CN114746096A - 使用阿伐替尼治疗嗜酸性粒细胞紊乱 - Google Patents
使用阿伐替尼治疗嗜酸性粒细胞紊乱 Download PDFInfo
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- CN114746096A CN114746096A CN202080081643.7A CN202080081643A CN114746096A CN 114746096 A CN114746096 A CN 114746096A CN 202080081643 A CN202080081643 A CN 202080081643A CN 114746096 A CN114746096 A CN 114746096A
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- eosinophilic
- compound
- pharmaceutically acceptable
- eosinophils
- patients
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Abstract
本发明涉及化合物(I)或其药学上可接受的盐,用于治疗嗜酸性粒细胞紊乱粒,包括嗜酸性粒细胞增多综合征的用途。
Description
相关申请的交叉引用
本申请要求2019年10月4日提交的美国临时申请第62/910931号的优先权。上述申请的全部内容通过引用并入本文。
背景技术
嗜酸性粒细胞是来源于骨髓的粒细胞,在宿主抵抗感染、抗肿瘤细胞毒性和伤口愈合中有重要作用。嗜酸性粒细胞涉及包括过敏性疾病在内的各种疾病,并被认为在过敏性疾病的发病中发挥重要作用,如慢性支气管哮喘和特应性皮炎(Adv.Immunol.,39,177(1986),Immunol.Today,13,501(1992))。除了上述疾病之外,嗜酸性粒细胞还涉及通常称为嗜酸性粒细胞增多综合征(HES)的疾病、嗜酸性粒细胞增多、嗜酸性粒细胞肠胃炎、嗜酸性粒细胞白血病、嗜酸性粒细胞肉芽肿和木村病(Ann.Intern.Med.,97,78(1982))。
嗜酸性粒细胞分为一些亚群,正常密度嗜酸性粒细胞和低密度嗜酸性粒细胞。已证实嗜酸性粒细胞在活化时是低密度嗜酸性粒细胞(Immunology,47,531(1982))。低密度嗜酸性粒细胞也称为活化的嗜酸性粒细胞。据报告,HES患者外周血中嗜酸性粒细胞除发生了定量变化外,还发生了定性变化(Clin.Exp.Immunol.,24,423(1976))。活化的嗜酸性粒细胞与HES症状的严重程度有关(Am.J.Cardiol.,52,321(1983))。除HES患者外,还在支气管哮喘患者的外周血和支气管肺泡灌洗液(BALE)中发现了活化的嗜酸性粒细胞(Am.Rev.Respir.Dis,132,981(1985))。各种受体,例如细胞因子的受体,在活化的嗜酸性粒细胞(低密度嗜酸性粒细胞)上表达(J.Immunol.,142,4416(1989))。与正常密度的嗜酸性粒细胞相比,这些低密度的嗜酸性粒细胞显示出对IL-5提高的敏感性(Clin.Exp.Immunol.,85,312(1991);J.Exp.Med.,172,1347(1990))。
目前,嗜酸性粒细胞紊乱患者的治疗包括施用类固醇。然而,类固醇施用通常与副作用有关。特别地,该治疗具有一些其它问题,使得当中断类固醇施用时,患者的病况会返回到原始状态,并且延长的类固醇施用可以诱导类固醇抗性。因此,需要对嗜酸性粒细胞相关紊乱进行安全且有效的治疗。
发明内容
现已发现,如下所示的化合物(I)有效降低患者的嗜酸性粒细胞水平(实施例1)。基于该发现,本文公开了使用化合物(I)或其药学上可接受的盐在有需要的受试者中降低嗜酸性粒细胞水平的方法。
本公开的一个方面是治疗嗜酸性粒细胞紊乱的方法,其包括向有需要的受试者施用治疗有效量的化合物(I)或其药学上可接受的盐。
本公开的另一个方面是化合物(I)或其药学上可接受的盐在制备用于治疗嗜酸性粒细胞紊乱的药物中的用途。
