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Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group

Suman Malempati, H. Stacy Nicholson, Joel M. Reid, Susan M. Blaney, Ashish M. Ingle, Mark Krailo, Linda C. Stork, Allen S. Melemed, Renee McGovern, Stephanie Safgren, Matthew M. Ames, Peter C. Adamson

From the Department of Pediatrics, Oregon Health & Science University, Portland, OR; Mayo Clinic and Foundation, Rochester, MN; Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX; Children's Oncology Group Operations Center, Arcadia, CA; Eli Lilly & Co, Indianapolis, IN; and The Children's Hospital of Philadelphia, Philadelphia, PA

Address reprint requests to Suman Malempati, MD, Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, CDRC-P, Portland, OR 97239-3098; e-mail: malempat{at}ohsu.edu

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 II studies is 1,910 mg/m² administered every 21 days with dexamethasone, folic acid, and vitamin B₁₂ supplementation.

Supported by National Cancer Institute Grant No. U01 CA97552 and National Center for Research Resources Grant No. M01 RR00188, and by Eli Lilly & Co.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.