A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma

<p> <strong> BACKGROUND </strong> : Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.</p><p> <strong> METHODS </strong> : This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (&ge;18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS&emsp14;&ge;60, and no prior bevacizumab or HDAC inhibitors.</p><p> <strong> RESULTS </strong> : Ninety patients (bevacizumab&emsp14;+&emsp14;vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab&emsp14;+&emsp14;vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P&emsp14;=&emsp14;0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P&emsp14;=&emsp14;0.08]), median OS (7.8 vs 9.3 mo, P&emsp14;=&emsp14;0.64, HR 0.93 [95% CI: 0.5, 1.6, P&emsp14;=&emsp14;0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade &ge;3) in 85 evaluable patients included hypertension (n =&emsp14;37), neurological changes (n =&emsp14;2), anorexia (n =&emsp14;2), infections (n =&emsp14;9), wound dehiscence (n =&emsp14;2), deep vein thrombosis/pulmonary embolism (n =&emsp14;2), and colonic perforation (n =&emsp14;1).</p><p> <strong> CONCLUSIONS </strong> : Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.</p>