Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors.

Background: The combination of irinotecan, temozolomide, and vincristine is appealing because of potentially synergistic mechanisms of action and non-overlapping toxicities. This phase I study was designed to determine the toxicity and maximum tolerated dose (MTD) of escalating daily protracted doses of irinotecan given in this combination. With extended accrual, we more fully explored the toxicity of multiple courses at the MTD.

Procedure: Patients under 22 years with recurrent or refractory solid tumors were eligible. A course of chemotherapy was given every 28 days. Cefpodoxime was given for diarrhea prophylaxis. Vincristine (1.5 mg/m2, max 2 mg) was given intravenously (IV) on days 1 and 8. Temozolomide (100 mg/m2/day) was given orally on days 1-5. Irinotecan was given IV over 1 hr on days 1-5 and 8-12. Dose escalation was done in the standard 3 + 3 cohort design, starting at 15 mg/m2/day.

Results: Twenty-five of 26 eligible patients were evaluable for toxicity and response. They received 111 courses (1-13, median 4). Dose limiting toxicity (DLT-pancreatitis, transaminitis) was seen in two of three patients at dose level 2 (20 mg/m2). No patients at level 1 had DLT during the first two cycles. Thus, the MTD of irinotecan in this combination is 15 mg/m2/day x 10 doses. Hematologic toxicity was mild and not prolonged. Grade 3 diarrhea was seen in five courses. Responses included two complete and two partial with 12 stable disease (SD) (median 6 months).

Conclusions: This combination is safe and shows activity in pediatric patients with recurrent malignancy.