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 O 6 -alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O 6 position of guanine. O 6 -benzylguanine (O 6 -BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O 6 -BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O 6 -BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O 6 -BG at a dose of 100 mg/m 2 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 O 6 -BG, 8-oxo-O 6 -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/m 2 ) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O 6 -BG rapidly disappeared from plasma (elimination half-life = 0.54 ± 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O 6 -BG (elimination half-life = 5.6 ± 2.7 hours) and further to 8-oxoguanine. There was no detectable O 6 -BG 5 hours after the start of the O 6 -BG infusion; however, 8-oxo-O 6 -BG and 8-oxoguanine concentrations were detected 25 hours after O 6 -BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O 6 -BG was 17.5 times greater than the mean AUC for O 6 -BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O 6 -BG at a dose of 100 mg/m 2 is 40 mg/m 2 administered at 6-week intervals. This study provides the foundation for a phase II trial of O 6 -BG plus BCNU in nitrosourea-resistant malignant glioma.

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Affiliated Institutions

• University of Chicago US
• Penn State Milton S. Hershey Medical Center US
• Advanced Bioscience Laboratories (United States) US
• Duke Medical Center US
• Pennsylvania State University US
• National Cancer Institute US

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