Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy
Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy
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DOI：
10.1007/s10637-018-0582-0
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发表时间：
2018-10-01
影响因子：
3.4
通讯作者：
Suh, Cheolwon
中科院分区：
文献类型：
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作者：
Cho, Hyungwoo;Yoon, Dok Hyun;Suh, Cheolwon
本研究的目的是评估CKD-581（一种新型泛组蛋白去乙酰化酶抑制剂）在标准治疗难治性淋巴瘤或多发性骨髓瘤（MM）患者中的安全性、剂量限制性毒性（DLTs）、最大耐受剂量（MTD）、药代动力学和抗肿瘤疗效。方法在I期研究中，CKD-581在28天周期的第1、8和15天静脉给药。采用标准3+3队列设计确定MTD。在患者亚群中测定外周血单核细胞中的乙酰化组蛋白H3和H4用于药效学评估。结果39例患者接受CKD-581治疗，剂量范围为10 ~ 210 mg/m2。DLT为3级中性粒细胞减少，延迟治疗> 2周（1例患者剂量为50 mg/m2）和4级血小板减少（2例患者剂量为210 mg/m2）。CKD-581的MTD为160 mg/m2。最常见的3/4级治疗相关不良事件为血小板减少症（n=5，12.8%）和中性粒细胞减少症（n=2，5.1%）。CKD-581的峰浓度和曲线下面积值与剂量成比例增加，表明线性药代动力学。在2例患者（5.6%）中观察到部分缓解，在16例（44.4%）患者中观察到疾病稳定。在药效学评价中，在50 mg/m2的所有剂量下均观察到H3和H4的乙酰化。结论CKD-581在标准治疗无效的淋巴瘤或MM患者中耐受性良好。它表现出与剂量成比例的药代动力学和适度的抗肿瘤功效。
Background The objective of this study was to assess the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and anti-tumor efficacy of CKD-581, a novel pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma (MM) refractory to standard therapy. Methods In this phase I study, CKD-581 was intravenously administered on days 1, 8, and 15 of a 28-daycycle. A standard 3+3 cohort design was used to determine the MTD. Acetylated histones H3 and H4 in peripheral blood mononuclear cells were measured for pharmacodynamic assessment in a subpopulation of patients. Results Thirty-nine patients were treated with CKD-581 at 9 dose levels from 10mg/m(2) to 210mg/m(2). The DLTs were grade 3 neutropenia that delayed the treatment for >2weeks (one patient at a dose of 50mg/m(2)) and grade 4 thrombocytopenia (two patients at a dose of 210mg/m(2)). The MTD of CKD-581 was 160 mg/m(2). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (n=5, 12.8%) and neutropenia (n=2, 5.1%). The peak concentration and area under the curve values for CKD-581 increased in proportion to the dose, indicating linear pharmacokinetics. A partial response was observed in 2 patients (5.6%), and stable disease was observed in 16 (44.4%) patients. In the pharmacodynamic evaluation, acetylation of H3 and H4 was observed at all doses of 50mg/m(2). Conclusion CKD-581 was well tolerated by the patients with lymphoma or MM refractory to standard therapy. It exhibited dose-proportional pharmacokinetics and modest anti-tumor efficacy.