Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial
Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial
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DOI：
10.1007/s10147-011-0348-6
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发表时间：
2013-02-01
影响因子：
3.3
通讯作者：
Ohtsu, Atsushi
中科院分区：
文献类型：
--
作者：
Doi, Toshihiko;Hamaguchi, Tetsuya;Ohtsu, Atsushi
使用组蛋白去乙酰化酶抑制剂（HDACi）控制表观遗传变化被认为是治疗胃肠道（GI）癌症的有希望的靶点。在这项研究中，我们评估了两种给药方案的安全性，药代动力学和有效性伏立诺他，口服HDACi，在胃肠道肿瘤患者中。患者接受伏立诺他300 mg bid连续3天，然后休息4天，每个周期（n = 10）或伏立诺他400 mg qd连续21天，每个周期（n = 6）。评估第一个治疗周期的药代动力学参数。通过肿瘤评估和治疗反应评估确定疗效，300 mg bid的中位治疗时间为52.0 d，400 mg qd的中位治疗时间为51.5 d。最常见的药物相关不良事件是厌食、恶心、疲劳和高血糖。两名服用400 mg qd的患者出现血小板减少的剂量限制性毒性（DLT）。服用300 mg bid的患者均未发生DLT。5例患者服用300 mg bid，2例患者服用400 mg qd，维持病情稳定> 8周，最长持续时间为245天。400 mg qd组的平均药物暴露量（+/- SD）通常较高（给药后第1天的曲线下面积[AUC（0-a）]为7.75 +/- A 2.79 mu M h）与300 mg bid（给药后第1天的AUC（0-a）为3.94 +/- A 1.56 mu M h）相比伏立诺他300 mg bid连续3天，然后休息4天，在GI癌患者中比每日一次更高剂量耐受性更好。此外，两组中均有患者达到稳定的疾病，大多数维持超过8周，这表明伏立诺他可能是治疗GI癌的活性药物。
Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors.Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response.The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for > 8 weeks, with the maximum duration of 245 days. Mean drug exposure (+/- SD) was generally higher with 400 mg qd (area under the curve [AUC(0-a)] of 7.75 +/- A 2.79 mu M h on Day 1 post-dose) compared with 300 mg bid (AUC(0-a) of 3.94 +/- A 1.56 mu M h on Day 1 post-dose).Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.