A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies
A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies
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DOI：
10.1158/1078-0432.ccr-08-2429
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
Takimoto, Chris H.
中科院分区：
文献类型：
--
作者：
Goel, Sanjay;Mita, Alain C.;Takimoto, Chris H.
目的：甲磺酸淫羊藿素(E7389)是一种非紫杉烷类微管动力学抑制剂，是一种结构简化的合成类似物，其作用机制不同于传统的微管蛋白靶向药物。这项I期研究确定了晚期实体肿瘤患者3/4周给药的最大耐受量(MTD)和药代动力学。实验设计：患者接受甲磺酸灯盏花素(1小时静脉注射。28天周期中的第1、8和15天)。剂量从0.25 mg/m(2)开始，以剂量限制毒性(DLT)为指导逐步递增。结果：32例患者应用甲磺酸灯盏花素(0.25、0.5、0.7、1.0或1.4 mg/m(2))治疗。中性粒细胞减少是主要的DLT：在1.4 mg/m(2)时，2例患者出现4级中性粒细胞减少，其中1例还出现3级疲劳；另外3例患者出现3级中性粒细胞减少，在第15天的第1周期中未接受治疗。因此，MTD为1.0 mg/m(2)。疲劳(53%，3级，无4级)、恶心(41%，均为1/2级)和厌食症(38%，3级，无4级)是最常见的eribuin相关不良事件。8例患者报告1/2级神经病变(无3/4级)。在所研究的剂量范围内，灯盏花素的药代动力学与剂量成比例。1名患者(宫颈癌)获得了持续79天的未确认部分应答。10例患者病情稳定。结论：28天周期的第1、8和15天给药，1.0 mg/m(2)剂量的耐受性可控，并受到中性粒细胞减少和疲劳的限制。
Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies.Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m(2) with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized.Results: Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m(2)). Neutropenia was the principal DLT: At 1.4 mg/m(2), two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m(2). Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease.Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m(2) with further dose escalation limited by neutropenia and fatigue.