A Bayesian Adaptive Randomized Phase II Multicenter Trial of Bevacizumab with or without Vorinostat in Adults with Recurrent Glioblastoma.
Puduvalli VK, Wu J, Yuan Y, Armstrong TS, Vera E, Wu J, Xu J, Giglio P, Colman H, Walbert T, Raizer J, Groves MD, Tran D, Iwamoto F, Avgeropoulos N, Paleologos N, Fink K, Peereboom D, Chamberlain M, Merrell R, Penas Prado M, Yung WKA, and Gilbert MR. A Bayesian Adaptive Randomized Phase II Multicenter Trial of Bevacizumab with or without Vorinostat in Adults with Recurrent Glioblastoma. Neuro Oncol 2020.
BACKGROUND: 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 antiangiogenic effects, would prevent acquired resistance to bevacizumab.
METHODS: 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 end points of overall survival (OS) and clinical outcomes assessment (MDASI-BT). Eligible patients were adults (≥18 yrs) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS≥60, and no prior bevacizumab or HDAC inhibitors.
RESULTS: Ninety patients (bevacizumab+vorinostat:49, bevacizumab:41) were enrolled of whom 74 were evaluable for PFS (bevacizumab+vorinostat:44, bevacizumab:30). Median PFS (3.7 vs 3.9 months, p=0.94, HR 0.63 [95% CI 0.38, 1.06, p=0.08]), median OS (7.8 vs 9.3 months, p=0.64, HR 0.93 [95% CI 0.5, 1.6, p=0.79]) and clinical benefit were similar between the two arms. Toxicity (≥grade 3) in 85 evaluable patients included hypertension (n=37), neurological changes (n=2), anorexia (n=2), infections (n=9), wound dehiscence (n=2), DVT/PE (n=2), and colonic perforation (n=1).
CONCLUSIONS: Bevacizumab combined with vorinostat did not yield improvement in PFS, OS or clinical benefit compared with bevacizumab alone nor 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.
ePub ahead of print