CN102834094B - 有机化合物的组合产品及其制药用途 - Google Patents
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Abstract
一种包含4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮与至少一种mTOR抑制剂的药物组合,以及用于治疗或预防增生性疾病的该药物组合。
Description
本发明涉及包含4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其药学上可接受的盐、或其水合物、或其溶剂化物和mTOR抑制剂的药物组合,以及这样的组合在治疗增生性疾病,如mTOR激酶依赖性疾病中的应用。
对于增生性疾病尽管有许多治疗选择,但仍需要有效安全的抗增生剂,并需要其在联合疗法中发挥有益作用。
已经惊奇地发现,含有4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其药学上可接受的盐、或其水合物、或其溶剂化物以及至少一种mTOR抑制剂(如下面所描述的)的组合对于增生性疾病,如mTOR激酶依赖性疾病,具有有益的效果。
4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮的结构如式I所示:
式I化合物抑制各种蛋白激酶,如酪氨酸受体激酶(RTK)。因而式I化合物及其盐可用于抑制新生血管生成和治疗增生性疾病。该化合物及其盐包括单乳酸盐的制备方法在美国专利号6,605,617、6,774,237、7,335,774、7,470,709,美国专利申请序列号10/982,757、10/982,543、10/706,328,PCT申请公布WO2006/127926、WO2009/115562中有描述,在此通过参考将各文献完整地并入本文。
式I化合物的单乳酸盐以多种多晶型存在,包括如单水合物形式和无水物形式。多晶型发生于同成分的物质(包括其水合物和溶剂化物)在不同晶格排列状态下结晶,这种不同的晶格排列造成了与特定晶型相对应的热动力学差异和物理性质差异。
酪氨酸受体激酶(RTK)是调节发育细胞生长与分化、成体组织再造与再生的跨膜多肽。已知作为生长因子或细胞因子的多肽配体可激活RTK。RTK信号传递涉及配体结合以及受体外部结构域构象改变,结果形成二聚体。配体结合到RTK引起受体在特定酪氨酸残基位点的转磷酸化,继而激活催化结构域对胞质内底物的磷酸化。
式I化合物抑制酪氨酸激酶。酪氨酸激酶可以是但不仅限于:Cdc2激酶(细胞***周期2激酶)、Fyn(与SRC、FGR、YES相关的FYN肿瘤基因激酶)、Lck(淋巴细胞特异性蛋白酪氨酸激酶)、c-Kit(干细胞因子受体或肥大细胞生长因子受体)、p60src(最初被鉴定为rous肉瘤病毒v-src肿瘤基因的酪氨酸激酶)、c-ABL(作为最初分离自Adelson白血病病毒的一种肿瘤基因产物的酪氨酸激酶)、VEGFR3、PDGFRα(血小板衍生生长因子受体α)、PDGFRβ(血小板衍生生长因子受体β)、FGFR3(成纤维细胞生长因子受体3)、FLT-3(fms样酪氨酸激酶-3),或者Tie-2(具有lg和EGF同源结构域的酪氨酸激酶)。在一些实施方案中,酪氨酸激酶是Cdc2激酶、Fyn、Lck、或Tie-2;另一些实施方案里,酪氨酸激酶是c-Kit、c-ABL、p60src、VEGFR3、PDGFRα、PDGFRβ、FGFR3、或FLT-3。
RTK的两个亚家族对血管内皮呈特异性。这些亚家族包括血管内皮生长因子(VEGF)亚家族和Tie受体亚家族。第III类RTK包括血管内皮生长因子受体1(VEGFR-1)、血管内皮生长因子受体2(VEGFR-2),以及血管内皮生长因子受体3(VEGFR-3)。
本技术涉及具有式I所示结构的4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其药学上可接受的盐、或其水合物、或其溶剂化物的用途:
