Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours
Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours
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DOI：
10.3747/co.19.866
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发表时间：
2012-02-01
期刊：
影响因子：
2.6
通讯作者：
Munzert, G.
中科院分区：
文献类型：
--
作者：
Frost, A.;Mross, K.;Munzert, G.
这项开放标签I期研究采用加速滴定设计，以确定BI 2536的最大耐受剂量，BI 2536是一种有效的、高选择性的小分子polo样激酶1 （Plk1）抑制剂。方法晚期实体瘤患者在每21天疗程的第1-3天静脉输注BI 2536 (50-70 mg)，每次60分钟。没有疾病进展或无法维持的毒性的受者可以接受额外的治疗疗程。最大耐受剂量是根据剂量限制性毒性确定的。其他评估包括根据实体肿瘤反应评价标准的安全性、药代动力学特征和抗肿瘤活性。结果共入组21例患者。在研究计划中，BI 2536的最大耐受剂量确定为60 mg。剂量限制性毒性包括血液学事件、高血压、肝酶升高和疲劳。最常见的药物相关不良事件是轻度至中度疲劳、白细胞减少、便秘、恶心、粘膜炎症、厌食和脱发。BI 2536的药代动力学在剂量范围内呈线性关系。血浆浓度谱表现出多室药代动力学行为，终末消除半衰期为20-30小时。在目前的研究中，BI 2536显示出可接受的安全性，值得进一步研究Plk1抑制剂在该患者群体中的应用。
BackgroundThis open-label phase I study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor.MethodsPatients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50-70 mg) on days 1-3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors.ResultsThe study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi-compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20-30 hours.ConclusionsIn the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.