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

From the National Cancer Institute, Bethesda, MD.

Address reprint requests to Katherine E. Warren, MD, National Cancer Institute Neuro-Oncology Branch, Building 82, Room 219, 9030 Old Georgetown Rd, Bethesda, MD 20892-8200; e-mail: warrenk{at}mail.nih.gov

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.

Presented in part at the 8th Annual Meeting of the Society of Neuro-Oncology, Keystone, CO, November 13-16, 2003.

This manuscript represents original work performed at the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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