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首页> 外文期刊>British Journal of Cancer >Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers
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Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers

机译：AZD1208的I期研究（一种前病毒整合性莫洛尼病毒激酶抑制剂在实体和血液癌症中的应用）

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Background Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. Methods Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. Results Sixty-seven patients received treatment: 32 in the AML study over a 120–900?mg dose range, and 25 in the solid tumour study over a 120–800?mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900?mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. Conclusions Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.
机译：背景技术Proviral整合莫洛尼病毒（PIM）激酶（PIM1、2和3）在几种肿瘤类型中过表达，并有助于肿瘤发生。 AZD1208是一种有效的ATP竞争性PIM激酶抑制剂，已针对患有复发性或难治性急性髓细胞性白血病（AML）或晚期实体瘤的患者进行了研究。方法进行了两项剂量递增研究，以评估AZD1208在AML和实体瘤中的安全性和耐受性，并确定最大耐受剂量（MTD）。次要目标是评估AZD1208的药代动力学，药效学（PD）和初步疗效。结果67例患者接受了治疗：AML研究中32例，剂量范围为120至900 mg，实体瘤研究中的25例，剂量范围为120至800 mg。两项研究中几乎所有患者（98.5％）都经历了不良事件，其中大部分是胃肠道疾病（92.5％）。限制剂量的毒性包括皮疹，疲劳和呕吐。 AZD1208的耐受量为900？mg，未确认方案定义的MTD。多次给药后AZD1208增加CYP3A4活性，导致药物清除率增加。没有临床反应; PD分析显示AZD1208的生物活性。结论尽管AZD1208缺乏单药临床疗效，但PIM激酶抑制仍可能具有抗癌作用，可能与其他药物联用。

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