4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其药学上可接受的盐可按一定剂量如500mg/天给药,例如口服给药,例如采用其乳酸盐形式,例如以其单乳酸盐的单水合物形式,例如500mg给药可按每星期里给药5天然后停药2天的方式进行。
本发明的组合包括能降低或抑制丝氨酸/苏氨酸mTOR激酶活性/功能的化合物。这样的化合物被作为“mTOR抑制剂”,包括但不仅限于:抑制mTOR激酶家族成员的蛋白或抗体,如RAD、雷帕霉素(西罗莫司)及其衍生物/类似物,如依维莫司或RAD001。西罗莫司还被称为RAPAMUNE,依维莫司或RAD001还被称为CERTICAN或AFINITOR。抑制mTOR激酶家族成员的其他化合物、蛋白或抗体包括:CCI-779、ABT578、SAR543,以及作为FK506乙基化类似物的子囊霉素。还包括Ariad的AP23573和AP23841。
合适的mTOR抑制剂包括,如:
I.大环内酯类免疫抑制剂雷帕霉素,由吸水链霉菌产生。
II.雷帕霉素衍生物,如:
a.取代的雷帕霉素,如40-O取代雷帕霉素,如US 5,258,389、WO 94/09010、WO 92/05179、US 5,118,677、US 5,118,678、US 5,100,883、US5,151,413、US 5,120,842、WO 93/11130、WO 94/02136、WO 94/02485和WO95/14023中所描述,将所有这些文献通过参考完整地并入本文;
b.16-O取代雷帕霉素,如WO 94/02136、WO 95/16691和WO96/41807中所描述,将所有这些文献通过参考完整地并入本文;
c.32-氢化雷帕霉素,如WO 96/41807及US 5256790中所描述,将所有这些文献通过参考完整地并入本文。
d.式II化合物的雷帕霉素衍生物
其中
R1是CH3或C3-6炔基,
R2是H或-CH2-CH2-OH、3-羟基-2-(羟甲基)-2-甲基-丙酰基或四唑基,且X是=O、(H,H)或(H,OH)
条件是当X=O且R1=CH3时,R2不是H,
或者当R2为-CH2-CH2-OH时是其前药,如其生理条件下可水解的醚。
式II化合物在WO 94/09010、WO 95/16691或WO 96/41807中有披露,将所有这些文献通过参考完整地并入本文。它们可按照这些文献里披露的或类似的流程来制备。
化合物可以是32-去氧雷帕霉素、16-戊-2-炔氧基-32-去氧雷帕霉素、16-戊-2-炔氧基-32(S)-双氢雷帕霉素、16-戊-2-炔氧基-32(S)-双氢-40-O-(2-羟乙基)-雷帕霉素,以及40-O-(2-羟乙基)-雷帕霉素,如WO 94/09010中的实施例8所披露的。
可用式II表示的雷帕霉素衍生物可以是40-O-(2-羟乙基)-雷帕霉素、40-[3-羟基-2-(羟甲基)-2-丙酸甲酯]-雷帕霉素(也被称作CCI779)、40-表-(四唑基)-雷帕霉素(也被称作ABT578)、32-去氧雷帕霉素、16-戊-2-炔氧基-32(S)-双氢雷帕霉素,或TAFA-93。
e.雷帕霉素衍生物也包括所谓的雷帕类似物,如WO 98/02441和WO01/14387中所描述的AP23573、AP23464或AP23841。
基于观察到的活性,例如在WO 94/09010、WO 95/16691或WO 96/41807中所描述的与巨菲蛋白12(也被称作FK-506结合蛋白或FKBP-12)的结合,发现雷帕霉素及其衍生物有免疫抑制剂的作用,可用于如急性移植排斥的治疗。
作为FK506乙基化衍生物的子囊霉素、AZD08055和OSI027是通过直接结合于酶上ATP-结合区来抑制mTOR激酶活性的化合物。
优选的mTOR抑制剂是40-O-(2-羟基)乙基-雷帕霉素(依维莫司)。
在前面所引用的每一个专利申请中,与化合物相关的主题都通过参考并入本专利申请。包含在内的有:以上所公开的化合物可能存在的药学上可接受盐、对应的外消旋物、非对映异构体、对映异构体、变构异构体,以及相应的结晶形式,例如这些文献中披露的溶剂化物、水合物和多晶型。在本技术的组合中用作活性成分的化合物可分别按引述资料中所描述的方法进行分别进行制备和给药。本发明范围内还包括了多于两种的如前述的单独活性成分的组合,即:本发明范围内的药物组合包含有三种或更多种活性成分。
在此提供的是一种药物组合,包含:
