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

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/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.

Dose escalation of intravenous irinotecan using oral cefpodoxime: A phase I study in pediatric patients with refractory solid tumors

“…Using activated charcoal, investigators were able to deliver more of the prescribed doses of irinotecan [26] and decrease the number of patients who developed diarrhea [32], but neither study attempted to increase the dosage. Two phase I studies in children [33,34] have included an oral cephalosporin when trying to combine intravenous irinotecan with other agents, but neither was able to advance the irinotecan dosage past 20 mg/m 2 /day. This study also supports that antibiotic use, to presumably decrease the levels of intestinal glucuronidase, is an effective mechanism for ameliorating irinotecan-associated diarrhea and even allows further escalation of the dosage.…”

A phase I study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non‐hematopoietic solid tumors

“…Grade 3 and 4 thrombocytopenia in up to 27% of courses has been reported in previous studies with oxaliplatin in children [14,16]. Minimal myelosuppression was observed when oxaliplatin was combined with protracted irinotecan schedule [15]. MTD for oxaliplatin was 40 mg/m 2 administered on day 1 and 8 with irinotecan at a dose of 15 mg/m 2 on days 1–5 and 8–12 of each 21-day course.…”

Selecting multimodal therapy for rhabdomyosarcoma

“…Irinotecan was subsequently tested in combination with other drugs, such as temozolomide [95,96], carboplatin [97] and oxaliplatin [98]. The irino tecan-vincristine combination, tested in the same setting, showed a 70% response rate, with an 8% rate of progression, proving to be the most active regimen to be tested by the COG in window trials [94].…”