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

Vinay K. Puduvalli, Jing Wu, Ying Yuan, Terri S. Armstrong, Elizabeth Vera, Jimin Wu, Jihong Xu, Pierre Giglio, Howard Colman, Tobias Walbert, Jeffrey Raizer, Morris D. Groves, David Tran, Fabio Iwamoto, Nicholas Avgeropoulos, Nina Paleologos, Karen Fink, David Peereboom, Marc Chamberlain, Ryan MerrellMarta Penas-Prado, W. K.Alfred Yung, Mark R Gilbert

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1 Scopus citations

Abstract

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 anti-angiogenic 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 endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) 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 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 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), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1). CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)1505-1515
Number of pages11
JournalNeuro-oncology
Volume22
Issue number10
DOIs
StatePublished - Oct 14 2020

Keywords

  • Bayesian adaptive trial design
  • bevacizumab
  • progression free survival
  • recurrent glioblastoma
  • vorinostat

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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