A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours
A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours
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DOI：
10.1016/j.ejca.2011.11.001
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发表时间：
2012-01-01
影响因子：
8.4
通讯作者：
Munzert, Gerd
中科院分区：
文献类型：
--
作者：
Schoffski, Patrick;Awada, Ahmad;Munzert, Gerd
背景：Volasertib （BI 6727）是一种有效的选择性细胞周期激酶抑制剂，通过靶向polo样激酶（Plk）诱导有丝分裂阻滞和细胞凋亡。这项I期剂量递增研究评估了volasertib的最大耐受剂量（MTD）、安全性和有效性以及药代动力学（PK）参数。方法：本试验采用开放标签、毒性指导剂量滴定设计。进行性晚期或转移性实体瘤患者每3周接受一次1小时的volasertib输注。共有65名患者接受了12-450毫克剂量的治疗。结果：可逆性血液学毒性为主要毒副作用；血小板减少、中性粒细胞减少和发热性中性粒细胞减少构成主要的剂量限制事件。贫血（所有级别22%，级别3:8%）、中性粒细胞减少症（15%，级别3/4:14%）、疲劳（15%，级别3:2%）和血小板减少症（14%，级别3/4:14%）是最常见的药物相关不良事件。MTD为400 mg；然而，基于总体耐受性，进一步发展的推荐剂量为300毫克。3例患者获得部分缓解。40%的患者报告病情稳定为最佳反应。两名患者保持无进展bb101年。PK分析显示，没有迹象表明偏离“剂量线性PK”行为，分布量大（约4000 l），清除率中等，半衰期长（类似于111 h）。结论：这项首次人体试验表明volasertib具有良好的PK特征，毒性可控。不出所料，最常见的是血液病。已观察到令人鼓舞的初步抗肿瘤活性，支持Plk抑制作为治疗方法。volasertib在II期单药和联合试验中的临床开发正在进行中。(C) 2011 Elsevier Ltd.版权所有。
Background: Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters.Methods: This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg.Results: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3:8%), neutropenia (15%; grade 3/4:14%), fatigue (15%; grade 3:2%), and thrombocytopenia (14%; grade 3/4:14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (similar to 111 h).Conclusion: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing. (C) 2011 Elsevier Ltd. All rights reserved.