Malempati Suman, Nicholson H Stacy, Reid Joel M, Blaney Susan M, Ingle Ashish M, Krailo Mark, Stork Linda C, Melemed Allen S, McGovern Renee, Safgren Stephanie, Ames Matthew M, Adamson Peter C
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
J Clin Oncol. 2007 Apr 20;25(12):1505-11. doi: 10.1200/JCO.2006.09.1694.
We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children.
Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment.
Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively.
Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.
我们报告培美曲塞（LY231514）用于难治性实体瘤儿童和青少年的I期试验及药代动力学研究结果。培美曲塞是一种新型抗叶酸剂，可抑制胸苷和嘌呤核苷酸生物合成所需的多种酶。本研究的目的是确定培美曲塞在儿童中的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学特性。
培美曲塞每21天静脉输注10分钟给药。患者接受维生素B12和叶酸补充以及地塞米松预防。每组3至6名儿童，剂量水平分别为400、520、670、870、1130、1470、1910和2480mg/m²。在第一个疗程中进行药代动力学研究。
共入组33例患者（31例可评估），中位年龄12岁。1470mg/m²剂量组的6例患者中有1例发生DLT，2480mg/m²剂量组的4例患者中有2例发生DLT。MTD为1910mg/m²。主要的DLT为中性粒细胞减少和皮疹。未观察到客观抗肿瘤反应。平均血浆清除率、半衰期和稳态分布容积值分别为2.3L/h/m²、2.5小时和5.4L/m²。
培美曲塞在难治性实体瘤儿童中耐受性良好，剂量与成人的MTD相似。II期研究的推荐剂量为1910mg/m²，每21天给药一次，并补充地塞米松、叶酸和维生素B12。