本公开的另一方面是用于治疗嗜酸性粒细胞紊乱的化合物(I)或其药学上可接受的盐。
附图说明
图1显示了在1期临床试验2周后,在用化合物(I)治疗的成年患者中,C1D15(第1周期第15天)的绝对嗜酸性粒细胞相对于基线水平的变化。化合物(I)的剂量范围在30mg和400mg之间。患者具有>0.5的基线绝对嗜酸性粒细胞计数。
图2显示了在1期临床试验2周后,在用化合物(I)治疗KIT等位基因分数<10%的成年患者中,C1D15(第1周期第15天)的绝对嗜酸性粒细胞相对于基线水平的变化。化合物(I)的剂量范围在30mg和400mg之间。患者具有>0.5的基线绝对嗜酸性粒细胞计数。
图3显示了在1期临床试验2周后,用化合物(I)(剂量为300mg)治疗KIT等位基因分数在10%和40%之间的成人患者中,C1D15(第1周期第15天)的绝对嗜酸性粒细胞相对于基线水平的变化。患者具有>0.5的基线绝对嗜酸性粒细胞计数。
图4显示了在1期临床试验2周后,用化合物(I)治疗KIT等位基因分数>40%的成人患者中,C1D15(第1周期第15天)的绝对嗜酸性粒细胞相对于基线水平的变化。化合物(I)的剂量范围在200mg和300mg之间。患者具有>0.5的基线绝对嗜酸性粒细胞计数。
发明详述
嗜酸性粒细胞与许多疾病和紊乱的发病机理有关。嗜酸性粒细胞是一类白细胞,其有助于对抗感染并在机体免疫应答中起作用。它们是血液和某些组织的正常细胞组分,包括脾脏、淋巴结、胸腺和胃肠道、呼吸道和泌尿生殖系统的粘膜下区域。每立方毫米的血液0-450个嗜酸性粒细胞的计数被认为是在正常限度内。
当在身体不同部位发现嗜酸性粒细胞高于正常量和/或当低密度与正常密度的嗜酸性粒细胞之比高于正常比率(例如大于30%)时,就会发生嗜酸性粒细胞紊乱。本文所述的嗜酸性粒细胞紊乱的特征在于过量的嗜酸性粒细胞(嗜酸性粒细胞增多)。嗜酸性粒细胞数量的增加使组织发炎并引起器官损伤。心脏、肺、皮肤和神经系统最常受到影响,但任何器官都可能受到损害。
根据嗜酸性粒细胞水平升高的位置诊断嗜酸性粒细胞紊乱:
嗜酸性粒细胞肺炎(肺)
嗜酸性粒细胞心肌病(心脏)
嗜酸性粒细胞食管炎(食管-EoE)
嗜酸性粒细胞胃炎(胃-EG)
嗜酸性粒细胞胃肠炎(胃和小肠-EGE)
嗜酸性粒细胞肠炎(小肠)
嗜酸性粒细胞结肠炎(大肠-EC)
嗜酸性粒细胞增多综合征(血液和任何器官-HES)
此外,嗜酸性粒细胞发挥作用的疾病和紊乱(即嗜酸性粒细胞紊乱)的非限制性实例是:哮喘、免疫球蛋白(IgE)介导的食物过敏、嗜酸性食管炎(食管炎症)、炎性肠病、慢性阻塞性肺病、过敏性结肠炎、星形-食管反流、嗜酸性胃肠疾病(EGID)、嗜酸性胃肠炎、心内膜心肌纤维化、Loeffler心内膜炎、Davies病、与嗜酸性粒细胞增多相关的发作性血管性水肿、嗜酸性粒细胞增多-肌痛综合征/西班牙毒性油综合征、肝硬化、疱疹样皮炎、大疱性类天疱疮、色斑综合征、急性骨髓性嗜酸性粒细胞白血病、急性淋巴细胞性嗜酸性粒细胞白血病、伴有嗜酸性粒细胞增多的系统性肥大细胞增多症、过敏性鼻炎、湿疹、Wegener肉芽肿病、结节性多动脉炎、嗜酸性筋膜炎和类风湿性关节炎。
因此,本公开的一个方面是治疗嗜酸性粒细胞紊乱的方法,其包括向受试者施用治疗有效量的化合物(I)或其药学上可接受的盐。在一个实施方案中,嗜酸性粒细胞紊乱选自嗜酸性粒细胞增多综合征、嗜酸性粒细胞增多、嗜酸性粒细胞肠胃炎、嗜酸性粒细胞白血病、嗜酸性粒细胞肉芽肿和木村病。
在一个实施方案中,嗜酸性粒细胞紊乱是嗜酸性粒细胞增多综合征。在一个具体的实施方案中,嗜酸性粒细胞增多综合征是特发性嗜酸性粒细胞增多综合征。在一个实施方案中,嗜酸性粒细胞紊乱是嗜酸性粒细胞白血病。在一个具体的实施方案中,嗜酸性粒细胞白血病是慢性嗜酸性粒细胞白血病。在另一个实施方案中,嗜酸性粒细胞紊乱对伊马替尼、舒尼替尼和/或瑞戈非尼的治疗是难治性的。在一个具体的实施方案中,嗜酸性粒细胞紊乱对伊马替尼的治疗是难治性的。
本公开的另一个方面是减少需要其的受试者中嗜酸性粒细胞数量的方法,其包括向所述受试者施用治疗有效量的化合物(I)或其药学上可接受的盐。
