Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

BACKGROUND: Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors. METHODS: This was a multicenter, open-label, single-arm dose escalation study in which subjects with refractory solid tumors received 21-day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin. RESULTS: Twenty-eight patients with a median age of 8.5 years (range, 1-21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m²/dose) experienced dose-limiting gastrointestinal toxicities requiring a dose de-escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m²/dose). Three of 6 subjects at the second dose level experienced dose-limiting gastrointestinal complications and bone marrow suppression. A further dose de-escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m²/dose resulted in dose-limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed. CONCLUSIONS: The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m²/ day × 10 days) given every 21 days.