Phase I Trial of Carmustine Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma

Abstract

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O⁶ position of guanine. O⁶-benzylguanine (O⁶-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O⁶-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O⁶-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O⁶-BG at a dose of 100 mg/m² followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O⁶-BG, 8-oxo-O⁶-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m²) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O⁶-BG rapidly disappeared from plasma (elimination half-life = 0.54 ± 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O⁶-BG (elimination half-life = 5.6 ± 2.7 hours) and further to 8-oxoguanine. There was no detectable O⁶-BG 5 hours after the start of the O⁶-BG infusion; however, 8-oxo-O⁶-BG and 8-oxoguanine concentrations were detected 25 hours after O⁶-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O⁶-BG was 17.5 times greater than the mean AUC for O⁶-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O⁶-BG at a dose of 100 mg/m² is 40 mg/m² administered at 6-week intervals. This study provides the foundation for a phase II trial of O⁶-BG plus BCNU in nitrosourea-resistant malignant glioma.