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Phase I Trial of Temozolomide Plus O⁶-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma

From the Departments of Surgery, Pathology, Radiology, and Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC; Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore; National Cancer Institute, Frederick Cancer Research and Development Center, Frederick; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD; Department of Medicine, Committee on Cancer Biology and Cancer Research Center, University of Chicago, Chicago, IL; Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Hershey, PA; Laboratory of Comparative Carcinogenesis, AOI Pharmaceuticals, Memphis, TN

Address reprint requests to Jennifer A. Quinn, MD, Brain Tumor Center at Duke, Room 047 Baker House, Trent Dr, S Hospital, Durham, NC 27710; e-mail: quinn008{at}mc.duke.edu

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O⁶-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O⁶-BG. In addition, plasma concentrations of O⁶-BG and O⁶-benzyl-8-oxoguanine were evaluated after O⁶-BG.

PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O⁶-BG infusion at 120 mg/m² followed by a continuous infusion at an initial dose of 30 mg/m²/d for 48 hours. The dose of the continuous infusion of O⁶-BG escalated until tumor AGT was depleted. Once the O⁶-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O⁶-BG infusion, was escalated until the MTD was determined.

RESULTS: The O⁶-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m² over 1 hour followed by a continuous infusion of 30 mg/m²/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m² with dose-limiting toxicities limited to myelosuppression.

CONCLUSION: This study provides the foundation for a phase II trial of O⁶-BG plus temozolomide in temozolomide-resistant MG.

Supported by National Institutes of Health Grants No. U01-CA62474 and NS30245. Pharmacological studies by the Pharmacology Core Facility at the University of Chicago Cancer Research Center were supported by National Cancer Institute Grant No. CA14599 (M.E.D.).

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

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