TW201821107A - 一種vegfr抑制劑與parp抑制劑聯合在製備治療胃癌的藥物中的用途 - Google Patents
一種vegfr抑制劑與parp抑制劑聯合在製備治療胃癌的藥物中的用途 Download PDFInfo
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Abstract
本發明涉及一種VEGFR抑制劑與PARP抑制劑聯合在製備治療胃癌的藥物中的用途。
Description
本發明涉及一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合,以及其在製備治療胃癌的藥物中的用途。
胃癌是嚴重威脅人類健康的最常見消化道惡性腫瘤之一。據統計,在所有惡性腫瘤中,胃癌發病率位居第4,而死亡率位居第3,每年有超過70萬人死於胃癌。由於早期症狀不典型,大部分胃癌患者就診時已至晚期,有效治療手段的缺乏則使其5年生存率多不超過20%,預後很差。
血管內皮生長因子(VEGF)是迄今證實最為重要的正性調控蛋白。VEGF藉由與其受體亞型VEGFR-2結合,誘導VEGFR-2磷酸化,並進而啟動一系列級聯反應,引起血管內皮細胞增殖,誘導血管生成。有研究表明,VEGF及其受體在胃癌組織中均呈高表現,其表現量與胃癌預後呈 正相關。因此,靶向VEGF或其受體從而破壞新生血管生成的治療無疑可為胃癌患者提供全新的治療方向及分子靶點。貝伐單抗(Bevacizumab)為重組人源抗VEGF單克隆抗體,是首個被批准應用於抗腫瘤血管生成的藥物。一項III期臨床試驗證實貝伐單抗聯合化療作為一線方案治療進展期胃癌療效顯著,為以新生血管生成為靶點的抗胃癌治療奠定基礎。WO2005000232A2(公開日2005-01-06)公開的小分子酪氨酸激酶抑制劑甲磺酸阿帕替尼(Apatinib)具備高度選擇性競爭細胞內VEGFR-2的ATP結合位點,阻斷下游信號轉導,抑制腫瘤新生血管的生成,最終達到治療腫瘤的目的。阿帕替尼能夠顯著延長二線治療失敗後的晚期胃癌患者的總生存期和無進展生存期,提高疾病的控制率,是目前獲批的胃癌靶向藥物中唯一的口服製劑,填補了晚期胃癌三線治療領域的空白,阿帕替尼(Apatinib)結構如式(I)所示
多聚二磷酸腺苷核糖聚合酶或聚ADP核糖聚合酶(PARP)在修復因不同原因誘發的DNA單鏈斷裂(SSB)過程中發揮重要作用。自2014年底FDA批准阿斯利康公司研 發的PARP抑制劑Olaparib上市用於治療BRCA1/2突變的卵巢癌以來,抗腫瘤治療的PARP抑制劑研發得以迅速發展。目前已有包括Niraparib、Veliparib、Rucaparib在內的多個PARP抑制劑處於III期臨床試驗中。臨床前研究證實,除了單藥應用,PARP抑制劑還可以作為放、化療增敏劑與放、化療聯用,增強抗腫瘤療效而減少放、化療用藥或放射劑量,降低毒副作用。最近的一項II期臨床試驗結果則表明,Olaparib對於具有DNA修復基因突變的晚期前列腺癌患者表現出88%的反應,能夠使其腫瘤生長被抑制甚至縮小,總生存期長於同類患者預期的存活時間。因此不斷拓展PARP抑制劑的使用方式及適應症範圍對於PARP抑制劑的研發及應用具有良好的推動作用。胃癌的發生發展被證實與DNA損傷修復功能異常密切相關。WO2012019427A1(公開日2012-02-16)公開了PARP抑制劑,能夠抑制多種腫瘤的生長,結構如式(B)所示
聯合使用一種以上靶點各異又相互關聯的抗腫瘤藥物,充分發揮各組分優勢,既能提高單藥的抗腫瘤活性又可降低藥物毒性,是一種被普遍接受的抗腫瘤療法。一項將PARP抑制劑Olaparib與藉由抑制VEGFR活性抗新生血 管生成的藥物Cediranib聯用的I期臨床試驗初步證實該聯用方案相較于兩藥單用在卵巢癌患者中療效更為顯著,表明上述兩類靶點的藥物聯用方案用於腫瘤治療具有良好的可行性。
