Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

Abstract

Purpose: This pediatric phase I trial of O⁶-benzylguanine (O⁶BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O⁶BG and to define the toxicity profile of the combination in children with solid tumors. Patients and Methods: Patients ≤ 21 years old with refractory solid tumors were eligible. O⁶BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O⁶BG infusion. Starting doses of O⁶BG and TMZ were 60 mg/m²/d and 28 mg/m²/d, respectively. O⁶BG was escalated to 90 and 120 mg/m²/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m²/d. Cycles were repeated every 28 days. Results: Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O⁶BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m²/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m²/d of TMZ combined with 120 mg/m²/d O⁶BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m²/d O⁶BG combined with TMZ doses of 55 mg/m²/d and above. Conclusion: The recommended doses of O⁶BG administered with TMZ on a 5-day schedule in children are 120 mg/m²/d of O⁶BG and 75 mg/m²/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.