a)4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮,结构如式I所示:
以及
b)至少一种mTOR抑制剂。
另一方面,提供了4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2- 基]-1H-喹啉-2-酮及至少一种mTOR抑制剂在制备用于治疗或预防增生性疾病的药物的用途。4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂可以分别给药、同时给药或序贯给药。
另一方面,提供了4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂在制备用于治疗或预防mTOR激酶依赖性疾病的药物的用途。4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂可以分别给药、同时给药或序贯给药。
另一方面,本发明涉及用于治疗或预防增生性疾病、或预防增生性疾病或者是mTOR激酶依赖性疾病的进展的如下组合:
1)4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其药学上可接受的盐、或其水合物、或其溶剂化物,如4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮的乳酸盐,以及
2)至少一种mTOR抑制剂,如前述的一种适合的mTOR抑制剂,如依维莫司,
所述疾病例如乳腺癌、膀胱癌、尿路上皮癌、胃肠道癌、神经内分泌肿瘤、淋巴瘤、肝细胞癌或肝癌、***癌、脑癌、肾癌如肾细胞癌(RCC)、肾上腺癌、胃癌、卵巢癌、胰腺癌、肺癌、***或甲状腺癌、肉瘤、胶质母细胞瘤、多发性骨髓瘤、或结肠癌、或结直肠腺瘤、或头颈部肿瘤、表皮过度增生、银屑病、***增生、瘤形成、上皮特征的瘤形成、腺样囊性癌(ACC)、肝细胞癌(HCC)、或白血病。
本发明还涉及用于治疗或预防疾病、或预防疾病的进展的如下组合:
1)4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其药学上可接受的盐、或其水合物、或其溶剂化物,如4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮的乳酸盐,以及
2)依维莫司,
所述疾病选自:乳腺癌、膀胱癌、尿路上皮癌、胃肠道癌、神经内分泌肿 瘤、淋巴瘤、多发性骨髓瘤、肝细胞癌或肝癌、***癌、肾癌如肾细胞癌(RCC)、腺样囊性癌(ACC)、肝细胞癌(HCC)。
4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂可以分别给药、同时给药或序贯给药。
在一些实施方案中,提供了通过施用4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂来治疗或预防疾病的方法。4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮及至少一种mTOR抑制剂可以分别给药、同时给药或序贯给药。
mTOR抑制剂可选自:RAD雷帕霉素(西罗莫司)及其衍生物/类似物,如依维莫司或RAD001;CCI-779、ABT578、SAR543、子囊霉素(FK506的乙基化类似物)、AP23573、AP23841、AZD08055和OSI027。
优选的mTOR抑制剂是40-O-(2-羟基)乙基-雷帕霉素(依维莫司)。依维莫司可按如下方法给药:至少2.5mg/日或5-10mg/日,如10mg/日。
术语“mTOR激酶依赖性疾病”包括但不限于如下疾病或状况:
·器官或组织移植排斥,如用于治疗例如心、肺、心-肺、肝、肾、胰腺、皮肤或角膜移植的接受者;移植物抗宿主病,如骨髓移植后;
·再狭窄
·错构瘤综合征,例如结节性硬化症或Cowden病
·***平滑肌瘤病
·视网膜色素变性
·自身免疫性疾病包括脑脊髓炎、胰岛素依赖型糖尿病、狼疮病、皮肌炎、关节炎和风湿性疾病
·类固醇抵抗型急性淋巴细胞白血病
·纤维化疾病包括硬皮病、肺纤维化、肾纤维化、囊性纤维化
·肺高血压