在一个实施方案中,所公开的方法减少了血液、骨髓、胃肠道(例如食道、胃、小肠和结肠)或肺中的嗜酸性粒细胞的数目。在另一个实施方案中,本文公开的方法减少了血液嗜酸性粒细胞的数量。在另一个实施方案中,本文公开的方法减少了肺嗜酸性粒细胞的数量。在又另一个实施方案中,本文公开的方法减少了嗜酸性粒细胞前体细胞的数量。
在另一个实施方案中,所公开的方法使嗜酸性粒细胞的数目减少(施用后)至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%;至少约90%、至少约95%或至少约99%。在一个具体的实施方案中,本文公开的方法将嗜酸性粒细胞的数目减少至检测限以下。
在另一个实施方案中,所公开的方法使嗜酸性粒细胞前体的数目减少(施用后)至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%或至少约99%。在一个具体实施方案中,本文公开的方法将嗜酸性粒细胞前体的数目减少至检测限以下。
在另一个实施方案中,所公开的方法在单次施用化合物(I)或其药学上可接受的盐后将嗜酸性粒细胞减少至低于检测的水平。在一个具体的实施方案中,单次施用化合物(I)或其药学上可接受的盐将嗜酸性粒细胞减少至低于检测水平至少约1天、至少约2天、至少约3天、至少约4天、至少约5天、至少约6天、至少约7天、至少约2周、至少约3周、至少约4周、至少约5周、至少约6周、至少约7周、至少约8周、至少约9周、至少约10周、至少约12周、至少约14周、至少约16周、至少约20周、或至少约25周。
在进一步的实施方案中,所公开的方法在单次施用化合物(I)或其药学上可接受的盐后减少嗜酸性粒细胞前体。在一个具体的实施方案中,单次施用化合物(I)或其药学上可接受的盐将嗜酸性粒细胞前体减少至低于检测水平至少约1天、至少约2天、至少约3天、至少约4天、至少约5天、至少约6天、至少约7天、至少约2周、至少约3周、至少约4周、至少约5周、至少约6周、至少约7周、至少约8周、至少约9周、至少约10周、至少约12周、至少约14周、至少约16周、至少约20周、或至少约25周。
本公开提供治疗嗜酸性粒细胞紊乱的方法,其包括向有需要的受试者每日一次施用30mg至400mg(例如100mg至300mg、或200mg至300mg)的量的化合物(I)和/或其药学上可接受的盐。在一些实施方案中,所述量为25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg每日一次。在一些实施方案中,所述量为25mg每日一次。在一些实施方案中,所述量为50mg每日一次。在一些实施方案中,所述量为75mg每日一次。在一些实施方案中,所述量为100mg每日一次。在一些实施方案中,所述量为150mg每日一次。在一些实施方案中,所述量为200mg每日一次。在一些实施方案中,所述量为250mg每日一次。在一些实施方案中,所述量为300mg每日一次。
如本文所用,“化合物(I)”是指具有化学名称(S)-1-(4-氟苯基)-1-(2-(4-(6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)哌嗪基-1-基)嘧啶-5-基)乙烷-1-胺的化合物,其具有以下结构:
化合物(I)公开于WO 2015/057873中,其全部教示以引用的方式并入本文中。化合物(I)的制备描述于WO 2015/057873的实施例7中。
化合物(I)被开发用于选择性靶向KIT D816V和其他KIT外显子17突变,并在体外证明了对KIT D816V的有效和选择性活性,在体内对酪氨酸激酶抑制剂(TKI)耐药的肥大细胞瘤模型具有强大的生长抑制作用,以及在毒理学和安全药理学研究中在活性剂量下的耐受性。在患有晚期系统性肥大细胞增多症(AdvSM)的患者中进行的化合物(I)的1期研究(NCT 02561988)正在评价安全性和初步疗效。推荐的2期剂量(RP2D)被确定为300mg每日一次(QD),并且该研究的扩展队列是在更大的患者队列中进一步评估该剂量的疗效和安全性,以及验证已经开发用于评估化合物(I)对患有AdvSM的患者的症状改善的影响的AdvSM症状评估表(AdvSM-SAF)。基于以300mg每日一次治疗的患者的新出现的安全性和疗效数据,增加了以200mg每日一次治疗的患者的另外的队列。
