A phase I trial of an oral subtype-selective histone deacetylase inhibitor, chidamide, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.
A phase I trial of an oral subtype-selective histone deacetylase inhibitor, chidamide, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.
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DOI：
10.21147/j.issn.1000-9604.2016.04.08
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Hu X;Wang L;Lin L;Han X;Dou G;Meng Z;Shi Y
本I期研究旨在评估新型亚型选择性组蛋白去乙酰化酶（HDAC）抑制剂奇达胺（chidamide）联合紫杉醇和卡铂治疗晚期非小细胞肺癌（NSCLC）患者的安全性、最大耐受剂量、药代动力学和初步抗肿瘤活性。10例患者口服奇达胺20、25或30 mg，每周2次，连续给予紫杉醇（175 mg/m2）和卡铂[曲线下面积（AUC） 5 mg/mL/min]，周期为3周。4个周期后反应和病情稳定的患者维持单药治疗，直到疾病进展或不可接受的毒性。所有患者在第1周期第一次口服奇达胺和第一次联合治疗后采集血样进行药代动力学分析。在30mg组中记录了两种剂量限制性毒性，包括第一周期的血小板减少症和延长的中性粒细胞减少症。所有患者在任何周期均观察到3/4级中性粒细胞减少，但未与显著并发症相关。其他3/4级血液学毒性包括血小板减少和白细胞减少。奇达胺和紫杉醇的药代动力学参数均未见明显变化。20mg组中有1例患者证实部分缓解（PR）。经4个周期治疗后，5例脑转移患者中有2例颅内完全缓解。奇达胺联合紫杉醇和卡铂通常耐受，没有意外的毒性或临床相关的药代动力学相互作用。奇达胺联合用药的推荐剂量为20mg，该方案在晚期NSCLC患者中的II期临床试验正在进行中。
This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase (HDAC) inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel (175 mg/m2) and carboplatin [area under the curve (AUC) 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacokinetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response (PR). Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.
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