·免疫调节
·多发性硬化
·VHL综合征
·Carney综合征
·家族性腺瘤性息肉病
·青少年息肉综合征
·Birt-Hogg-Dube综合征
·家族性肥厚型心肌病
·Wolf-Parkinson-White综合征
·神经退行性病变如帕金森病、亨廷顿舞蹈症、由tau基因突变导致的阿尔茨海默病和痴呆症、脊髓小脑共济失调3型、SOD1突变导致的运动神经元病、神经蜡样质脂褐素沉积病/巴滕病(小儿神经退行性疾病)
·湿性和干性黄斑变性
·肌肉萎缩(萎缩、恶病质)以及肌病如Danon病
·细菌和病毒感染,包括结核分枝杆菌、A型链球菌、I型HSV、HIV感染
·神经纤维瘤,包括I型神经纤维瘤
·Peutz-JegPeutz-Jeghers综合征
此外,“mTOR激酶依赖性疾病”还包括癌症和其他相关恶性肿瘤。与病理性mTOR信号传递级联相关联的癌症的非限定性列表包括乳腺癌、肾细胞癌、尿路上皮癌、胃肿瘤、神经内分泌肿瘤、淋巴瘤、多发性骨髓瘤、腺样囊性癌、肝细胞癌和***癌。
增生性疾病的例子有,例如良性或恶性肿瘤、脑癌、肾癌如肾细胞癌(RCC)、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、尿路上皮癌、胃癌、卵巢癌、结肠癌、直肠癌、***癌、胰腺癌、肺癌、***或甲状腺癌、肉瘤、胶质母细胞瘤、多发性骨髓瘤,或胃肠道癌特别是结肠癌或结直肠腺瘤,或头颈部肿瘤、表皮过度增生、银屑病、***增生、瘤形成、上皮特征的瘤形成、淋巴瘤、腺样囊性癌、乳癌、肝细胞癌(HCC)或白血病。
适当的临床研究可以是,例如:针对增生性疾病患者的开放标签、剂量递增研究。这样的研究特别证明本发明药物组合中活性成分的协同作用。对增生性疾病的有益效果可直接通过本领域技术人员熟知的这些研究的结果来确定。这些研究特别适用于对采用活性组分的单一疗法与本发明组合疗法进行比较。优选地,药物(a)剂量递增直到达到最大耐受剂量,而药物(b)以固定剂量 给药。也可以是,药物(a)以固定剂量给药,而药物(b)剂量递增。每位病人可按每日或间歇方式接受药物(a)给药。通过这样的方式可确定治疗功效,如:在12、18或24星期后,通过每6星期评价症状记分来确定。
本发明的药物组合的给药不仅可达到有益的效果,如在减轻、延迟进展或抑制症状上发挥协同的疗效,还可带来进一步的意想不到的益处,如,与只采用本发明组合中的一个药物活性成分的单一疗法相比,更少的副作用、日常生活质量的改善或发病率的降低。
进一步的益处是本发明的组合中的活性组分的使用剂量可以更低,例如,往往不仅是剂量可以较小,而且可减少给药次数,这样可减少副作用的发生或严重程度。这是符合被治疗患者的愿望和需求的。
本发明提供了一定含量的药物组合物,所述含量可使该组合在治疗或预防增生性疾病中成为共同治疗有效的。该组合中,药物(a)和药物(b)可以以合并的单位剂型或两种分开的单位剂型一同给药、相继给药或分别给药。单位剂型也可以是固定的组合。
根据本发明的用以将药物(a)和药物(b)分别给药或以固定组合方式给药的药物组合物(例如包含至少两种组合成员(a)和(b)的单一盖仑组合物)可以用已知的方式来制备,且所述药物组合物是适合哺乳动物(温血动物)包括人经肠给药(如口服或直肠)以及非经肠给药的组合物,其仅包含治疗有效量的至少一种如上所述的具药理活性的组合成员,或包含所述成员与一种或多种药学可接受载体或稀释剂的组合,其特别适合于经肠或非经肠应用。
适合的药物组合物可包含,例如:约0.1%到约99.9%、优选约1%到约60%的活性成分。联合疗法中用于经肠或非经肠给药途径的药物制剂是,例如:那些单位剂型的制剂,如糖衣片、胶囊或栓剂,或安瓿瓶。如无特别注明,这些制剂形式以公知的方式制备,如,通过传统的混合、制粒、包糖衣、溶解或冻干等工艺。应该赞同,各剂型的单剂中包含的组合成员的单位含量其本身不必构成有效量,因为必要的有效量可以通过多个剂量单元的给药来达到。
