Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors: a children's oncology group study.
BACKGROUND
For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors.


METHODS
Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan-associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed.


RESULTS
Thirteen patients were enrolled. Dose-limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m(2); irinotecan at a dose of 20 mg/m(2)). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m(2)/dose oxaliplatin; 15 mg/m(2)/dose irinotecan) experienced a dose-limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re-escalated (60 mg/m(2)) with irinotecan at a dose of 15 mg/m(2), 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC(0-->infinity)) was 5.9 microg . hour/mL (range, 1.8-7.6 microg . hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively.


CONCLUSIONS
The oxaliplatin MTD was 40 mg/m(2) per dose on Days 1 and 8 in combination with irinotecan 15 mg/m(2) per dose on Days 1-5 and Days 8-12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed.
McGregor
Lisa M
LM
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. lisa.mcgregor@stjude.org
Spunt
Sheri L
SL
Furman
Wayne L
WL
Stewart
Clinton F
CF
Schaiquevich
Paula
P
Krailo
Mark D
MD
Speights
Roseanne
R
Ivy
Percy
P
Adamson
Peter C
PC
Blaney
Susan M
SM
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000099148:UGT1A1 Enzyme