A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors
A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors
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DOI：
10.1007/s10637-009-9374-x
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发表时间：
2011-06-01
影响因子：
3.4
通讯作者：
LoRusso, Patricia
中科院分区：
文献类型：
--
作者：
Burris, Howard A., III;Jones, Suzanne F.;LoRusso, Patricia
目的：研究晚期实体瘤患者每周静脉输注1小时，连续3周（共28天）的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、安全性和药代动力学特征。实验设计30例患者入组，采用初始加速剂量递增阶段，随后是标准剂量递增阶段，剂量范围为1- 8mg /m(2)/周。在第1周期治疗期间获得药代动力学样本、皮肤穿刺活检和肿瘤活检（在可触及肿瘤的患者中）。每两个治疗周期进行一次疾病评估。MTD定义为7 mg/m(2)，每周1小时滴注，连续3周，共28天。MTD超过8mg /m(2)，原因是2级（1例）和3级中性粒细胞减少（1例）的dlt导致无法在第1周期给予第15天的剂量。中性粒细胞最低点出现在大约第8天，恢复期为3-7天。最常见的毒性是恶心、腹泻、疲劳和中性粒细胞减少。未见脱发、粘膜炎和神经病变。据报道，在9例患者中，病情稳定是治疗的最佳反应。结论ispinesib推荐剂量为7 mg/m(2)，每周1 h，连续3周，28天疗程。
Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. Experimental Design Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1-8 mg/m(2)/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. Results The MTD was defined as 7 mg/m(2) administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m(2) due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3-7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. Conclusion The recommended dose of ispinesib is 7 mg/m(2) over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.