特别是,本发明组合中每个组合成员的治疗有效量可被同时给药或按任何顺序序贯给药,各组分可被分开给药或作为固定组合给药。例如,预防或治疗增殖性疾病的方法可包含:同时地或以任何顺序序贯地(i)施用游离形式或药学 上可接受的盐形式的第一药物(a)以及(ii)施用游离形式的或药学上可接受的盐形式的药物(b),所述施用以联合治疗有效量、优选以协同有效量进行,例如,以本文描述的每日剂量或间歇剂量进行。本发明组合中的各组合成员可以在治疗过程中的不同时间点分别给药,或以独立的或单一的组合形式同时给药。另外,术语“给药”也涵盖组合成员的前药的使用,该前药在体内转化成该组合成员。应该理解本发明涵盖了所有这些同时或交替治疗的方案,对“给药”这个词应作出相应的解释。
本发明组合中采用的每个组合成员的有效剂量可根据所用的特定化合物或药物组合物、给药方式、所治疗的病症、所治疗病症的严重程度而变化。因此本发明组合的给药方案根据各种因素来选择,包括给药途径以及病人的肝肾功能。普通技能的临床医生或医师都可以容易地确定并在处方中开出减轻、对抗或阻止病症进展所需的单个活性成分的有效量。在有效无毒性的范围内达到活性成分最优的精确浓度需要一个基于活性成分对所治疗病症的利用度动力学参数的治疗方案。
附图简要说明
图1/6显示当用式I化合物、RAD001以及两者的组合治疗时,第1、3、4、6和9组裸小鼠中源自人肾透明细胞癌的Caki-1肿瘤细胞系直至第23天的肿瘤生长。
图2/6显示当用式I化合物、RAD001以及两者的组合治疗时,第1-10组裸小鼠中源自原发性人肾透明细胞癌的786-O肿瘤细胞系直至第77天的肿瘤生长。
图3/6显示当用式I化合物、RAD001以及两者的组合治疗动物时,随时间变化的肿瘤体积(肿瘤生长)。
图4/6显示用运载体、式I化合物、RAD001或组合治疗的动物的体重。
图5/6显示用运载体、式I化合物、RAD001或组合治疗的动物的肿瘤重量。
图6/6显示当用运载体、式I化合物、RAD001或组合治疗动物时的肿瘤照片。
以下以实施例方式加以描述。
实施例1
Caki-1肿瘤细胞系来源于人肾透明细胞癌的皮肤转移。肿瘤被移植到裸鼠体内维持。在每只实验动物右肋皮下植入1mm3的切块。每周两次用卡尺测量肿瘤,当平均体积接近100-150mm3时每日测量一次。肿瘤细胞植入15天后,研究开始的D1(第1天)将动物分成9组,每组10只,个体的肿瘤体积为75-196mm3,组平均肿瘤体积为128-138mm3。肿瘤体积(mm3)按下式计算:
其中“w”指肿瘤宽度,“l”是肿瘤长度,单位mm。肿瘤重量按照1mg相当于1mm3体积的假设来估算。
为了研究疗效,RAD001及其运载体(运载体2)、以及TKI258-CU及其运载体(运载体3)各自口服给药(p.o.),每日一次连续21天(qd×21)。紫杉醇静脉注射隔天一次,共五个剂量(qod×5)。组合里所有药物在30-60分钟内完成给药。给药体积按10mL/kg(0.2mL/20g小鼠)基于每只动物在给药当天的体重计算,周末除外,此时使用前次的体重。
裸小鼠各组(n=10/组)的治疗方案如下:
第1组小鼠接受RAD001运载体(运载体2)和TKI258-CU运载体(运载体3),作为所有分析的对照组。另外,第1组接受另一药物的运载体(运载体1),该药物不属于本申请的一部分。第3组接受TKI258-CU单一疗法,30mg/kg(相当于23.5mg/kg游离碱)。第4组接受RAD001单一疗法,5mg/kg。第6组接受5mg/kg RAD001与30mg/kg TKI258-CU的双组合治疗。
第9组接受30mg/kg紫杉醇疗法作为阳性对照。
试验研究开始于第1天(D1)。根据23天(D23)里肿瘤体积变化确定疗效。疗效在第23天确定。
出于数据和图表分析的目的,测量每只动物的ΔTV,即在D1(给药起点)到终点日之间肿瘤体积的差异。对于每个治疗组,在终点日的响应结果按以下关系式计算:
T/C(%)=100×ΔT/ΔC,ΔT>0
其中的ΔT=(终点日测得的药物治疗组平均肿瘤体积)-(D1测得的药物 治疗组平均肿瘤体积);ΔC=(终点日测得的对照组平均肿瘤体积)-(D1测得的对照组平均肿瘤体积)
T/C值达到40%或以下的治疗被归为具有潜在治疗活性的治疗。
图/表1/2显示到第23天的治疗响应。(n)是一组内未因治疗相关、意外事故或未知原因死亡的动物数。平均体积是指组平均肿瘤体积;变化是指D1与D23之间的差异。T/C是100×(ΔT/ΔC),其是D1与D23之间治疗组平均肿瘤体积变化(ΔT)相对于对照组1平均肿瘤体积变化(ΔC)的百分比(ΔV)。统计学显著性分析根据Kruskal-Wallis检验结合Dunn多重比较法检验进行:ns=无显著性;*=p<0.05;**=p<0.01;以及***=p<0.0001,与所示试验组相比(G1到G7)。
