Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent malignant glioma: Results of a phase I part of a phase I/II trial.

Abstract

2029^ Background: Antiangiogenic therapy using b evacizumab (Bev) has shown promising activity against recurrent glioblastoma (GBM). However, most patients have disease progression after striking but transient responses. Salvage therapies have been uniformly ineffective, suggesting development of resistance mechanisms including upregulation of other proangiogenic factors and increased activity of hypoxia inducible factors (HIF)-1a. Vorinostat, a histone deacetylase (HDAC) inhibitor has single agent activity against recurrent GBM and downregulates HIF-1a and other proangiogenic and invasive factors. We hypothesized that HDAC inhibition combined with Bev would result in improved clinical outcome. We report the results of the Phase I portion of the study preceding the initiation of the 2-arm adaptive randomized Phase II study. Methods: Adults with recurrent malignant glioma, KPS ≥ 60, normal hepatic, renal and marrow organ function and no prior exposure to Bev or Vorinostat were enrolled to the combination therapy after the confirmation of recurrent GBM. A conventional 3+3 Phase I design was used to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of Bev and Vorinostat. The starting dose was Bev at 10mg/kg administered on days 1 and 15 intravenously and Vorinostat 400 mg/day orally on days 1 to 7, and days 15 to 21 with each cycle being 28 days. Results: A total of 6 patients were enrolled and all 6 patients were evaluable. Three patients were enrolled in the first cohort at the starting dose of the combination and completed the first cycle. One patient experienced a grade 3 ALT elevation and grade 3 hyperglycemia, which were designated as possibly related to vorinostat and constituting a dose-limiting toxicity (DLT). No grade 4 toxicities were noted. The cohort was expanded by 3 more patients with none of these patients experienced a DLT in the first cycle. The starting dose level of Bev and v orinostat was declared the Phase II dose. Conclusions: Combination of Bev (10 mg/kg q 2 weeks) and of vorinostat (400 mg on days 1 to 7 and 15 to 21) has tolerable toxicity profile. This will be followed by a multicenter Bayesian adaptive randomized Phase II study.