© Copyright 2009 by the Society for Neuro-Oncology
Received July 29, 2008
Accepted October 22, 2008
Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma
Jennifer A. Quinn 1*,
Sara Xiaoyin Jiang 2,
David A. Reardon 2,
Annick Desjardins 2,
James J. Vredenburgh 2,
Jeremy N. Rich 2,
Sridharan Gururangan 2,
Allan H. Friedman 2,
Darell D. Bigner 3,
John H. Sampson 2,
Roger E. McLendon 4,
James E. Herndon Jr. 5,
Amy Walker 2,
Henry S. Friedman 2
1 Dept. of Medicine, Div. of Neurology, Duke University Medical Center, 047 Baker House, Box 3624, Durham, NC 27710, USA
2 Department of Surgery, Duke University Medical Center, Durham, NC, USA
3 Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA
4 Department of Pathology, Duke University Medical Center, Durham, NC, USA
5 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: quinn008{at}mc.duke.edu.
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Abstract |
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This is a phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide in combination with O6-BG. Both temozolomide 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 hour on days 1, 3, and 5, along with a continuous infusion of O6-BG at 30 mg/m2/day. Temozolomide was administered at the end of the first bolus infusion of O6-BG and then every 24 hours for 5 days during the continuous infusion of O6-BG. Patients were accrued to one of three 5-day dosing regimens of temozolomide. Twenty-nine patients were enrolled onto this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for temozolomide was determined for three different 5-day dosing schedules, as follows: Schedule 1 at a dose of 200 mg/m2 on day1 and 50 mg/m2/day on days 2-5, Schedule 2 at a dose of 50 mg/m2/day on days 1-5, and Schedule 3 at a dose of 50 mg/m2/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day temozolomide dosing schedule that maximizes the total dose of temozolomide when combined with O6-BG would be Schedule 1. This study provides the foundation for a phase II trial of O6-BG in combination with a 5-day dosing schedule of temozolomide in temozolomide-resistant MG.
Key Words:
malignant glioma, O6-benzylguanine, phase I, recurrent, temozolomide
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