第6组中(图/表1/2),5mg/kg RAD001与30mg/kg TKI258-CU的双重疗法,其结果是ΔT为375mm3,相当于27%T/C,产生了显著的中位生长抑制(P<0.001)。相比于第3、第4组的TKI258-CU、RAD001的单一疗法,双重疗法下呈现显著的改善(P<0.001)。
实施例2
786-O肿瘤系来源于原发性人肾透明细胞癌。肿瘤被移植到裸小鼠体内维持。在每只裸小鼠右肋皮下接种0.2ml 786-O细胞悬液(1×107个细胞)。每周两次用卡尺测量肿瘤,当平均体积接近150-220mm3时每日测量一次。肿瘤细胞植入8天后,研究开始的D1(第1天),将动物分成10组,每组10只,个体肿瘤体积为172-196mm3,组平均肿瘤体积为174mm3。肿瘤体积(mm3)按下式计算:
其中“w”指肿瘤宽度,“l”是肿瘤长度,单位mm。肿瘤重量按照1mg相当于1mm3体积的假设来估算。
为了研究疗效,所有治疗(TKI258和RAD001)通过口腔强饲(p.o.)给药,每日一次连续21天(qd×21)。联合疗法中,在RAD001给药60分钟后进行TKI258给药。给药体积按10mL/kg(0.2mL/20g小鼠)基于每只动物在给药当天的体重计算,周末除外,此时使用前次的体重。
10组裸小鼠(n=10/组)的治疗方案如下:
第1组小鼠接受两种运载体,作为所有分析的对照组。第10组小鼠不作任何处理,作为运载体治疗组的对照。第2组、第3组接受TKI258-CU单一疗法,剂量分别为15和30mg/kg(分别相当于11.7和23.5mg/kg游离碱)。第4组、第5组接受RAD001单一疗法,剂量分别为2.5和5mg/kg。第6组、第7组分别接受2.5mg/kg RAD001与15和30mg/kg的TKI258-CU的联合用药。第8组、第9组分别接受5mg/kg RAD001与15和30mg/kg的TKI258-CU的联合用药。
试验研究开始于第1天(D1)。根据长达77天(D77)中肿瘤体积的变化,或者是到达终点肿瘤体积(800mm3)的时间来确定长期疗效。
出于数据和图表分析的目的,测量每只动物的ΔTV,即在D1(给药起点)到终点日之间肿瘤体积的差异。每个治疗组在终点日的响应结果按以下关系式计算:
T/C(%)=100×ΔT/ΔC,ΔT>0
其中的ΔT=(终点日测得的药物治疗组平均肿瘤体积)-(D1测得的药物治疗组平均肿瘤体积);ΔC=(终点日测得的对照组平均肿瘤体积)-(D1测得的对照组平均肿瘤体积)
T/C值达到40%或以下的治疗被归为具有潜在治疗活性的治疗。
动物在瘤体达到终点体积(800mm3)时或在研究的最后一天(D77)被安乐死。达到终点体积的动物其到达终点的时间(TTE)根据以下公式计算:
其中TTE的单位是天,终点体积的单位是mm3,在对数转换的肿瘤生长数据的线性回归曲线上,b是截距,m是其斜率。整套数据包括超过研究终点体积时的首个观察数据,以及达到终点体积之前紧邻的连续三个观察数据。计算得到的TTE往往低于动物达到肿瘤体积指标而被安乐死的天数。对于未达到终点体积的动物,将最后一天的数值作为其TTE。对于被归类为死于治疗相关(TR)原因或非治疗相关转移(NTRm)的动物,将死亡时的天数作为其TTE。死于非治疗相关(NTR)原因的动物不纳入TTE计算。
根据肿瘤生长的延迟(TGD)来确定疗效,TGD被定义为治疗组相对于对照组TTE中值的增加:
TGD=T–C,以天表示,或者表示为相对于对照组的TTE中值的百分比:
其中T是治疗组的TTE中值,C是对照组的TTE中值
疗效还可根据研究最后一天时仍在实验组内的动物的肿瘤体积,以及发生消退响应的数量来确定。MTV(n)被定义为D77时还在实验组内其肿瘤尚未达到终点体积的动物的肿瘤体积中值,n是这些动物的数量。
治疗可导致动物肿瘤的部分消退(PR)或完全消退(CR)。PR是指研究过程中连续三次测得的肿瘤体积是D1时的50%或更小,且三次数据中有一次或更多次大于或等于13.5mm3。CR是指研究过程中连续三次测得的肿瘤体积小于13.5mm3。在研究实验结束时CR动物被归为无瘤生存者(TFS)。