專利申請WO2010096627A1(公開日2010-08-26)、WO2014004376A2(公開日2014-01-03)、WO2016116602A1(公開日2016-07-28)、WO2016179123A1(公開日2016-11-10)中公開了VEGFR與PARP抑制劑聯用在治療惡性腫瘤(如乳腺癌或卵巢癌等),但不知曉聯用對胃癌的抑制效果是否具備協同作用。
本發明要解決的技術問題是提供一種VEGFR抑制劑與PARP抑制劑聯合後具備協同作用在製備治療胃癌的藥物中的用途
本發明的技術方案如下:本發明提供一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途。
較佳地,所述VEGFR抑制劑選自VEGFR-2抑制劑。
進一步較佳地,所述VEGFR-2抑制劑結構如通式(I)所示或其可藥用的鹽,
上述方案所述可藥用的鹽選自鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽或苯磺酸鹽等。
上述方案所述多聚二磷酸腺苷核糖聚合酶抑制劑選自奧拉帕尼、Niraparib、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
上述方案所述多聚二磷酸腺苷核糖聚合酶抑制劑結構如通式(B)所示或其可藥用的鹽,
在本發明一個較佳的方案中,所述胃癌選自腺癌、腺鱗癌或鱗狀細胞癌。
在本發明一個較佳的方案中,所述胃癌選自晚期胃癌。
特別較佳地,本發明中VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶還進一步聯合第三組分,所述第三組分可以選自鉑類抗癌藥或紫杉醇類抗癌藥。
在本發明一個較佳的方案中,所述鉑類抗癌藥選自順鉑、卡鉑、奧沙利鉑、奈達鉑或樂鉑。
在本發明一個較佳的方案中,所述紫杉醇類抗癌藥選自紫杉醇或多西他賽,紫杉醇的給藥形式沒有限制,例如紫杉醇的注射液、紫杉醇脂質體或白蛋白結合型紫杉醇。
本發明所述聯合具有協同藥效作用。
本發明所述聯合的給藥方式選自:同時給藥、或先後給藥。
本發明所述的用途,其中,所述VEGFR抑制劑為0.1-1000mg。
本發明所述的用途,其中,所述多聚二磷酸腺苷核糖聚合酶抑制劑為0.1-1000mg。
本發明進一步涉及一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途,其中,VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的比例為0.001~1000,較佳係1:1、5:3或2:1。
本發明進一步涉及一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途,其中,VEGFR抑制劑的給藥劑量為1-850mg,較佳係2.5mg、3mg、5mg、6mg、10mg、15mg、20mg、25mg、30mg、40mg、50mg、80mg、100mg、150mg、200mg、250mg、350mg、400mg、450mg 500mg、550mg、600mg、650mg、700mg、750mg、800mg或850mg,多聚二磷酸腺苷核糖聚合酶抑制劑的給藥劑量為1-500mg,較佳係3mg、6mg、9mg、10mg、12mg、 15mg、18mg、20mg、21mg、24mg、25mg、27mg、30mg、33mg、36mg、40mg、45mg、60mg、80mg、100mg、120mg、150mg、160mg、200mg、250mg、270mg、300mg、350mg、400mg或450mg。
本發明進一步涉及一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途,其中,VEGFR抑制劑推薦一天一次,多聚二磷酸腺苷核糖聚合酶抑制劑推薦一天兩次、間隔12小時。
