Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors
Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors
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DOI：
10.1159/000448621
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发表时间：
2016-01-01
期刊：
影响因子：
3.5
通讯作者：
Richards, Donald
中科院分区：
文献类型：
--
作者：
Calvo, Emiliano;Braiteh, Fadi;Richards, Donald
目的：LY2603618是一种选择性的检查点激酶1(CHK1)抑制剂，也是DNA损伤检查点的关键调节因子，可增强抗代谢药物的作用。这项I期研究确定了LY2603618联合吉西他滨的推荐II期剂量。患者和方法：晚期/转移性疾病患者在吉西他滨(1000 mg/m(2))后给予LY2603618(70-250 mg/m(2)或平定剂量200或230 mg/m(2))。安全性和药代动力学(PK)评价。结果：在入选的50名患者中，可能与研究药物治疗有关的常见不良事件包括疲劳(44%)、血小板下降(42%)、中性粒细胞下降(32%)、恶心(26%)和血红蛋白下降(20%)。LY2603618的全身暴露呈剂量依赖性增加，而清除量相对剂量无关。LY2603618的平均半衰期各不相同，但持续时间仍然适合维持人体暴露，同时将累积降至最低。吉西他滨对LY2603618 PK无明显影响。在非临床模型中，所有剂量的血浆暴露都与最大药效作用相关。1例非小细胞肺癌患者部分缓解，22例病情稳定。结论：LY2603618联合吉西他滨的最大耐受量为200 mg/m(2)，推荐的II期剂量为LY2603618 230 mg联合吉西他滨。(C)2016年S.Karger AG，巴塞尔
Objective: LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine. Patients and Methods: Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m(2) or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m(2)). Safety and pharmacokinetics (PK) were assessed. Results: Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease. Conclusions: The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m(2), but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose. (C) 2016 S. Karger AG, Basel