图/表2/2显示到研究终点(第77天(D77)或肿瘤体积达到800mm3,两指标中的先到达者)时的治疗响应。(n)是组内非死于治疗相关、意外事故或未知原因的动物数。TTE是到达终点的时间;T-C是治疗组与对照组之间TTE中值(天)的差值;%TGD=[(T-C)/C]×100。用Logrank检验进行统计学显著性分析:相对于所指实验组(G1到G5),ns=无统计意义;*=p<0.05;**=p<0.01;***=p<0.0001。MTV(n)是进行TGD分析时数量为n的动物的肿瘤体积中值(mm3)(不包括达到终点体积的动物)。
77天的疗效研究
第7组中,2.5mg/kg RAD001与30mg/kg TKI258-CU联合治疗使TTE中值达到65.3天,相应的%TGD为49。生存期延长具统计显著性(P<0.05)。联合治疗相比于对应的第3组TKI258-CU单一疗法(P<0.05)以及第4组RAD001单一疗法(P<0.001)有了显著改善。第7组内有4只动物存活到D77,其MTV为460mm3,还出现了一例PR响应。
第8组中,5mg/kg RAD001与15mg/kgTKI258-CU的联合治疗使TTE中值达到63.5天,相应的%TGD为45。生存期延长具统计显著性(P<0.05)。联合治疗与对应的第2组TKI258-CU单一疗法相比有显著改善(P<0.001),与 对应的第5组RAD001单一疗法相比无显著性差异。第8组内有3只动物存活到D77,其MTV为486mm3,还出现了一例PR响应。
第9组中,5mg/kg RAD001与30mg/kg TKI258-CU的联合治疗使TTE中值达到66.0天,相应的%TGD为51。生存期延长具统计显著性(P<0.01)。联合治疗与对应的第3组TKI258-CU单一疗法相比有显著改善(P<0.01),与对应的第5组RAD001单一疗法相比无显著性差异。第9组内有4只动物存活到D77,其MTV为161mm3,还出现了一例PR响应。
实施例3
异种移植模型:所有小鼠饲养于负压隔离器,供给灭菌的食物和水自由采食,12小时昼夜交替周期。以前已采用原发性HCC来建立异种移植细胞系,其中的细胞系07-0409、29-0909A、01-0909被用来在9至10周龄的雄性SCID小鼠(Animal Resources Centre,Canning Vale,Western Australia)体内形成肿瘤。
肿瘤的治疗:治疗前先将式I化合物和RAD001以合适浓度溶于运载体中。患有指定肿瘤的小鼠每天以5mg/kg RAD001或30mg/kg式I化合物口服给药,或者是以指定天数以两种化合物联合给药。每个治疗组含10只动物,每个实验至少重复两次。治疗开始于肿瘤植入后的第7天。在此时间点,肿瘤体积约达100mm3。监测肿瘤生长,按所描述的方法计算肿瘤体积。研究结束时,处死小鼠,记录体重和肿瘤重量,采集肿瘤用于分析。式I化合物的疗效用T/C比值来确定,其中T和C分别是治疗结束时药物治疗组和运载体治疗组的肿瘤重量的中值。按照美国国家癌症研究所癌症治疗部药物评价分部(Drug Evaluation Branch of the Division of Cancer Treatment,National Cancer Institute)的标准,T/C比值如低于0.42被认作具有活性。
结果:观察了式I化合物对源于病人的HCC异种移植细胞系(07-0409、29-0909A、01-0909)的抗肿瘤活性,仅显示了HCC07-0409的数据。在整个治疗过程中,未观察到明显的体重减少或者急性死亡,表明式I化合物的治疗是安全的,其毒性是可接受的。图3/6、5/6和6/6显示,异种移植肿瘤的生长率受式I化合物或RAD001单药物治疗的抑制,但未诱发肿瘤消退。当两种药物被组合时,其抗肿瘤效果明显优于单个药物,表明两个化合物具有协同作用。
Claims (9)
1.一种药物组合产品,包含:
a)4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其混合物、或其药学上可接受的盐,
