title: Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA. malempat@ohsu.edu
authors: Suman
authors: S
authors: Malempati
authors: H Stacy
authors: HS
authors: Nicholson
authors: Joel M
authors: JM
authors: Reid
authors: Susan M
authors: SM
authors: Blaney
authors: Ashish M
authors: AM
authors: Ingle
authors: Mark
authors: M
authors: Krailo
authors: Linda C
authors: LC
authors: Stork
authors: Allen S
authors: AS
authors: Melemed
authors: Renee
authors: R
authors: McGovern
authors: Stephanie
authors: S
authors: Safgren
authors: Matthew M
authors: MM
authors: Ames
authors: Peter C
authors: PC
authors: Adamson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005500:Follow-Up Studies; D005971:Glutamates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006776:Hospitals, Pediatric; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008495:Medical Oncology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000068437:Pemetrexed; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine