Kitazono Satoru, Fujiwara Yutaka, Nakamichi Shinji, Mizugaki Hidenori, Nokihara Hiroshi, Yamamoto Noboru, Yamada Yasuhide, Inukai Eri, Nakamura Osamu, Tamura Tomohide
Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Cancer Chemother Pharmacol. 2015 Jun;75(6):1155-61. doi: 10.1007/s00280-015-2741-8. Epub 2015 Apr 7.
This study was performed to evaluate the safety and determine the recommended dose (RD) of resminostat monotherapy, an oral histone deacetylase (HDAC) inhibitor, in Japanese patients with advanced solid tumors.
Resminostat was administered to patients with advanced solid tumors on a 14-day cycle consisting of once-daily administration on days 1-5. The dose was initiated at 400 mg and increased to 600 mg and then 800 mg. Treatment with resminostat was continued until disease progression or discontinuation for any other reason. Dose-limiting toxicities (DLTs) were assessed according to the adverse drug reactions occurring in the first cycle. Secondary objectives included the pharmacokinetics, pharmacodynamics, and efficacy.
A total of 12 patients were enrolled in the study and received resminostat. No DLTs were reported in any patient. The maximum tolerated dose was not reached. Frequently reported grade 3/4 adverse drug reactions were as follows: lymphocytopenia (33.3 %), thrombocytopenia (25.0 %), neutropenia (16.7 %), and leukocytopenia (16.7 %). Pharmacokinetic analysis revealed that there was no accumulation of the drug over the 5-day administration period and no significant difference in pharmacokinetic parameters between the single dose and multiple doses. Measurement of acetylated H4 histone protein levels in peripheral blood mononuclear cells demonstrated that resminostat inhibited HDAC activity at all the doses assessed. No patients had a complete or partial response, whereas three patients had stable disease.
Resminostat was safely administered to Japanese patients with advanced solid tumors. The RD of resminostat monotherapy in Japanese patients was estimated to be 800 mg.
本研究旨在评估口服组蛋白去乙酰化酶（HDAC）抑制剂雷斯替尼单药治疗晚期实体瘤日本患者的安全性，并确定推荐剂量（RD）。
对晚期实体瘤患者每14天为一个周期给予雷斯替尼，在第1 - 5天每日给药一次。起始剂量为400mg，随后增至600mg，再增至800mg。持续给予雷斯替尼治疗直至疾病进展或因任何其他原因停药。根据首个周期出现的药物不良反应评估剂量限制性毒性（DLT）。次要目标包括药代动力学、药效学和疗效。
共有12例患者入组并接受了雷斯替尼治疗。未报告任何患者出现DLT。未达到最大耐受剂量。常见的3/4级药物不良反应如下：淋巴细胞减少（33.3%）、血小板减少（25.0%）、中性粒细胞减少（16.7%）和白细胞减少（16.7%）。药代动力学分析显示，在5天给药期内药物无蓄积，单剂量与多剂量之间药代动力学参数无显著差异。对外周血单核细胞中乙酰化H4组蛋白水平的检测表明，雷斯替尼在所有评估剂量下均抑制HDAC活性。无患者出现完全缓解或部分缓解，3例患者病情稳定。
雷斯替尼在晚期实体瘤日本患者中给药安全。日本患者雷斯替尼单药治疗的RD估计为800mg。
