Phase I trial of carmustine plus O-6-benzylguanine for patients with recurrent or progressive malignant glioma

Purpose: The major mechanism of resistance to alkylnitrosourea therapy invo lves the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT), wh ich removes chloroethylation or methylation damage from the O-6 position of guanine. O-6-benlylguanine (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 prog ressive 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 le ast 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O-6-BG, 8-oxa-O-6-BG, and 8-oxoguanine con centration. Results: Twenty-three patients were treated (22 with glioblastoma multiform e 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 comp licated by grade 3 or 4 thrombocytopenia and neutropenia. O-6-BG rapidly di sappeared from plasma (elimination half-life = 0.54 +/- 0.14 hours) and was converted to ct longer-lived metabolite, 8-oxo-O-6-BG (elimination half-li fe = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectabl e 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 inf usion. 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 combi nation 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. (C) 2000 by Am erican Society of Clinical Oncology.