在嗜酸性粒细胞紊乱中发现D816位置的活化突变,最常见的突变是D816V和D816Y。在激酶结构域的活化环中发现D816V突变并导致KIT激酶的组成型活化。
用KIT抑制剂如伊马替尼的初步治疗也已显示有益于嗜酸性粒细胞紊乱的初始治疗。具体地,伊马替尼被批准用于治疗特应性嗜酸性粒细胞增多综合征。然而,在数月内通过体细胞突变发生对伊马替尼的耐药性。这些次生伊马替尼抗性突变最常见地位于外显子11、13、14、17或18上。需要治疗剂来治疗嗜酸性粒细胞紊乱患者,特别是具有外显子17突变的患者。
化合物(I)或其药学上可接受的盐可对外显子17中的一个或多个KIT突变(例如D816V、D816Y、D816F、D816K、D816H、D816A、D816G、D820A、D820E、D820G、N822K、N822H、Y823D和A829P)具有活性,并且对野生型KIT的活性小得多。
在一个实施方案中,化合物(I)或其药学上可接受的盐可对外显子17中的KIT中的D816突变具有活性。在一个具体的实施方案中,所述D816突变是D816V。在另一个具体的实施方案中,所述D816突变是D816Y。
如本文所用,术语“药学上可接受的盐”是指本公开的化合物的无毒的盐形式。化合物(I)的药学上可接受的盐包括衍生自合适的无机和有机酸和碱的那些。药学上可接受的盐是本领域熟知的。合适的药学上可接受的盐是例如公开在Berge,S.M.,等人J.Pharma.Sci.66:1-19(1977)中的那些。该文章中公开的药学上可接受的盐的非限制性实例包括:乙酸;苯磺酸盐;苯甲酸盐;碳酸氢盐;酒石酸氢盐;溴化物;依地酸钙;樟脑磺酸盐;碳酸盐;氯化物;柠檬酸盐;二盐酸盐;乙二胺四乙酸盐;乙二磺酸盐;雌内酯;乙磺酸盐;富马酸酯;葡庚糖酸盐;葡糖酸盐;谷氨酸盐;乙醇酰胂酸盐;己基间苯二酚酯;哈胺;氢溴酸盐;盐酸盐;羟基萘甲酸盐;碘化物;羟乙基磺酸盐;乳酸;乳糖酸盐;苹果酸盐;马来酸酯;扁桃酸盐;甲磺酸盐;溴甲烷;硝酸甲酯;硫酸二甲酯;粘酸盐;萘磺酸酯;硝酸盐;双羟萘酸盐(思波酸盐);泛酸盐;磷酸盐/二磷酸盐;聚半乳糖醛酸盐;水杨酸酯;硬脂酸盐;碱式乙酸酯;琥珀酸酯;硫酸盐;单宁酸盐;酒石酸盐;氯茶碱盐;三乙基碘化物;苄星青霉素;氯普鲁卡因;胆碱;二乙醇胺;乙二胺;葡甲胺;普鲁卡因;铝;钙;锂;镁;钾;钠;和锌。
衍生自适当的酸的药学上可接受的盐的非限制性实例包括:与无机酸如盐酸、氢溴酸、磷酸、硫酸或高氯酸形成的盐;与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸形成的盐;以及通过使用本领域中使用的其它方法如离子交换形成的盐。药学上可接受的盐的另外的非限制性实例包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸酯、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酮酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、和戊酸酯盐。衍生自适当碱的药学上可接受的盐的非限制性实例包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4盐。本公开还设想了本文公开的化合物的任何碱性含氮基团的季铵化。碱金属和碱土金属盐的非限制性实例包括钠、锂、钾、钙和镁。药学上可接受的盐的其它非限制性实例包括使用抗衡离子如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根形成的铵、季铵和胺阳离子。药学上可接受的盐的其它非限制性实例包括苯磺酸盐和葡糖胺盐。
如本文所用,本文公开的化合物的“治疗有效量”是指将在受试者中引起生物学或医学响应,例如降低或抑制酶或蛋白质活性、改善症状、缓解病症或减缓或延迟疾病进展的化合物的量。
