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

From the Departments of Surgery, Medicine, Pathology, Radiology, and Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC; Department of Medicine, University of Chicago, Chicago, IL; Department of Cellular and Molecular Physiology and Pharmacology, Pennsylvania State University School of Medicine, Milton S. Hershey Medical Center, Hershey, PA; Chemistry of Carcinogenesis Laboratory, Advanced Bioscience Laboratories, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick; and Investigational Drug Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Address reprint requests to Jennifer A. Quinn, MD, The Brain Tumor Center, Duke University Medical Center, Box 3624, Durham, NC 27710; email: quinn008{at}mc.duke.edu

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.

H.S.F. had a consulting relationship with Procept, Boston, MA, which held the license for O⁶-benzylguanine at the time of this study and now has a consulting relationship with Access Oncology, New York, NY, which currently holds the license. M.E.D., A.E.P., and R.C.M. are coinventors of O⁶-benzylguanine.

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