Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study
Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study
复制标题
DOI：
10.1200/jco.2011.35.7806
复制
发表时间：
2011-09-10
影响因子：
45.3
通讯作者：
Gilbertson, Richard J.
中科院分区：
文献类型：
--
作者：
Fouladi, Maryam;Stewart, Clinton F.;Gilbertson, Richard J.
PurposeTo估计的最大耐受剂量（MTD），描述剂量限制性毒性（DLT），并表征MK-0752，γ分泌酶抑制剂，在儿童难治性或复发性CNS malignances.Patients和MethodsMK-0752给药的药代动力学特性，每天一次，连续3天，每7天在递增剂量从200 mg/m2开始。采用改良的持续再评估方法估计MTD。疗程为28天。在第一个疗程期间进行药代动力学分析。在MK-0752治疗之前和之后，在外周血单个核细胞（PBMC）中评估NOTCH和毛状分裂增强子（HES）蛋白的表达。（中位年龄8.1岁;范围，2.6 - 17.7岁），诊断为脑干胶质瘤（n = 6），室管膜瘤（n = 8），髓母细胞瘤/原始神经外胚层肿瘤（n = 4），多形性胶质母细胞瘤（n = 2）、非典型畸胎瘤/横纹肌样瘤（n = 1）、恶性胶质瘤（n = 1）和脉络丛癌（n = 1）。17例患者的毒性完全可评价。200 mg/m2/剂组3例患者未发生DLT。在260 mg/m2/剂时，6例患者中有2例发生DLT，均发生3级ALT和AST。无4级毒性;非剂量限制性3级毒性包括低钾血症和淋巴细胞减少症。MK-0752的群体药代动力学值（%变异系数）为表观口服清除率，0.444（38%）L/h/m（2）;表观分布容积，7.36（24%）L/m（2）;和k（a），0.358（99%）hr（-1）。采用3天给药，随后4天停药方案的II期推荐剂量为260 mg/m2/剂，每日一次。
PurposeTo estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.Patients and MethodsMK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.ResultsTwenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1).ConclusionMK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.