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Phase I Trial of Polifeprosan 20 With Carmustine Implant Plus Continuous Infusion of Intravenous O⁶-Benzylguanine in Adults With Recurrent Malignant Glioma: New Approaches to Brain Tumor Therapy CNS Consortium Trial

Jon Weingart, Stuart A. Grossman, Kathryn A. Carson, Joy D. Fisher, Shannon M. Delaney, Mark L. Rosenblum, Alessandro Olivi, Kevin Judy, Stephen B. Tatter, M. Eileen Dolan

From the New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD; and the Department of Medicine, University of Chicago, Chicago, IL

Address reprint requests to Joy Fisher, Cancer Research Building 2, Suite 1M16, 1550 Orleans St, Baltimore, MD 21231; e-mail: jfisher{at}jhmi.edu

Purpose This phase I trial was designed to (1) establish the dose of O⁶-benzylguanine (O⁶-BG) administered intravenously as a continuous infusion that suppresses O⁶-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O⁶-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O⁶-BG and its metabolite.

Patients and Methods The first patient cohort (group A) received 120 mg/m² of O⁶-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O⁶-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT).

Results Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O⁶-BG dose of 30 mg/m²/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O⁶-BG were 0.1 to 0.4 µmol/L, and levels for O⁶-benzyl-8-oxoguanine were 0.7 to 1.3 µmol/L.

Conclusion Systemically administered O⁶-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.

Supported by New Approaches to Brain Tumor Therapy Grant No. CA62475, a supplement to Grant No. CA69852 (M.E.D.), and the University of Chicago Cancer Research Center Support Grant No. P30 CA14599.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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