本發明較佳實施方案中,一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途,其中,多聚二磷酸腺苷核糖聚合酶抑制劑抑制劑的給藥劑量為10mg、20mg,30mg,40mg、60mg、80mg及100mg進行劑量遞增,分別聯合固定劑為250mg的VEGFR。
上述方案中,順鉑推薦靜脈滴注、連續給藥期間每週期第1天、第8天、第15天給藥,固定劑量20mg/m2,在使用多聚二磷酸腺苷核糖聚合酶抑制劑和VEGFR抑制劑1h後給藥,靜脈滴注時間應大於3小時。
上述方案中,紫杉醇注射液推薦靜脈滴注、連續給藥期間每週期第1天、第8天、第15天給藥,固定劑量60mg/m2,在使用多聚二磷酸腺苷核糖聚合酶抑制劑和VEGFR抑制劑1h後給藥,靜脈滴注時間應大於3小時。
顯著地,本發明的VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合應用具有協同藥效作用。
本發明的還涉及一種VEGFR抑制劑與多聚二磷酸腺 苷核糖聚合酶抑制劑的藥物組合物,包含視需要的一種或多種醫藥載體、賦形劑和/或稀釋劑。所述藥物組合物可以製成藥學上可接受的任一劑型。例如,VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的藥物製劑可以配製為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑(包括注射液、注射用無菌粉末與注射用濃溶液)、栓劑、吸入劑或噴霧劑。
此外,本發明的所述藥物組合物還可以以任何合適的給藥方式,例如口服、腸胃外、直腸、經肺或局部給藥等方式施用於需要這種治療的患者或受試者。當用於口服給藥時,所述藥物組合物可製成口服製劑,例如口服固體製劑,如片劑、膠囊劑、丸劑、顆粒劑等;或,口服液體製劑,如口服溶液劑、口服混懸劑、糖漿劑等。當製成口服製劑時,所述藥物製劑還可包含適宜的填充劑、粘合劑、崩解劑、潤滑劑等。
本發明的VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑藥物組合物可以單獨給藥,或者與一種或多種治療劑聯合使用。因此,在某些較佳的實施方案中,所述的藥物組合物還含有一種或多種治療劑。在某些較佳的實施方案中,所述治療劑選自:抗體、烷化劑、抗代謝類、抗生素類、生物鹼類或激素類,所述烷化劑選自苯達莫司汀或替莫唑胺,所述抗代謝類選自5-氟尿嘧啶或阿糖胞苷,所述抗體選自赫賽汀,所述抗生素類選自阿黴素或絲裂黴素C,所述生物鹼類選自長春鹼類或三尖杉酯鹼類,所述 激素類選自潑尼松或甲狀腺素。
待組合的各成分(例如,VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑及第二治療劑)可同時給藥或依次順序地分開用藥。例如,可以在將本發明VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯用之前、同時或之後,施用第二治療劑。此外,待組合的各成分還可以以同一製劑形式或以分開的不同製劑的形式聯合給藥。
本發明中,所謂“聯合用藥”或“聯用”是一種給藥方式,其包括兩種藥物先後,或同時給藥的各種情況,此處所謂“同時”是指在同一給藥週期給予VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑,例如在2天內,或1天內給予兩種藥物。所謂“先後或相繼”給藥,則包括在不同給藥週期內分別給予VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的情況。這些給藥方式,均屬於本發明所述的聯合給藥。
本發明還提供了一種治療胃癌的方法,包括向胃癌患者給予前述的VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑。
