Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors: a children's oncology group study.

Abstract

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.

• Authors: Lisa M McGregor, Sheri L Spunt, Wayne L Furman, Clinton F Stewart, Paula Schaiquevich, Mark D Krailo, Roseanne Speights, Percy Ivy, Peter C Adamson, Susan M Blaney
• Journal: Cancer (Cancer) Vol. 115 Issue 8 Pg. 1765-75 (Apr 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19170226 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Organoplatinum Compounds
• Oxaliplatin
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Camptothecin

Topics

• Adolescent
• Adult
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives)
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Male
• Neoplasms (drug therapy, genetics)
• Organoplatinum Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Oxaliplatin