Treatment > Chemoresistance · Temozolomide Clinical Trials

Meeting Abstract

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

J. A. Quinn, J. Weingart, H. Brem, J. Rich, D. Reardon, J. Sampson, A. Friedman, H. S. Friedman, O. M. Colvin, E. Dolan

and Brain Tumor Center at Duke Sub-Sites; Duke Univ Medical Center, Durham, NC; Johns Hopkins Hospital, Baltimore, MD; University of Chicago, Chicago, IL

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 temozolomide (Temodar) (T) plus O⁶-BG to define the maximal tolerated dose (MTD) of T 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 T at a single dose of 100 mg/m² given at the end of the IV push of O⁶-BG.
T 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.
Fifty-two patients have been treated to date, 36 with glioblastoma multiforme (GBM), 14 with anaplastic astrocytoma (AA) and 2 with anaplastic oligodendroglioma (AO).
Seven patients received T at 100 mg/m², 7 patients received 200 mg/m², 6 patients received 267 mg/m², 6 patients received 355 mg/m², 7 patients received 472 mg/m², 5 patients received 628 mg/m², and 14 patients received 500 mg/m².
Dose-limiting toxicities observed thus far have been limited to five episodes of grade 4 thrombocytopenia, 6 episodes of grade 4 leukopenia, and 10 episodes of grade 4 neutropenia.
Stable disease has been observed in 17 patients.
One patient with AA who previously failed T has shown a complete response while completing 12 cycles of this drug combination.
Although no one achieved a partial response, 5 patients demonstrated a near partial response.
The MTD of this drug combination was found to be 472 mg/m².

© Copyright 2003 American Society of Clinical Oncology All rights reserved worldwide