Treatment > Carmustine · Chemoresistance

Meeting Abstract

Phase I study of Gliadel combined with a continuous intravenous infusion of O6-benzylguanine in patients with recurrent malignant glioma

Mark Rosenblum, J Weingart, Eileen Dolan, S Tatter, K Judy, J Olson, E Bohan, J Fisher

Henry Ford Hospital, Detroit, MI; Johns Hopkins Hospital, Baltimore, MD; University of Chicago, Chicago, IL; Wake Forest University, Winston-Salem, NC; University of Pennsylvania, Philadelphia, PA; Emory University, Atlanta, GA; NABTT CNS Consortium, Baltimore, MD

The primary objectives of this trial are to
1) establish the continuous intravenous infusion (CI) dose of O6-benzylguanine (O6-BG) that completely suppresses alkylguanine-DNA alkyltransferase (AGT) in recurrent malignant glioma, and
2) to evaluate the safety and tolerance of increasing the duration of the continuous intravenous O6-BG infusion at the dose which completely suppresses tumor AGT activity.
This infusion is combined with intracranially implanted Gliadel wafers containing 3.85% BCNU by weight.
The rationale for this study is to take advantage of the finding that O6-BG is a potent AGT inhibitor that potentiates the therapeutic effect of BCNU.
Thus, BCNU is released locally into the brain while AGT levels are suppressed by the systemic infusion of O6-BG.
The length of the CI will be increased to a maximum of 2 weeks after surgery in planned increments.
To date, 31 patients have been entered on this protocol and 6 more are needed to complete the study.
The first cohort of patients (n=13) received an O6-BG bolus dose of 120 mg/m2 over 1 hour followed by CI of 30 mg/m2/day for 2 days prior to surgery.
Tumor samples in 11 of 13 patients had unmeasureable AGT levels.
The second (n=18) cohort was treated with the bolus dose, insertion of the Gliadel wafer, and the CI dose of 30 mg/m2/day that was established in the first cohort of patients.
The length of the CI of O6-BG was increased from 2 days following surgery to 2 weeks.
Steady sate pK data, outcomes, and toxicities will be presented.
The results of this study will provide the data required for a formal evaluation of efficacy for this novel approach to improve results with the administration of local chemotherapy.

© Copyright 2002 American Society of Clinical Oncology