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Clinical Trial
. 2020 Oct 14;22(10):1505-1515.
doi: 10.1093/neuonc/noaa062.

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

Vinay K Puduvalli  1 , Jing Wu  2 , Ying Yuan  3 , Terri S Armstrong  2 , Elizabeth Vera  2 , Jimin Wu  3 , Jihong Xu  1 , Pierre Giglio  1 , Howard Colman  4 , Tobias Walbert  5 , Jeffrey Raizer  6 , Morris D Groves  7 , David Tran  8 , Fabio Iwamoto  9 , Nicholas Avgeropoulos  10 , Nina Paleologos  11 , Karen Fink  12 , David Peereboom  13 , Marc Chamberlain  14 , Ryan Merrell  15 , Marta Penas Prado  16 , W K Alfred Yung  16 , Mark R Gilbert  2
Affiliations
Clinical Trial

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

Vinay K Puduvalli et al. Neuro Oncol. .

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.

Keywords: Bayesian adaptive trial design; bevacizumab; progression free survival; recurrent glioblastoma; vorinostat.

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Figures

Fig. 1
Fig. 1
Consolidated Standards of Reporting Trials (CONSORT) diagram.
Fig. 2
Fig. 2
Kaplan–Meier curves for PFS (left) and OS (right) (E = evaluable, N = total).
See this image and copyright information in PMC

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