Treatment > Carmustine · Chemoresistance

Meeting Abstract

Phase II Trial of BCNU Plus O⁶-Benzylguanine for Patients with Recurrent or Progressive Malignant Glioma

Jennifer A. Quinn, M. Eileen Dolan, Anthony E. Pegg, Robert C. Moschel, James Pluda, Roger E. McLendon, James Provenzale, William Petros, Sandra Tourt-Uhlig, Jeremy N. Rich, Sridharan Gururangan, Mary L. Affronti, Waynette Buchanan, O. Michael Colvin, Elizabeth S. Stewart, Allan H. Friedman, Darell D. Bigner, Henry S. Friedman

Duke University Medical Center, Durham, NC; The University of Chicago, Chicago, IL; Milton S. Hershey Medical Center, Hershey, PA; National Cancer Institute, Frederick, MD; Ivestigational Drug Branch, Rockville, MD

The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (AGT) which removes chlorethylation or methylation damage from the O⁶-position of guanine. 
O⁶-benzylguanine (O⁶-BG) is an AGT substrate which inhibits AGT by suicide inactivation. 
We are conducting a phase II trial of BCNU plus O⁶-BG to define the activity and toxicity of this drug combination in the treatment of adults with progressive or recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or gliosarcoma (GS) resistant to a nitrosourea.
Patients with progressive or recurrent disease within 8 weeks of receiving a nitrosourea are treated with IV O⁶-BG at a dose of 120 mg/m² followed one hour later by 40 mg/m² IV BCNU. 
Treatment cycles are repeated at six-week intervals. 
Radiographic response criteria were utilized to evaluate activity using T1-weighted, enhanced MRI images. 
Eighteen patients have been treated to date, 17 with glioblastoma multiforme, and 1 with anaplastic astrocytoma. 
Three patients have demonstrated stable disease after two cycles. 
Ten patients have progressive disease after one cycle. 
One patient has progressive disease after three cycles. 
Four patients are too early for evaluation. 
Toxicity observed thus far has been limited to four patients with grade 4 neutropenia, 3 patients with grade 3 neutropenia, 8 patients with grade 3 thrombocytopenia and 1 patient with grade 4 anemia. 
Further enrollment will continue to determine the activity and toxicity of this drug combination in the treatment of nitrosourea-resistant malignant glioma.