如本文所用,术语“患者”或“受试者”是指待通过本公开的方法治疗的生物体。生物体的非限制性实例包括哺乳动物,例如鼠类、猿类、马类、牛类、猪类、犬类、猫类等。在一些实施方案中,所述生物体是人。
如本文所用,术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”当与紊乱或病症结合使用时包括导致紊乱或病症的改善的任何作用,例如减轻、降低、调节、改善和/或消除。疾病或病症的任何症状的严重性的改善或减轻可以根据本领域已知的标准方法和技术容易地进行评估。
嗜酸性粒细胞增多综合征是一类血液病症,其特征在于大量嗜酸性粒细胞-白细胞,其在免疫系统中起重要作用。随着时间的推移,过量的嗜酸性粒细胞进入各种组织,最终损伤器官。
HES的当代分类包括(1)特发性HES,其中HE的原因仍然未知,(2)原发性(肿瘤性)HES,其中嗜酸性粒细胞被发现是克隆的,和(3)继发性(反应性)HES,其中存在细胞因子驱动的非克隆HE。继发性HES的独特形式称为淋巴细胞,其中异常T细胞可在血液中鉴定。
药物组合物
本文所述的化合物(I)和/或其药学上可接受的盐可用作活性药物成分(API)以及用于制备药物组合物的材料,所述药物组合物掺入一种或多种药学上可接受的赋形剂并且适合施用于人类受试者。
在一些实施方案中,本公开提供药物组合物,其包含化合物(I)和/或其药学上可接受的盐和至少一种另外的药学上可接受的赋形剂。如本文所用,术语“药学上可接受的赋形剂”是指药学上可接受的材料、组合物和/或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。每种赋形剂在与主体组合物及其组分相容并且对患者无害的意义上必须是“药学上可接受的”。除非任何常规的药学上可接受的赋形剂与化合物(I)和/或其药学上可接受的盐不相容,如通过产生任何不期望的生物效应或以有害方式与药学上可接受的组合物的任何其它组分相互作用,否则其用途预期在本公开的范围内。
可用作药学上可接受的赋形剂的材料的一些非限制性实例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)黄蓍胶粉末;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,如可可脂和栓剂蜡;(9)油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇类,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯类,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原的水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲液;和(21)药物制剂中使用的其它无毒相容物质。
Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia ofPharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,MarcelDekker,New York,其各自的内容通过引用并入本文,还公开了药学上可接受的赋形剂的另外的非限制性实例,以及用于制备和使用它们的已知技术。
本文公开的药物组合物可以口服、肠胃外、通过吸入喷雾、局部、直肠、鼻、颊、阴道或经由植入的储液器施用。本文所用的术语“肠胃外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。在一些实施方案中,本公开的组合物经口、腹膜内或静脉内施用。本公开的药物组合物的无菌可注射形式可以是水性或油性悬浮液。这些悬浮液可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂配制。无菌可注射制剂也可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂的非限制性实例是水、林格氏溶液和等渗氯化钠溶液。此外,无菌不挥发性油通常用作溶剂或悬浮介质。
