Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
Cancer Science Institute of Singapore, National University of Singapore; Department of Haematology-Oncology, National University Hospital.
Ann Oncol. 2011 Nov;22(11):2516-2522. doi: 10.1093/annonc/mdq784. Epub 2011 Mar 8.
The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.
Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs).
Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose.
SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.
本研究旨在评估新型组蛋白去乙酰化酶（HDAC）抑制剂 SB939 在晚期实体瘤患者中的安全性、最大耐受剂量（MTD）、药代动力学、药效学和初步疗效。
三个至六个剂量递增组的患者每 3 周接受 3 次口服 SB939 治疗，每 4 周为一个周期。在外周血单核细胞（PBMC）中测量乙酰化组蛋白 H3（acH3）。
30 名患者在五个剂量（10-80mg/天）中的一个剂量接受了 79 个 SB939 周期（范围为 1-12 个周期）。剂量限制性毒性作用是疲劳、低钾血症、肌钙蛋白 T 升高和 QTc 延长。峰值血浆浓度（C(max)）和从浓度时间曲线外推至无穷大的曲线下面积与剂量呈比例增加。SB939 的 MTD 为 80mg/天。SB939 的平均消除半衰期和口服清除率分别为 7.2±0.6h 和 53.0±8.5l/h，在第 15 天没有明显蓄积。在第 3 小时观察到 acH3 增加，与剂量和 C(max)相关。在≥40mg 治疗的几种肿瘤类型中观察到疾病稳定。在 60mg 时观察到一致的 HDAC 抑制，这是推荐剂量。
SB939 可安全地在推荐剂量下给药，达到强烈抑制 PBMCs 中 HDAC 的血浆水平。这些数据支持进一步研究 SB939 的疗效。
