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

• Published in: Cancer 2009-04, Vol.115 (8), p.1765-1775
• Main Authors: McGregor, Lisa M., Spunt, Sheri L., Furman, Wayne L., Stewart, Clinton F., Schaiquevich, Paula, Krailo, Mark D., Speights, RoseAnne, Ivy, Percy, Adamson, Peter C., Blaney, Susan M.
• Format: Article
• Language: English
• Subjects: adolescent; child; irinotecan; oxaliplatin; phase 1 clinical trial
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.24175

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/m2; irinotecan at a dose of 20 mg/m2). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m2/dose oxaliplatin; 15 mg/m2/dose irinotecan) experienced a dose‐limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re‐escalated (60 mg/m2) with irinotecan at a dose of 15 mg/m2, 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 (AUC0→∞) was 5.9 μg · hour/mL (range, 1.8‐7.6 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/m2 per dose on Days 1 and 8 in combination with irinotecan 15 mg/m2 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. Cancer 2009. © 2009 American Cancer Society. This phase 1 dose‐finding study of oxaliplatin combined with irinotecan in children with refractory solid tumors indicated that the maximum tolerated doses were oxaliplatin at a dose of 40 mg/m2 per dose on Days 1 and 8 in combination with irinotecan at a dose of 15 mg/m2 per dose on Days 1 through 5 and Days 8 through 12. Evidence of antitumor activity was observed; however, severe toxicity, which was expected (diarrhea) and unexpected (elevation in pancreatic enzymes), also was noted.