Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer
Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer
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DOI：
10.1200/jco.2015.64.5788
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发表时间：
2016-05-20
影响因子：
45.3
通讯作者：
Bendell, Johanna
中科院分区：
文献类型：
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作者：
Hong, David;Infante, Jeffrey;Bendell, Johanna
目的主要目的是确定检查点激酶 1 抑制剂 LY2606368 作为单一疗法的安全性、毒性和推荐的 II 期剂量方案。患者和方法这项 I 期非随机、开放标签剂量递增试验采用 3 + 3 剂量递增方案，纳入晚期实体瘤患者。静脉注射LY2606368的剂量按时间表1（每14天第1天至第3天）从10 mg/m(2)递增至50 mg/m(2)，或按时间表2（每14天第1天）从40至130 mg/m(2)。评估了安全性措施和药代动力学，并测量了血液、毛囊和循环肿瘤细胞中的药效学。结果 45 名患者接受治疗；七名患者出现了剂量限制性毒性（均为血液学毒性）。最大耐受剂量 (MTD) 为 40 mg/m(2)（附表 1）和 105 mg/m(2)（附表 2）。最常见的 3 级或 4 级治疗相关不良事件是中性粒细胞减少症、白细胞减少症、贫血、血小板减少症和疲劳。 73.3% 的患者出现 4 级中性粒细胞减少症，且症状为暂时性（通常为 5 天）。发热性中性粒细胞减少症的发生率较低（7%）。每个方案的 MTD 下前 72 小时内 LY2606368 的暴露（0 至 72 小时曲线下的面积）与导致最大肿瘤反应的小鼠异种移植物中的暴露一致。在两个方案的 MTD 下均观察到 LY2606368 的少量周期内和周期间积累。两名患者 (4.4%) 出现部分缓解；一名患有肛门鳞状细胞癌 (SCC)，一名患有头颈部鳞状细胞癌。 15 名患者 (33.3%) 获得了稳定疾病的最佳总体反应（范围为 1.2 至 6.7 个月），其中 6 名患有鳞状细胞癌。结论 每 14 天一次 LY2606368 剂量 105 mg/m(2) 正在评估为鳞状细胞癌患者剂量扩展队列中的推荐 II 期剂量。
PurposeThe primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy.Patients and MethodsThis phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m(2) on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m(2) on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells.ResultsForty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m(2) (schedule 1) and 105 mg/m(2) (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically, 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC.ConclusionAn LY2606368 dose of 105 mg/m(2) once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.