Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors

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 _o→∞) was 5.9 μg· hour/mL (range, 1.87.6 μg· 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.