Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

Abstract

PURPOSE:

This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy.

EXPERIMENTAL DESIGN:

This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS.

RESULTS:

Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%).

CONCLUSION:

The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

• Authors: Jennifer A Quinn, Sara Xiaoyin Jiang, James Carter, David A Reardon, Annick Desjardins, James J Vredenburgh, Jeremy N Rich, Sridharan Gururangan, Allan H Friedman, Darell D Bigner, John H Sampson, Roger E McLendon, James E Herndon 2nd, Stevie Threatt, Henry S Friedman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 3 Pg. 1064-8 (Feb 01 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19188181 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Decanoic Acids
• Polyesters
• O(6)-benzylguanine
• Guanine
• decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer
• O(6)-Methylguanine-DNA Methyltransferase
• Carmustine

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Brain Neoplasms (drug therapy, metabolism)
• Carmustine
• Decanoic Acids (administration & dosage, adverse effects)
• Female
• Glioblastoma (drug therapy, metabolism)
• Guanine (administration & dosage, adverse effects, analogs & derivatives)
• Humans
• Male
• Middle Aged
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Polyesters (administration & dosage, adverse effects)
• Recurrence
• Survival Analysis