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Phase I trial of temozolomide plus O⁶-benzylguanine 5-day regimen with recurrent malignant glioma

Departments of Surgery (J.A.Q., S.X.J., D.A.R., A.D., J.J.V., J.N.R., S.G., A.H.F., D.D.B., J.H.S., A.W., H.S.F.), Pathology (D.D.B., R.E.M.), and Biostatistics and Bioinformatics (J.E.H.), Duke University Medical Center, Durham, NC, USA

Address correspondence to Jennifer A. Quinn, Dept. of Medicine, Division of Neurology, Duke University Medical Center, 047 Baker House, Box 3624, Durham, NC 27710, USA (quinn008{at}mc.duke.edu).

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O⁶-benzylguanine (O⁶-BG). Both TMZ and O⁶-BG were administered on days 1–5 of a 28-day treatment cycle. A bolus infusion of O⁶-BG was administered at 120 mg/m² over 1 h on days 1, 3, and 5, along with a continuous infusion of O⁶-BG at 30 mg/m²/day. TMZ was administered at the end of the first bolus infusion of O⁶-BG and then every 24 h for 5 days during the continuous infusion of O⁶-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m² on day 1 and 50 mg/m²/day on days 2–5; schedule 2, 50 mg/m²/day on days 1–5; and schedule 3, 50 mg/m²/day on days 1–5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O⁶-BG was schedule 1. This study provides the foundation for a phase II trial of O⁶-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Key Words: malignant glioma • O⁶-benzylguanine • phase I • recurrent • temozolomide

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