Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group.
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.
Malempati
Suman
S
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA. malempat@ohsu.edu
Nicholson
H Stacy
HS
Reid
Joel M
JM
Blaney
Susan M
SM
Ingle
Ashish M
AM
Krailo
Mark
M
Stork
Linda C
LC
Melemed
Allen S
AS
McGovern
Renee
R
Safgren
Stephanie
S
Ames
Matthew M
MM
Adamson
Peter C
PC
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
D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine