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首页> 外文期刊>Cell cycle >A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors.
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A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors.

机译：人类第一个阶段的PHA-793887 I剂量递增研究是多种细胞周期蛋白依赖性激酶（CDK2、1和4）的抑制剂，揭示了实体瘤患者意外的肝毒性。

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BACKGROUND: PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887. RESULTS: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses >/=44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. PATIENTS AND METHODS: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated. CONCLUSION: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.
机译：背景：PHA-793887是多种细胞周期蛋白依赖性激酶（CDK）的抑制剂，对CDK2，CDK1和CDK4具有活性。这项首次人体研究的主要目标是确定PHA-793887的剂量极限毒性（DLT），最大耐受剂量（MTD）和II期推荐剂量。结果：尽管在初始剂量水平下毒性是可以接受的，但在> / = 44 mg / m2的剂量下，PHA-793887的耐受性差。在所有剂量水平上，最常见的事件是胃肠道或神经系统事件。三名患者中有两名在66 mg / m2的剂量水平经历了DLT，九名患者中有三名在44 mg / m2的剂量水平经历了DLT。除一名患者外，其余所有患者均具有肝毒性。在以44 mg / m2剂量治疗的一名患者中观察到致命性肝肾衰竭。没有客观反应，但有五名患者观察到疾病稳定。在所研究的剂量范围内，药代动力学研究表明，全身暴露于PHA-793887随剂量增加，并且与时间无关。由于严重的肝毒性，该研究在招募19名患者后终止。患者和方法：以4、11、22、44和66 mg / m2的PHA-793887剂量在4周的第1天，第8天和第15天以1小时静脉输注的方式治疗3到6名患者。研究了安全性和药代动力学。结论：PHA-793887诱导了严重的，剂量相关的肝毒性，这是临床前模型无法预测的，目前尚无法进一步临床开发。

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