Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma

Jennifer A. Quinn, Annick Desjardins, Jon Weingart, Henry Brem, M. Eileen Dolan, Shannon M. Delaney, James Vredenburgh, Jeremy Rich, Allan H. Friedman, David A. Reardon, John H. Sampson, Anthony E. Pegg, Robert C. Moschel, Robert Birch, Roger E. McLendon, James M. Provenzale, Sridharan Gururangan, Janet E. Dancey, Jill Maxwell, Sandra Tourt-UhligJames E. Herndon, Darell D. Bigner, Henry S. Friedman

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Abstract

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 O 6-BG escalated until tumor AGT was depleted. Once the O 6-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/m 2/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.

Original languageEnglish (US)
Pages (from-to)7178-7187
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number28
DOIs
Publication statusPublished - Dec 1 2005

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Quinn, J. A., Desjardins, A., Weingart, J., Brem, H., Dolan, M. E., Delaney, S. M., ... Friedman, H. S. (2005). Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. Journal of Clinical Oncology, 23(28), 7178-7187. https://doi.org/10.1200/JCO.2005.06.502