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

Background—Administration of an oral cephalosporin allowed advancement of the dosage of oral irinotecan. This study investigates whether administration of an oral cephalosporin increases the maximum tolerated dose (MTD) of intravenous irinotecan. Procedure—Irinotecan was administered intravenously on Days 1– 5 and Days 8 – 12 of a 21day cycle with continuous oral cefpodoxime starting 2 days prior to irinotecan. Cohorts of 3 to 6 pediatric patients with refractory solid tumors were enrolled at 4 dosage levels, starting at the single-agent irinotecan MTD of 20 mg/m 2 /dose. Results—The 17 evaluable patients received 39 courses of therapy. None of the patients treated with 20 mg/m 2 /dose experienced dose-limiting toxicity (DLT). One of 6 patients treated at 30 mg/ m 2 /dose experienced dose-limiting neutropenia. Two of 3 patients treated with 45 mg/m 2 /dose and 2 of 5 treated with 40 mg/m 2 /dose experienced dose-limiting diarrhea, with associated dehydration and anorexia. Two unconfirmed partial responses were observed after one course in a patient with Ewing sarcoma and one with paraganglioma. A child with refractory neuroblastoma had disease stabilization through 12 courses of therapy. Median (range) systemic exposure to SN-38 at the MTD (30 mg/m 2 /dose) was 67 ng-h/mL (36 to 111 ng-h/mL).