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

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 (O ⁶-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 O⁶-BG was schedule 1. This study provides the foundation for a phase II trial of O ⁶-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.