本發明所述的“有效量”包含足以改善或預防醫學病症的症狀或病症的量。有效量還意指足以允許或促進診斷的量。用於特定患者或獸醫學受試者的有效量可依據以下因素而變化:如待治療的病症、患者的總體健康情況、給藥的方法途徑和劑量以及副作用嚴重性。有效量可以是避免顯著副作用或毒性作用的最大劑量或給藥方案。
本發明所述的胃癌患者較佳為經一線化療治療失敗或不耐受的,一線化療方案需包含以鉑類和/或氟尿嘧啶類藥物為基礎的方案,且患者的組織學或細胞學確診較佳為復發或轉移性胃腺癌(包括胃食管結合部腺癌)。
注:治療失敗的定義:治療過程中疾病進展或治療結束後復發,接受系統化療必須1個週期。
如無相反解釋,本發明中術語具有如下含義:總生存期(OS)指從隨機日期至任何原因導致死亡的日期。末次隨訪時仍存活的受試者,其OS以末次隨訪時間計為設限資料。失訪的受試者,其OS以失訪前末次證實存活時間計為設限資料。設限資料的OS定義為從隨機分組到設限的時間。
客觀緩解率(Objective response rate,ORR)指腫瘤縮小達到一定並且保持一定時間的病人的比例,包含了CR和PR的病例。採用實體瘤緩解評估標準(RECIST 1.1標準)來評定腫瘤客觀緩解。受試者在基線時必須伴有可測量的腫瘤病灶,療效評定標準根據RECIST 1.1標準分為完全緩解(CR)、部分緩解(PR)、穩定(SD)、進展(PD)。
疾病控制率(Disease Control Rate,DCR)指經確認的完全緩解、部分緩解和疾病穩定(8周)病例數在可評價療效患者中的百分比。
生活品質評分QoL參考EORTC QLQ-C30(版本3,中文版)。評價方法:觀察治療前後腫瘤患者相關臨床症狀及客觀檢查結果的變化進行計分,按生活品質量表的要求將 量表各領域的打分結果記錄在eCRF表中。
完全緩解(CR):所有靶病灶消失,全部病理淋巴結(包括靶結節和非靶結節)短直徑必須減少至<10mm。
部分緩解(PR):靶病灶直徑之和比基線水準減少至少30%。
疾病進展(PD):以整個實驗研究過程中所有測量的靶病灶直徑之和的最小值為參照,直徑和相對增加至少20%(如果基線測量值最小就以基線值為參照);除此之外,必須滿足直徑和的絕對值增加至少5mm(出現一個或多個新病灶也視為疾病進展)。
疾病穩定(SD):靶病灶減小的程度沒達到PR,增加的程度也沒達到PD水準,介於兩者之間,研究時可以直徑之和的最小值作為參考。
發明的有益效果
與現有技術相比,本發明的技術方案具有以下優點:
(1)本發明VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合用藥可有效解決耐藥性問題、提高藥物的療效。
(2)經研究表明,本發明VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合用藥可對一線化療失敗後的繼續治療;化學穩定性高,能夠滿足生產運輸儲存的醫藥要求,生產技術穩定、可重複可控,能夠適應於工業化生產。
以下提供本發明的組合物在治療胃癌的藥物中的用途的示例性試驗方案,以顯示本發明組合物的有利活性或有益技術效果。但是應當理解,下述試驗方案僅僅是對本發明內容的示例,而不是對本發明範圍的限制。本領域技術人員在本說明書的教導下,能夠對本發明的技術方案進行適當的修改或改變,而不背離本發明的精神和範圍。
實施例1、本發明組合物對人胃癌PDX模型STO#069荷瘤裸小鼠皮下移植瘤的療效
供試品:化合物A(甲磺酸阿帕替尼,可按照專利申請WO2010031266A1中的方法製備)、化合物B(可按照專利申請WO2012019427A1中的方法製備)、順鉑(購自Sigma公司)、紫杉醇(購自台州市科瑞生物技術有限公司)。
實驗動物:BALB/c裸小鼠,6-7周齡,雌性,購自北京維通利華實驗動物技術有限公司,實驗動物使用許可證號:SCXK(滬)2015-0022;動物合格證號:11400700166108,飼養環境:SPF級。
對照組:溶劑組。
供試品溶液配製:
