Treatment > Chemoresistance · Temozolomide Clinical Trials

Meeting Abstract

Phase I trial of temodar plus O⁶-benzylguanine in the treatment of patients with recurrent or progressive cerebral anaplastic gliomas

Henry S Friedman, James Pluda, Jon Weingart, Henry Brem, Brandon Evans, William Petros, Jeremy Rich, Sandra Tourt-Uhlig, Sridharan Gururangan, David Reardon, John Sampson, Allan Friedman, James Provenzale, Roger McLendon, O. M Colvin, Darell D Bigner, M. E Dolan, Anthony Pegg, Robert Moschel, Jennifer Quinn

Duke University Medical Center, Durham, NC; Investigational Drug Branch, NCI, Rockville, MD; Johns Hopkins School of Medicine, Baltimore, MD; University of Chicago, Chicago, IL; Milton S. Hershey Medical Center, Hershey, PA; National Cancer Institute-Frederick, Frederick, 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 I trial of Temodar plus O⁶-BG to define the maximal tolerated dose (MTD) of Temodar along with the toxicity and activity of this drug combination in the treatment of adults with progressive or recurrent, World Health Organization (WHO) grade 3 or greater astrocytoma, oligodendroglioma, or mixed glial tumor. 
Patients are treated with IV O⁶-BG and a 48-hour infusion of O⁶-BG. 
Following demonstration of the dose of O⁶-BG (120 mg/m² over 1 hour followed by the 48 hour infusion of 30 mg/m²/day) that depletes tumor AGT levels, we started Temodar at a single dose of 100 mg/m² given at the end of the IV push of O⁶-BG. 
Temodar doses are escalated in cohorts of 3 - 6 patients. 
Treatment cycles are repeated at 28-day intervals. 
Radiographic response criteria were utilized to evaluate activity using T₁-weighted, enhanced MRI images. 
Twenty-one patients have been treated to date, 15 with glioblastoma multiforme (GBM), 5 with anaplastic astrocytoma (AA) and 1 with anaplastic oligodendroglioma (AO). 
Seven patients received Temodar at 100 mg/m², 7 patients received 200 mg/m², 6 patients received 267 mg/m² and 1 patient received 355 mg/m². 
Toxicities observed thus far have been limited to one patient with grade-3 neutropenia, and one patient with grade-3 alanine amino-transferase (ALT) elevation. 
Stable disease has been observed in four patients; two after one cycle and two after two cycles. 
A patient who previously failed Temodar has shown a partial response while completing 5 cycles of this drug combination. 
Further enrollment will continue to determine the MTD and toxicity of this drug combination.

© Copyright 2002 American Society of Clinical Oncology