Phase I, Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-Day Schedule in Patients with Advanced Cancer
Phase I, Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-Day Schedule in Patients with Advanced Cancer
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DOI：
10.1158/1078-0432.ccr-11-0509
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发表时间：
2012-01-15
影响因子：
11.5
通讯作者：
Schwartz, Gary K.
中科院分区：
文献类型：
--
作者：
Flaherty, Keith T.;LoRusso, Patricia M.;Schwartz, Gary K.
目的：确定同类首次口服CDK 4/6抑制剂PD 0332991每日一次给药21/28天的剂量限制性毒性（DLT）和最大耐受剂量（MTD）（3/1方案）治疗视网膜母细胞瘤蛋白（Rb）阳性晚期实体瘤患者，并描述相对于药物作用的药代动力学-药效学关系。这项开放标签的I期研究（NCT 00141297）在标准的3 + 3设计中招募了6个剂量递增队列中口服PD 0332991的患者。在75、125和150 mg每日一次剂量水平下，共5例患者（12%）观察到DLT。PD 0332991的MTD和II期推荐剂量为125 mg每日一次。中性粒细胞增多症是唯一的剂量限制效应。第1周期后，分别有5例（12%）、3例（7%）和1例（2%）患者发生3级中性粒细胞减少、贫血和白细胞减少。最常见的非血液学不良事件包括疲劳、恶心和腹泻。37例患者可评价肿瘤反应; 10例（27%）疾病稳定>4个周期，其中6例获得长期获益（>= 10个周期）。PD 0332991被缓慢吸收（中位Tmax，5.5小时），并缓慢消除（平均半衰期为25.9小时），分布容积大（平均值，2，793 L）。浓度-时间曲线下面积随剂量线性增加。使用E-max模型，中性粒细胞减少症被证明是成比例的exposure.Conclusions：PD 0332991保证II期试验在125毫克每天一次，在该剂量中性粒细胞减少症是唯一的显着毒性。临床癌症研究; 18（2）; 568-76。(C)2011年AACR。
Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects.Experimental Design: This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design.Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for >4 cycles of whom six derived prolonged benefit (>= 10 cycles). PD 0332991 was slowly absorbed (median T-max, 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E-max model, neutropenia was shown to be proportional to exposure.Conclusions: PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. Clin Cancer Res; 18(2); 568-76. (C) 2011 AACR.