Phase II Trial of Gliadel plus O6-Benzylguanine in Adults with Recurrent Glioblastoma Multiforme

Purpose: This phase 11 trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O-6-benzylguanine (O-6-BG) that suppresses tumor O-6-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 11, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O-6-BG was administered at 120 mg/m(2) over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m(2)/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 O-6-BG. Although systemically administered O-6-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 O-6-BG results in increased efficacy of Gliadel wafers without added toxicity.