Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia.
Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia.
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DOI：
10.1111/cas.12814
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发表时间：
2015-11
期刊：
影响因子：
5.7
通讯作者：
Naoe T
中科院分区：
文献类型：
--
作者：
Kobayashi Y;Yamauchi T;Kiyoi H;Sakura T;Hata T;Ando K;Watabe A;Harada A;Taube T;Miyazaki Y;Naoe T
这项在日本急性髓性白血病患者中进行的I期试验评价了volasertib（BI 6727）（一种选择性波罗样激酶抑制剂）的安全性、最大耐受剂量和药代动力学。主要终点为volasertib的最大耐受剂量和剂量限制性毒性的发生率。次要终点为最佳缓解和缓解持续时间。其他终点包括安全性和药代动力学。不适合接受标准诱导治疗或患有复发性或难治性疾病的患者在28天周期的第1天和第15天接受volasertib单药治疗2小时输注，剂量递增遵循3 + 3设计。共19例患者接受了3种volasertib剂量治疗：350、400和450 mg。1例接受volasertib 450 mg治疗的患者报告了剂量限制性毒性4级肝功能检查异常，450 mg被确定为最大耐受剂量。最常报告的不良事件为发热性中性粒细胞减少（78.9%）、食欲减退（42.1%）、恶心和皮疹（各36.8%）以及败血症、疲乏、低钾血症、口腔炎和鼻衄（各26.3%）。最佳缓解为完全缓解（n = 3）、完全缓解伴血细胞计数不完全恢复（n = 3）和部分缓解（n = 1）。6例完全缓解或完全缓解伴血细胞计数不完全恢复的患者的中位缓解持续时间为85天（范围56-358天）。Volasertib表现出多房室药代动力学行为，在输注结束后快速分布，随后是较慢的消除相。Volasertib单药治疗在临床上可管理，不良事件和抗白血病活性可接受。
This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo‐like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose‐limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2‐h infusion on days 1 and 15 of a 28‐day cycle, with dose escalation following a 3 + 3 design. A total of 19 patients were treated with three volasertib doses: 350, 400 and 450 mg. One patient receiving volasertib 450 mg reported a dose‐limiting toxicity of grade 4 abnormal liver function test and 450 mg was determined as the maximum tolerated dose. The most frequently reported adverse events were febrile neutropenia (78.9%), decreased appetite (42.1%), nausea and rash (36.8% each), and sepsis, fatigue, hypokalemia, stomatitis and epistaxis (26.3% each). Best responses were complete remission (n = 3), complete remission with incomplete blood count recovery (n = 3) and partial remission (n = 1). The median remission duration of the six patients with complete remission or complete remission with incomplete blood count recovery was 85 days (range 56–358). Volasertib exhibited multi‐compartmental pharmacokinetic behavior with a fast distribution after the end of infusion followed by slower elimination phases. Volasertib monotherapy was clinically manageable with acceptable adverse events and anti‐leukemic activity.