Vinay K Puduvalli1, Jing Wu2, Ying Yuan3, Terri S Armstrong2, Elizabeth Vera2, Jimin Wu3, Jihong Xu1, Pierre Giglio1, Howard Colman4, Tobias Walbert5, Jeffrey Raizer6, Morris D Groves7, David Tran8, Fabio Iwamoto9, Nicholas Avgeropoulos10, Nina Paleologos11, Karen Fink12, David Peereboom13, Marc Chamberlain14, Ryan Merrell15, Marta Penas Prado16, W K Alfred Yung16, Mark R Gilbert2. 1. Division of Neuro-Oncoology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 2. Neuro-Oncology Branch, National Institute of Health, Bethesda, Maryland. 3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas. 4. Department of Neurosurgery, Huntsman Cancer Center, University of Utah, Salt Lake City, Utah. 5. Department of Neurology and Neurosurgery, Henry Ford Health System, Detroit, Michigan. 6. Department of Neurology, Northwestern University, Chicago, Illinois. 7. Texas Oncology Austin Brain Tumor Center, Austin, Texas. 8. Department of Medicine, Washington University, St Louis, Missouri. 9. Division of Neurooncology, Columbia University, New York, New York. 10. Orlando Health UF Health Cancer Center, Orlando, Florida. 11. Advocate Health Care, Downers Grove, Illinois. 12. Baylor University Medical Center, Dallas, Texas. 13. Department of Medicine, Cleveland Clinic, Cleveland, Ohio. 14. Department of Neurology, University of Washington, Seattle, Washington. 15. Department of Neurology, North Shore University Health System, Evanston, Illinois. 16. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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 tobevacizumab 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 priorbevacizumab 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.
RCT Entities:
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.
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