化合物A:稱取化合物A(100mg),加入0.5%羧甲基纖維素溶液(10mL),渦旋或超音波至溶液溶清,4℃保存,給藥體積為5mL/kg;化合物B:稱取化合物B(540mg)溶于純水(31mL)中,然後加入0.2%吐溫80(0.18mL)和10% PEG 400(9.0mL),渦 旋至溶清,再加入純水至溶液體積為90mL,4℃保存,給藥體積為5mL/kg;順鉑:稱取順鉑(3mg)溶於生理鹽水(6.0mL)中,溶液濃度為0.5mg/mL,配製該溶液總計6.0mL,4℃保存,每次使用前用0.22μm Millipore Millex®膜過濾;紫杉醇:取6mg/mL的紫杉醇(1.5mL)用生理鹽水(6.0mL)配製1.5mg/mL的溶液,4℃保存,每次使用前新鮮配製。
腫瘤模型:
將病人胃癌STO#069腫瘤組織(病理診斷為胃低分化腺癌)剪成小塊(~30mm3),植入至裸鼠的右側皮下,待腫瘤長至600-700mm3後在裸鼠身上進行繼代培養,將其定義為0代(P0),植入0代(P0)腫瘤後定義為1代(P1),在裸小鼠中持續植入以此順序定義,從FP5產生的下一代定義為FP6,以此類推,FP6腫瘤組織用於此研究。
實驗方法:
(1)腫瘤植入:將STO#069 FP6腫瘤組織(病理診斷為胃低分化腺癌)剪成小塊(~30mm3),植入至裸鼠的右側皮下,待腫瘤大小平均接近150-250mm3後開始分組,治療,共7組、每組6隻荷瘤小鼠,對小鼠的實驗方法按照表1實驗設計中的預定方案進行:
(2)觀察與記錄:每週測2-3次瘤體積,稱鼠重,記錄資料。
(3)腫瘤測量與終點
腫瘤體積用卡尺每週測量兩次、測量兩個維度,單位為mm3;腫瘤體積(V)計算公式為: V=1/2×a×b2,其中a、b分別表示長、寬。
T/C(%)=(T-T0)/(C-C0)×100%,其中T、C分別為實驗結束時給藥組和溶劑組的腫瘤體積;T0、C0分別為為實驗開始時給藥組和溶劑組的腫瘤體積。
實驗的終點:功效研究的終點設為21天,如果腫瘤體積>2000mm3或如果裸鼠體重減少超過20%或者病得很嚴重,並且不能獲得足夠的食物或水,將該裸鼠移出實驗組並安樂死。
資料分析:
匯總統計,包括平均值和平均值的標準誤差(SEM),組間腫瘤體積的差異統計分析和在最後一次給藥(分組後的第21天)後在最佳治療時間點進行的藥物相互作用所獲得的資料分析。藉由單因子變異數分析(One Way ANOVA)分析腫瘤體積資料,然後使用Dunnett(α=0.05)進行個體比較,P<0.05被認為是統計學上有意義。
實驗結果:
實驗結論:
由實驗結果可知化合物A單用(50mg/kg)能夠抑制人胃癌STO#069裸小鼠皮下移植瘤的生長,在給藥第21天時,腫瘤抑制率為55.32%,化合物B(30mg/kg,BID×21)分別與順鉑(5mg/kg,QW×3)、紫杉醇(15mg/kg,QW×3)、化合物A(50mg/kg,QD×21)聯用的腫瘤抑制率分別為61.40%、55.34%、72.79%,說明化合物A與化合物B聯用對胃癌細胞的腫瘤體積的抑制作用優於化合物A單一組分、化合物B與順鉑的聯用、化合物B與紫杉醇的聯用;化合物A(50mg/kg)、化合物B(30mg/kg)與順鉑(5mg/kg)或紫杉醇(15mg/kg)三藥聯用顯示非常明顯的抗腫瘤效果,腫瘤抑制率分別為84.86%、75.34%,說明三組分聯用效果(化合物A/化合物B與順鉑的聯用、化合物A/化合物B與順紫杉醇的聯用)優於單一組分或兩組分聯用;
綜上所述,本發明的VEGFR抑制劑化合物A,PARP抑制劑化合物B聯用具有顯著的協同作用,對胃癌細胞增殖的抑制作用顯著優於單一組分的VEGFR抑制劑化合物A。因此,本發明VEGFR抑制劑與PARP抑制劑聯合應用對胃癌細胞的抑制效果顯著。而進一步與順鉑或紫杉醇三藥聯用則更優於單藥或兩組分聯用。
實施例2:本發明組合物治療胃癌的有效和安全性
I期臨床(NCT03026881)入組10位經一線化療治療失敗或不耐受的受試者,一線化療方案需包含以鉑類和/或氟尿嘧啶類藥物為基礎的方案,且受試者的組織學或細胞學 確診為復發或轉移性胃腺癌(包括胃食管結合部腺癌)。
