Background: Bevacizumab (Bev) is approved in the US for patients (pts) with recurrent glioblastoma based on response rate. However, adaptive resistance to antiangiogenic agents can result in tumor recurrence. Deacetylase inhibitors such as vorinostat (Vor) have pleotropic effects against several pathways potentially relevant to adaptive resistance to Bev. Methods: We conducted a phase II multicenter trial with Bayesian adaptive randomization of patients to Bev alone or Bev+Vor with a primary endpoint of progression-free survival (PFS) and secondary end points of overall survival (OS) and patient-reported symptoms using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Eligible patients were adults ( ≥ 18y) with histologically confirmed GB who had recurrent disease after prior radiation and temozolomide therapy, KPS ≥ 60, and no prior Bev or HDAC inhibitors. Results: Of the 90 pts (Bev+V: 49, Bev: 41) enrolled between Oct 2012 and Oct 2014, 83 were evaluable for the primary endpoint (Bev+V: 46, Bev: 37). MDASI-BT scores were available for 81 pts. There was no significant difference between the two arms in median PFS (4.2 vs.3.6 months, p = 0.53) or median OS (8.3 vs. 7.0 months, p = 0.93). Analysis of the MDASI-BT scores showed no significant differences between the two arms in overall symptom burden or interference (p = 0.48, 0.71 respectively). Overall, 61 pts had died by the time of analysis (Bev+V: 35, Bev: 26) with one treatment related death due to pulmonary embolism. Toxicity ≥ grade 3 included hypertension (n = 17), neurological changes (n = 2), infections (n = 2), wound dehiscence (n = 2), DVT/PE (n = 2), and colonic perforation (n = 1). Conclusions: In this trial, Bev+Vor did not yield an improved PFS or OS or clinical benefit in terms of reduced symptom burden compared with Bev alone in patients with recurrent GB and does not warrant further investigation. To our knowledge, this trial represents the first prospective Bayesian adaptive randomized therapeutic study against gliomas and demonstrates the feasibility of conducting studies with adaptive trial designs in a multicenter setting. Clinical trial information: NCT01266031