Phase II trial of continuous low-dose temozolomide (TMZ) for recurrent malignant glioma (MG) with and without prior exposure to bevacizumab (BEV).

Abstract

2065 Background: The prognosis of recurrent MG, including glioblastoma (GBM), grade 3 anaplastic astrocytoma (AA) and oligodendroglioma (AO) is poor, especially after BEV failure. Metronomic TMZ schedules have been proposed as salvage therapy for recurrent MG, with the goal of targeting angiogenesis through inhibition of endothelial cell proliferation and repair occurring during the resting period of conventional chemotherapy regimens. Metronomic TMZ may also overcome chemoresistance mediated by O-6-methylguanine-DNA methyltransferase (MGMT). Methods: In this prospective phase II study, pts with recurrent/progressive MG with no limit in number of recurrences were treated with continuous, daily TMZ (50 mg/m2) until progression. The primary endpoint was 6m-progression free survival (PFS). A Simon two-stage design was utilized (n = 37 planned GBM, with additional 10 AA/AO for exploratory analysis). Results: To date, 41 pts have been enrolled (GBM: 30, AA: 8, AO: 3; median age: 56 y, range 29-84; median KPS: 80, range 60-100; 14 were women). The MGMT promoter was methylated in 3 pts, unmethylated in 16 and not available in 22. In addition to standard chemoradiotherapy with TMZ, previous treatments included Bev in 16 pts, other cytotoxic agents in 6 and experimental targeted therapies in 8. Median followup of survivors was 10 m. In the GBM group, 6mPFS was 24% (95% CI 7.41); median PFS: 2 m; median overall survival (OS): 7 m; objective response rate (RR): 6.6%. Pts with prior BEV exposure fared worse than pts with no BEV exposure (6 m PFS 14% vs. 36%, p = 0.12; median OS 4 m vs. 18 m, p = 0.005). In the AA/AO group, 6 m PFS was 27% (95% CI 1.54), median OS was 16 m, RR = 9%. Grades 3 or 4 toxicities were limited to lymphopenia in 9 pts. Conclusions: This regimen was well tolerated in this heavily pretreated population. A modest increase in efficacy was observed in the overall GBM population, and results in non-BEV failures were particularly encouraging. Results in BEV failures are difficult to interpret due to lack of historical controls. This study highlights the need for stratification according to previous BEV exposure and new historical controls for future trials in recurrent MG. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Cepahlon, Eisai, Genentech, ImClone Systems, Schering-Plough, Sigma-Tau Genentech Brain Tumor Funders' Collaborative, Dana Foundation, Genentech, Keryx, National Brain Tumor Foundation, National Cancer Institute, Novartis, Pfizer, Schering-Plough, Sigma-Tau, Voices Against Brain Cancer