为此目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油酯衍生物可用于制备注射剂,天然的药学上可接受的油如橄榄油或蓖麻油,尤其是它们的聚氧乙烯化形式也是如此。这些油溶液剂或悬浮剂还可以含有长链醇稀释剂或分散剂,例如羧甲基纤维素或通常用于配制药学上可接受的剂型(包括乳剂和混悬剂)的类似的分散剂。其它常用于制备药学上可接受的固体、液体或其它剂型的常用的表面活性剂,如吐温、司盘,和其它乳化剂或生物利用度增强剂,其也可用于制剂目的。
本文公开的药物组合物还可以以任何口服可接受的剂型口服施用,所述剂型包括但不限于胶囊剂、片剂、水性混悬剂或溶液剂。当口服使用需要水性悬浮液时,活性成分通常与乳化剂和悬浮剂组合。如果需要,也可以添加某些甜味剂、调味剂或着色剂。在一些实施方案中,包含化合物(I)和/或其药学上可接受的盐的药物组合物是使用本领域已知的方法制备的片剂。在一些实施方案中,片剂是用于口服施用的立即释放片剂。在一些实施方案中,化合物(I)和/或其药学上可接受的盐与药用赋性剂共混以形成立即释放片剂。在一些实施方案中,构成片剂的赋形剂是微晶纤维素、共聚维酮、交联羧甲基纤维素钠和硬脂酸镁。在一些实施方案中,将制剂共混物碾压,压缩成圆形片剂,并在美学上进行膜包衣。
具体实施方式
以下实施例旨在是说明性的,而不旨在以任何方式限制本公开的范围。
实施例1
这是一项旨在评价在患有晚期系统性肥大细胞增多症(AdvSM)和复发性或难治性骨髓恶性肿瘤的成年患者中口服施用化合物(I)的安全性、耐受性、药物代谢动力学、药效学和初步抗肿瘤活性的1期开放标签研究。
本研究由2个部分组成:剂量递增(第1部分)和扩展(第2部分)。第1部分中约有25名患者,第2部分中约有55名患者。
用于研究合格性的系统性肥大细胞增多症诊断确认将使用WHO诊断和亚分类标准进行评估。根据修改后的IWG-MRT-ECNM标准的可评价C-结果用于评估反应。
治疗周期持续时间为28天。患者在C1D1到研究中心进行研究药物的首次给药以及连续PK采样、PD样品采集、生命体征测量、心电图(ECG)监测、患者对症状严重程度的总体印象(PGIS)和欧洲研究和治疗组织癌症核心生活质量问卷(EORTCQLQ-C30)、安全性监测和不良事件(AE)记录。
通过成像(磁共振成像[MRI]或计算机断层扫描[CT])和骨髓(BM)评价,在C3D1、C5D1(仅成像)、C7D1、C11D1和C18D1评估晚期系统性肥大细胞增多症(Advanced SM)响应。C18后,每6个周期评估一次AdvSM的响应。
所有患者均在研究药物的最后一次给药后14(±7)天内参加治疗结束(EOT)访视。EOT访视必须在研究药物的最后一次给药后不超过21天进行。
第1部分(剂量递增)
本研究的剂量递增部分入组了患有AdvSM或复发性或难治性骨髓恶性肿瘤的患者。采用3个患者队列的3+3剂量递增设计。
第一患者队列以30mg的起始剂量每日一次(QD)接受化合物(I)。剂量递增以最高达100%的增量进行,直至以给定剂量水平治疗的≥1名患者具有≥2级非血液学AE或4级血液学AE,并且AE(非血液学或血液学)不能明确归因于除化合物(I)以外的原因,或剂量超过在GIST,BLU-285-1101中进行的化合物(I)首次人体(FIH)研究中确定为安全的最高剂量。
每个队列最初入组了3名患者,当队列由于剂量限制性毒性(DLT)而需要扩展时,入组了另外3名患者(总共6名)。继续剂量递增,直至确定最大耐受剂量(MTD)或低于MTD的推荐2期剂量(RP2D)。
第2部分(扩展)
一旦确定MTD或RP2D,在第2部分中入组最多3组患有以下AdvSM诊断的患者并在RP2D下使用化合物(I)治疗。
·患有ASM的患者。
·患有SM-AHN的患者。
·患有MCL的患者。
基于可用的疗效、PK和长期安全性数据,选择化合物(I)200mg QD作为研究的剩余部分的起始剂量;所有新入组本研究第2部分的患者接受200mg作为其起始剂量。
