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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.Irinotecan was administered intravenously on Days 1–5 and Days 8–12 of a 21-day cycle with continuous oral cefpodoxime starting 2 days prior to irinotecan. Cohorts of 3–6 pediatric patients with refractory solid tumors were enrolled at 4 dosage levels, starting at the single-agent irinotecan MTD of 20 mg/m2/dose.The 17 evaluable patients received 39 courses of therapy. None of the patients treated with 20 mg/m2/dose experienced dose-limiting toxicity (DLT). One of six patients treated at 30 mg/m2/dose experienced dose-limiting neutropenia. Two of three patients treated with 45 mg/m2/dose and two of five treated with 40 mg/m2/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/m2/dose) was 67 ng-h/mL (36 to 111 ng-h/mL).The MTD of intravenous irinotecan administered on a protracted schedule was increased by 50% from 20 to 30 mg/m2/dose with the addition of oral cefpodoxime. The most prominent DLT remained diarrhea. High interpatient variability in irinotecan pharmacokinetics was observed; however, SN-38 exposure at the MTD was greater than most reported exposures with the 20 mg/m2 dosage. Pediatr Blood Cancer 2012; 58: 372–379. © 2011 Wiley Periodicals, Inc.