Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas

Abstract

2003 Background: Recurrent malignant gliomas have low response rates to current treatments. Malignant gliomas have high concentrations of VEGF receptors which are poor prognostic indicators. Bevacizumab is a humanized IgG1 monoclonal antibody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor with modest activity against recurrent malignant gliomas. Methods: We report the mature data for our FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. We enrolled 68 patients (35 with grade IV tumors and 33 with grade III tumors.) All patients had progressive disease and received prior radiation therapy and temozolomide. The first 32 patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 (non EIAED) or 340 mg/m2 (EIAED). The last 36 patients were treated with irinotecan 125 mg/m2 (non EIAED) or 350 mg/m2 (EIAED) on days 1, 8, 22, and 29 and bevacizumab 15 mg/kg on days 1 and 22. Results: The regimen was well tolerated. Only 1 CNS hemorrhage occurred after 10 cycles of treatment. Eight patients were taken off study for thrombotic complications (four PE, two DVT, one TTP, one thrombotic stroke) and 2 of these patients died (one with PE and one with thrombotic stroke). Two patients were discontinued secondary to grade 2 proteinuria and 3 were discontinued because they required non-neurosurgical surgery. The response rate was 59% (38 PRs and 2 CRs). In Grade IV, the median PFS was 23 weeks (95% confidence intervals 17–34). The 6 month PFS was 43% (95% confidence intervals 29%-63%), the median overall survival was 40 weeks (95% confidence intervals 34–50). In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% (95% confidence intervals 46%-80%), the medial overall survival was 60 weeks (95% confidence intervals 37%-73%). The follow-up for the second cohort is short with similar efficacy and more toxicity. Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas. [Table: see text]