第2部分入组了2个队列。根据修改后的IWG-MRT-ECNM标准,在基线时没有可测量的C-结果的患者,归因于SM,入组到队列1。根据修改后的IWG-MRT-ECNM标准,基线时至少有1个可测量的C-结果的患者,归因于SM,入组到队列2。根据响应裁定委员会(RAC)裁定的修改后的IWG-MRT-ECNM,第2队列中的患者是确定ORR主要目的的可评价群体。
嗜酸性粒细胞测定
通过常规血液测试参见例如LaGow B等人,eds.PDR Lab Advisor.AComprehensive Point-of-Care Guide for Over 600Lab Tests.1st ed.Montvale,NJ:Thomson PDR,2007;Pagana K,Pagana TJ eds.Mosby's Manual of Diagnostic andLaboratory Tests.5th Ed.St.Louis,Missouri.2014;https://www.ebmconsult.com/articles/lab-test-eosinophil-count和https://www.cancer.net/cancer-types/ leukemia-eosinophilic/diagnosis,在C1D15(第1周期第15天)测量患者中的嗜酸性粒细胞,
上述参考文献和网页的全部教导在此通过引用并入本文。
测试结果在图1-4中示出,其显示使用化合物(I)显著减少患者中绝对嗜酸性粒细胞的数目。
Claims (23)
2.如权利要求1所述的方法,其中所述嗜酸性粒细胞紊乱选自嗜酸性粒细胞增多综合征、嗜酸性粒细胞增多、嗜酸性粒细胞肠胃炎、嗜酸性粒细胞白血病、嗜酸性粒细胞肉芽肿和木村病。
3.如权利要求1所述的方法,其中所述嗜酸性粒细胞紊乱是嗜酸性粒细胞增多综合征。
4.如权利要求1所述的方法,其中所述嗜酸性粒细胞紊乱是嗜酸性粒细胞白血病。
5.如权利要求4所述的方法,其中所述嗜酸性粒细胞白血病是慢性嗜酸性粒细胞白血病。
6.如权利要求1至5中任一项所述的方法,其中所述嗜酸性粒细胞紊乱对伊马替尼、舒尼替尼和/或瑞戈非尼的治疗是难治性的。
7.如权利要求1-6中任一项所述的方法,其中所述受试者在KIT外显子17中具有突变。
8.如权利要求1-7中任一项所述的方法,其中所述受试者在KIT外显子17中具有D816突变。
9.如权利要求8所述的方法,其中所述D816突变是D816V。
10.如权利要求9所述的方法,其中所述D816突变是D816Y。
11.如权利要求1-10中任一项所述的方法,其中所述治疗有效量为30-400mg。
12.如权利要求1-10中任一项所述的方法,其中所述治疗有效量为100-300mg/天。
13.如权利要求1-10中任一项所述的方法,其中所述治疗有效量为100mg/天。
14.如权利要求1-10中任一项所述的方法,其中所述治疗有效量为200mg/天。
15.如权利要求1-10中任一项所述的方法,其中所述治疗有效量为300mg/天。
17.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少20%。
18.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少30%。
19.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少40%。
20.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少50%。
21.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少60%。
22.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少70%。
23.如权利要求16所述的方法,其中施用后绝对嗜酸性粒细胞计数减少至少80%。
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