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Neuro-Oncology 2009 11(5):556-561; doi:10.1215/15228517-2009-007
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Copyright 2009 by the Society for Neuro-Oncology

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma

Jennifer A. Quinn, Sara Xiaoyin Jiang, 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, Jr., Amy Walker and Henry S. Friedman

Departments of Surgery (J.A.Q., S.X.J., D.A.R., A.D., J.J.V., J.N.R., S.G., A.H.F., D.D.B., J.H.S., A.W., H.S.F.), Pathology (D.D.B., R.E.M.), and Biostatistics and Bioinformatics (J.E.H.), Duke University Medical Center, Durham, NC, USA

Address correspondence to Jennifer A. Quinn, Dept. of Medicine, Division of Neurology, Duke University Medical Center, 047 Baker House, Box 3624, Durham, NC 27710, USA (quinn008{at}mc.duke.edu).


  Abstract

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O6-benzylguanine (O6-BG). Both TMZ and O6-BG were administered on days 1–5 of a 28-day treatment cycle. A bolus infusion of O6-BG was administered at 120 mg/m2 over 1 h on days 1, 3, and 5, along with a continuous infusion of O6-BG at 30 mg/m2/day. TMZ was administered at the end of the first bolus infusion of O6-BG and then every 24 h for 5 days during the continuous infusion of O6-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m2 on day 1 and 50 mg/m2/day on days 2–5; schedule 2, 50 mg/m2/day on days 1–5; and schedule 3, 50 mg/m2/day on days 1–5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O6-BG was schedule 1. This study provides the foundation for a phase II trial of O6-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Keywords: malignant glioma, O6-benzylguanine, phase I, recurrent, temozolomide

Received July 29, 2008; Accepted January 21, 2009


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