注:治療失敗的定義:治療過程中疾病進展或治療結束後復發,接受系統化療必須1個週期。
給藥方案:
化合物A:初始劑量250mg,口服,每天一次;化合物B:起始劑量20mg,30mg,40mg,每天兩次;首次療效評價(包括影像學檢查和血清學檢查)經研究者評估未有效緩解且用藥期間未出現3級及以上不良事件,經受試者本人同意,可以提高劑量。
紫杉醇:靜脈注射
資料獲取:
療效資料獲取見表3
從10例臨床病例資料來看,受試者的疾病部分緩解率(PR)為50%,2週期,受試者疾病穩定率(SD)為37.5%,疾病控制率(DCR)高達87.5%。
不良事件多發生在血液學毒性,包括白細胞減少,中性粒細胞減少和血紅蛋白降低等,低磷血症不良事件僅在30mg劑量組中出現1例3級。
Claims (19)
- 一種VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑聯合在製備治療胃癌的藥物中的用途。
- 如申請專利範圍第1項所述的用途,其中,該VEGFR抑制劑係選自VEGFR-2抑制劑。
- 如申請專利範圍第2項所述的用途,其中,該VEGFR-2抑制劑結構係如通式(I)所示或其可藥用的鹽,
- 如申請專利範圍第3項所述的用途,其中,該可藥用的鹽係選自鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽或苯磺酸鹽。
- 如申請專利範圍第1至4項中任一項所述的用途,其中,該多聚二磷酸腺苷核糖聚合酶抑制劑係選自奧拉帕尼、Niraparib、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
- 如申請專利範圍第1至4項中任一項所述的用途,其中,該多聚二磷酸腺苷核糖聚合酶抑制劑結構如通式(B)所示或其可藥用的鹽,
- 如申請專利範圍第1項所述的用途,其中,該胃癌係選自腺癌、腺鱗癌或鱗狀細胞癌。
- 如申請專利範圍第1項所述的用途,其中,該胃癌係選自晚期胃癌。
- 如申請專利範圍第1至8項中任一項所述的用途,其中,該聯合係視需要包含第三組分,該第三組分係選自鉑類抗癌藥或紫杉醇類抗癌藥。
- 如申請專利範圍第9項所述的用途,其中,該鉑類抗癌藥係選自順鉑、卡鉑、奧沙利鉑、奈達鉑或樂鉑。
- 如申請專利範圍第9項所述的用途,其中,該紫杉醇類抗癌藥係選自紫杉醇或多西他賽。
- 如申請專利範圍第1至11項中任一項所述的用途,其中,該聯合係具有協同藥效作用。
- 如申請專利範圍第1至12項中任一項所述的用途,其中,該VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的比例為0.001至1000。
- 如申請專利範圍第13項所述的用途,其中,該VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的比例為1:1、5:3或2:1。
- 如申請專利範圍第1至12項中任一項所述的用途,其中,該VEGFR抑制劑的給藥劑量為1至500mg。
- 如申請專利範圍第15項所述的用途,其中,該VEGFR抑制劑的給藥劑量為50mg、100mg、150mg、200mg、250mg、350mg、400mg或450mg。
- 如申請專利範圍第1至12項中任一項所述的用途,其中,該多聚二磷酸腺苷核糖聚合酶抑制劑的給藥劑量為1至500mg。
- 如申請專利範圍第17項所述的用途,其中,該多聚二磷酸腺苷核糖聚合酶抑制劑的給藥劑量為10mg、15mg、20mg、25mg、30mg、40mg、60mg、100mg、250mg或300mg。
- 含有申請專利範圍第1至18項中任一項所述的VEGFR抑制劑與多聚二磷酸腺苷核糖聚合酶抑制劑的藥物組合物,其中,包含一種或多種可藥用的賦形劑、稀釋劑或載體。
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