First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer
First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer
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DOI：
10.1007/s00280-011-1756-z
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发表时间：
2012-03-01
影响因子：
3
通讯作者：
Holen, Kyle D.
中科院分区：
文献类型：
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作者：
Chung, Vincent;Heath, Elisabeth I.;Holen, Kyle D.
目的GSK 923295是CENP-E的抑制剂，CENP-E是在有丝分裂期间染色体排列中重要的关键细胞蛋白。这是一项I期、开放标签、人体最短时间、剂量递增研究，旨在确定GSK 923295的最大耐受剂量（MTD）、安全性和药代动力学。患者和方法既往接受过治疗的实体瘤成人患者连续入组，GSK 923295剂量范围为10 - 250 mg/m2。GSK 923295静脉滴注1 h，每周1次，连续3周，每4周为1个周期。GSK 923295的MTD确定为190 mg/m2。观察到的剂量限制性毒性（均为3级）如下：疲乏（n = 2，5%）、AST升高（n = 1，2.5%）、低钾血症（n = 1，2.5%）和缺氧（n = 1，2.5%）。在所有剂量中，疲劳是最常报告的药物相关不良事件（n = 13; 33%）。腹泻（n = 12，31%）、恶心（n = 8，21%）和呕吐（n = 7，18%）的胃肠道毒性通常为轻度。中性粒细胞减少症的发生率较低（13%）。有2例神经病变报告，无粘膜炎或脱发报告。GSK 923295在10 - 250 mg/m2范围内表现出与剂量成比例的药代动力学，每周给药后不会蓄积。GSK 923295的平均终末消除半衰期为9-11 h。1例尿路上皮癌患者在250 mg/m2剂量水平下出现了持久的部分缓解。结论新型CENP-E抑制剂GSK 923295具有剂量比例的药代动力学和低数量的3级或4级不良事件。观察到的骨髓抑制和神经病变的发生率较低。进一步的研究可能会提供一个更完整的了解的潜力，GSK 923295作为一种抗增殖剂。
Purpose GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, Wrst-time-in-human, dose-escalation study, to determine the maximumtolerated dose (MTD), safety, and pharmacokinetics of GSK923295.Patients and methods Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.Results A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level.Conclusions The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.