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

Abstract

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O6-alkylguanine-DNA alkyltransferase inhibitor O6-benzylguanine (O6-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O6-BG at an intravenous dose of 120 mg/m2 followed 1 hour later by 40 mg/m2 of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible ≥ grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 ± 0.21 hour v 0.54 ± 0.20 hour) or area under the curve values (4.8 ± 1.7 μg/mL/h v 5.0 ± 1.3 μg/mL/h) of O6-BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O6-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.