mg/kg培米替尼及3 mg/kg EV,(vii) 0.3 mg/kg培米替尼及10 mg/kg EV,(viii) 1 mg/kg培米替尼及3 mg/kg EV或(ix) 1 mg/kg培米替尼及10 mg/kg EV之RT112/84荷瘤小鼠於接種後100天之時段內之整體存活之卡普蘭-麥爾圖。
圖 7係描繪投與(i)媒劑,(ii) 0.3 mg/kg培米替尼,(iii) 1 mg/kg培米替尼,(iv) 3 mg/kg EV,(v) 0.3 mg/kg培米替尼及3 mg/kg EV,或 (vi) 1 mg/kg培米替尼及3 mg/kg EV之UM-UC-14荷瘤小鼠之腫瘤體積之圖。
Claims (20)
- 一種治療患者之癌症之方法,其包含向該患者投與: (i) 培米替尼(pemigatinib)或其醫藥學上可接受之鹽;及 (ii) 恩諾單抗(enfortumab vedotin)。
- 如請求項1之方法,其中培米替尼與恩諾單抗同時投與。
- 如請求項1之方法,其中培米替尼與恩諾單抗依序投與。
- 如請求項1至3中任一項之方法,其中培米替尼經口投與。
- 如請求項1至4中任一項之方法,其中培米替尼以約1 mg至約20 mg之日劑量投與。
- 如請求項1至4中任一項之方法,其中培米替尼以約13.5 mg之日劑量投與。
- 如請求項1至4中任一項之方法,其中培米替尼以約9 mg之日劑量投與。
- 如請求項1至7中任一項之方法,其中恩諾單抗靜脈內投與 。
- 如請求項1至8中任一項之方法,其中恩諾單抗以約0.5 mg/kg至約2.0 mg/kg之劑量以靜脈內輸注形式投與。
- 如請求項1至8中任一項之方法,其中恩諾單抗以約1.25 mg/kg之劑量以靜脈內輸注形式投與。
- 如請求項1至10中任一項之方法,其進一步包含投與一或多種其他治療劑。
- 如請求項11之方法,其包含投與一種其他治療劑。
- 如請求項12之方法,其中該其他治療劑係PD-1或PD-L1之抑制劑。
- 如請求項1至13中任一項之方法,其中該癌症係膀胱癌。
- 如請求項1至13中任一項之方法,其中該癌症選自肝細胞癌、膀胱癌、乳癌、子宮頸癌、結腸直腸癌、子宮內膜癌、肛門癌、默克爾細胞癌(Merkel cell carcinoma)、胃癌、頭頸癌、腎癌、肝癌、肺癌、卵巢癌、前列腺癌、食道癌、膽囊癌、胰臟癌、甲狀腺癌、皮膚癌、白血病、多發性骨髓瘤、 慢性淋巴球性淋巴瘤、成人T細胞白血病、B-細胞淋巴瘤、急性骨髓性白血病、霍奇金氏或非霍奇金氏淋巴瘤(Hodgkin’s or non-Hodgkin’s lymphoma)、華氏巨球蛋白血症(Waldenstrom's Macroglubulinemia)、毛細胞淋巴瘤、伯基特淋巴瘤(Burkett's lymphoma)、膠質母細胞瘤、黑色素瘤、橫紋肌肉瘤及腺癌。
- 如請求項1至13中任一項之方法,其中該癌症選自肉瘤、頭頸癌、黑色素瘤及非小細胞肺癌。
- 如請求項1至13中任一項之方法,其中該癌症係膽管癌。
- 如請求項1至13中任一項之方法,其中該癌症係髓樣/淋巴樣贅瘤。
- 如請求項18之方法,其中該髓樣/淋巴樣贅瘤係8p11骨髓增生性症候群。
- 如請求項1至13中任一項之方法,其中該癌症係泌尿生殖系統癌症。
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-
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- 2022-04-11 JP JP2023562514A patent/JP2024513575A/ja active Pending
- 2022-04-11 EP EP22724166.8A patent/EP4323405A1/en active Pending
- 2022-04-11 US US17/717,464 patent/US20220324986A1/en active Pending
- 2022-04-11 TW TW111113722A patent/TW202304459A/zh unknown
- 2022-04-11 WO PCT/US2022/024210 patent/WO2022221170A1/en active Application Filing
- 2022-04-11 CA CA3215903A patent/CA3215903A1/en active Pending
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US20220324986A1 (en) | 2022-10-13 |
JP2024513575A (ja) | 2024-03-26 |
CA3215903A1 (en) | 2022-10-20 |
WO2022221170A1 (en) | 2022-10-20 |
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