b)至少一种mTOR抑制剂,其中所述的mTOR抑制剂是依维莫司。
2.根据权利要求1的药物组合产品,其用于治疗或预防肾细胞癌和肝细胞癌进展。
3.根据权利要求1或2的药物组合产品,其中所述的4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮以及至少一种mTOR抑制剂被分别给药、同时给药或序贯给药。
4.权利要求1的组合产品在制备用于治疗或预防肾细胞癌和肝细胞癌进展的药物中的用途。
5.根据权利要求4的用途,其中所述药物的给药方式为所述的4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮以及至少一种mTOR抑制剂被分别给药、同时给药或序贯给药。
6.根据权利要求1的组合产品,其中所述的4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其混合物、或其药学上可接受的盐,按每天500mg剂量,给药5天/停药2天的方式给药。
7.根据权利要求1的药物组合产品,其中所述的依维莫司以至少2.5mg/天的剂量给药。
8.根据权利要求7的药物组合产品,其中所述的依维莫司以5-10mg/天的剂量给药。
9.根据权利要求1的药物组合产品,其中所述的4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体、或其混合物是其乳酸盐的形式。
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WO2012158994A1 (en) * | 2011-05-19 | 2012-11-22 | Novartis Ag | 4-amino-5-fluoro-3- [6- (4 -methylpiperazin- 1 - yl) - 1h - benzimidazol - 2 - yl] - 1h - quinoli n-2-one for use in the treatment of adenoid cystic carcinoma |
GB201217890D0 (en) * | 2012-10-05 | 2012-11-21 | Virttu Biolog Ltd | Treatment of cancer |
US20160030401A1 (en) | 2013-03-13 | 2016-02-04 | The Board Of Regents Of The University Of Texas System | Use of mtor inhibitors for prevention of intestinal polyp growth and cancer |
US9814703B2 (en) | 2013-11-14 | 2017-11-14 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for treating cancer by activation of BMP signaling |
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WO2011128405A1 (en) | 2011-10-20 |
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IL222313A0 (en) | 2012-12-31 |
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CA2795089A1 (en) | 2011-10-20 |
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JP2013525292A (ja) | 2013-06-20 |
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SG184311A1 (en) | 2012-11-29 |
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