TY - JOUR
T1 - Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors
T2 - The Children's Oncology Group
AU - Malempati, Suman
AU - Nicholson, H. Stacy
AU - Reid, Joel M.
AU - Blaney, Susan M.
AU - Ingle, Ashish M.
AU - Krailo, Mark
AU - Stork, Linda C.
AU - Melemed, Allen S.
AU - McGovern, Renee
AU - Safgren, Stephanie
AU - Ames, Matthew M.
AU - Adamson, Peter C.
PY - 2007/4/20
Y1 - 2007/4/20
N2 - Purpose: 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. Patients and Methods: 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. Results: 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. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.
AB - Purpose: 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. Patients and Methods: 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. Results: 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. Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase 11 studies is 1,910 mg/m 2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.
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U2 - 10.1200/JCO.2006.09.1694
DO - 10.1200/JCO.2006.09.1694
M3 - Article
C2 - 17442992
AN - SCOPUS:34248227619
SN - 0732-183X
VL - 25
SP - 1505
EP - 1511
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 12
ER -