Background: Prognosis for recurrent glioblastoma (GBM) remains dismal with a 9-15% 6-month progression-free survival (PFS). However, the addition of bevacizumab (BEV), a humanized monoclonal IgG1 antibody with effects at human vascular endothelial growth factor, has improved 6-month PFS to 40-50% and median overall survival (OS) to 9.2 months. Vorinostat (VOR) is a small molecule derivative of hydroxamic acid that crosses the blood-brain barrier and has anti-tumor effects directly by inhibition of histone deacetylase and indirectly by anti-angiogenic promotion. In light of VOR’s mechanism of action and favorable toxicity/safety profile, we sought to evaluate the efficacy of VOR combined with BEV in recurrent GBM. Methods: A phase II single-center open-label, single arm study was performed to evaluate VOR and BEV in recurrent GBM. Primary endpoint was 6-month PFS. Secondary endpoints were safety/tolerability, radiographic response, PFS, and OS. Major eligibility criteria included age ≥ 18 yrs, KPS ≥ 70 and ≤ 2 prior progressions. Dosing regimen was BEV 10mg/kg IV q2weeks combined with VOR 400mg PO daily for 7 days, then 7 days off in a 28 day cycle. Results: Forty recurrent GBM patients were enrolled. To date, median follow-up time is 13.2 months with 6-month PFS of 30% (95% CI: 16.8%, 44.4%). Median OS is 10.4 months (95% CI: 9.3-13.1 months). Objective radiographic responses included 9 partial responses, 29 stable responses, and 1 radiographic progression with 1 patient not assessed due to early death (sudden death of vascular origin). Most common treatment related grade 2-3 toxicities were lymphopenia (55%), leukopenia (43%), neutropenia (33%) and hypertension (33%). Grade 4 toxicities were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and thromboembolic event (3%). Two deaths occurred on study; one due to disease progression and the other was a sudden death of vascular origin. Conclusions: VOR and BEV combination therapy was well-tolerated in recurrent GBM, although it did not improve 6-month PFS when compared to BEV monotherapy. There was a trend towards improved OS in VOR and BEV in comparison to BEV monotherapy. Continued follow-up and research is needed to delineate better the role of chemotherapy in combination with BEV. Clinical trial information: NCT01738646