Phase II Trial of Temozolomide (Temodar®) in Patients with Progressive or Recurrent Low Grade Glioma.
Sandra Tourt-Uhlig, Jennifer A. Quinn, Jeremy N. Rich, David A. Reardon, John H. Sampson, James M. Provenzale, Roger E. McLendon, Shari Edwards, Sridharan Gururangan, Mary L. Affronti, Waynette Buchanan, Susanne Jackson, Deborah Allen, Kara Penne, Christy Lentz, Darell D. Bigner, Michael Haglund, Allan H. Friedman, Nicholas Avgeropoulos, David Korones, Valerie Stafford-Fox, Sara Zaknoen, Henry S. Friedman, Duke University Medical Center, Durham, NC; Walt Disney Memorial Institute, Orlando, FL; The University of Rochester, Rochester, NY; Oncology Biotech, Chapel Hill, NC; Schering-Plough Research Institute, Kenilworth, NJ.
Temozolomide is an imidazole tetrazinone with a precise mechanism of action similar to that of dacarbazine, notably conversion to the active methylating agent MTIC. Unlike dacarbazine, however, which requires metabolic dealkylation to form MTIC, Temozolomide undergoes chemical conversion to MTIC under physiological conditions. Previous studies have confirmed activity of Temozolomide in the treatment of recurrent anaplastic astrocytoma and newly diagnosed and recurrent glioblastoma multiforme. We have extended these results and now report results of a phase 2 trial of Temozolomide for patients with progressive low-grade glioma (LGG). Temozolomide was administered orally, in a fasting state, once a day for 5 consecutive days at a starting dose of 200 mg/m2/day. Treatment cycles were repeated every 28 days following the first daily dose of Temozolomide from the previous cycle. Radiographic response criteria were utilized to evaluate activity using MRI. Thirty-nine patients with LGG have been treated to date, six of whom previously received radiotherapy. Eighteen patients had astrocytomas, fifteen had oligodendroglioma, two had mixed gliomas, and four had pilocytic astrocytomas one of which involved the optic chiasm. Twenty-four patients demonstrate stable disease (for up to 27+ months), nine had progressive disease, two was unable to be evaluated, and four are too early for evaluation. Toxicity observed during the study was limited to six patients. Three patients experienced grade 3 neutropenia with duration greater than 3 weeks in one patient. Two patients experienced grade 3 thrombocytopenia. One patient experienced grade [greater than or equal to] 4 toxicity with neutropenia, sepsis, and death. These initial results suggest that Temozolomide may be active in the treatment of LGG and warrant further evaluation of this agent in the treatment of these tumors.