A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors
A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors
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DOI：
10.1158/1078-0432.ccr-07-1786
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发表时间：
2008-02-01
影响因子：
11.5
通讯作者：
DeBono, Johann S.
中科院分区：
文献类型：
--
作者：
Steele, Nicola L.;Plumb, Jane A.;DeBono, Johann S.
目的：研究新型羟酸酯组蛋白去乙酰化酶抑制剂belinostat（先前命名为PXD101）在晚期难治性实体瘤患者中的安全性、剂量限制性毒性、最大耐受剂量、药代动力学和药效学特征。实验设计：3 - 6例患者按顺序剂量递增，在21天周期的第1- 5天静脉输注belinostat，每次30分钟。在所有剂量水平下评估药代动力学变量。药效学测量包括从外周血单个核细胞中提取的组蛋白乙酰化，细胞角蛋白-18的caspase依赖性裂解和白细胞介素-6水平。结果：46例患者在6个剂量水平（150- 1200mg /m(2)/d）中接受belinostat治疗。剂量限制性毒性为3级疲劳（1例600 mg/m）；1例（1200mg /m）， 3级腹泻合并疲劳（1例（1200mg /m））， 3级心房颤动（1例（1200mg /m））；1例患者剂量为1000mg /m(2)， 2级恶心/呕吐导致无法完成完整的5天周期（2例患者剂量为1000mg /m(2)）。最大耐受剂量为1,000 mg/m(2)/d。l.v. belinostat在C-max和AUC方面呈线性药动学。中间消除半衰期为0.3 ~ 1.3 h，与剂量无关。每次输注后观察组蛋白H4超乙酰化，并以剂量依赖性方式持续4 ~ 24 h。白介素-6水平升高后检测belinostat治疗。共有18例（39%）患者观察到疾病稳定，其中15例治疗>= 4周期，这与caspase依赖性细胞角蛋白-18的裂解有关。在接受最大耐受剂量（1,000 mg/m(2)/d）治疗的24例患者中，50%的患者病情稳定。结论：belinostat具有良好的耐受性和剂量依赖性，具有良好的抗肿瘤活性。
Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors.Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels.Results: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. l.v. belinostat displayed linear pharmacokinetics with respect to C-max and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for >= 4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease.Conclusions: l.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.