Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report
Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report
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DOI：
10.1200/jco.2009.25.9119
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发表时间：
2010-08-01
影响因子：
45.3
通讯作者：
Adamson, Peter C.
中科院分区：
文献类型：
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作者：
Fouladi, Maryam;Park, Julie R.;Adamson, Peter C.
本研究的目的是确定伏立诺他单药和联合13-顺式维甲酸（13 cRA）治疗儿童难治性实体瘤的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学;评价儿童难治性白血病实体瘤MTD的耐受性;患者和方法伏立诺他每天口服给药，起始剂量为180 mg/m2/d，计划以30%的增量递增。采用初始剂量进行药代动力学研究。乙酰组蛋白（H3）的积累进行了评估外周血单个核细胞（PBMC）的Western印迹。在实体瘤患者中，MTD为230 mg/m2/d，300 mg/m2/d时出现剂量限制性中性粒细胞减少、血小板减少和低钾血症。13 cRA和伏立诺他联合用药观察到的DLT包括血小板减少症、中性粒细胞减少症、厌食症和高血糖症，导致伏立诺他的MTD为180 mg/m2/d，每周4次，13 cRA为80 mg/m2/剂，每天2次，第1天至第14天，每28天一次。伏立诺他分布存在广泛的患者间变异性，230 mg/m2/d胶囊（范围：1，415 - 9，291 ng/mL x hr）和口服混悬剂（范围：1，186 - 4，780 ng/mL x hr）的浓度-时间曲线下面积。在给予伏立诺他后，特别是在较高剂量下，观察到PBMC中乙酰化H3组蛋白的显著蓄积。一名神经母细胞瘤患者经历了一个完整的响应combination.ConclusionIn复发性实体瘤的儿童，伏立诺他是耐受性良好，在230 mg/m2/d，与适度的剂量减少时，需要结合伏立诺他与13 cRA。药物处置与成人中观察到的相似。
PurposeThe purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.Patients and MethodsVorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).ResultsSixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.ConclusionIn children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.