Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial
Abstract
PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (64)
James R. Perry
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
Emma Viktoria Hyddmark
Global Coalition for Adaptive Research, Larkspur, CA
Timothy Cloughesy
University of California Los Angeles, Global Coalition for Adaptive Research, Los Angeles, CA
Brian Alexander
Mark D. Anderson
Lars Anker
Donald A. Berry
Berry Consultants, LLC, Austin, TX
Nicholas S. Berry
Berry Consultants, Austin, TX
Nicholas A. Blondin
Yale University, New Haven, CT
Omar H. Butt
Meredith B. Buxton
Global Coalition for Adaptive Research, Larkspur, CA
Webster K. Cavenee
Department of Medicine, University of California at San Diego
Tim Cloughesy
Howard Colman
Jennifer Connelly
1Medical College of Wisconsin, Milwaukee, United States
Denise M. Damek
University of Colorado School of Medicine, Aurora, CO
John de Groot
University of California San Francisco, San Francisco, CA
Macarena I. De La Fuente
Michelle A. Detry
Berry Consultants, Austin, TX
Jan Drappatz
22Department of Neurology and Medicine, University of Pittsburgh, Pittsburgh, PA
Erin Dunbar
Piedmont Brain Tumor Center, Atlanta, GA
Benjamin M. Ellingson
Mark Fitzgerald
Berry Consultants, Austin, TX
Evanthia Galanis
Mayo Clinic, Rochester, MN
Pierre Giglio
The Ohio State University Wexner Medical Center, Columbus, OH
Gary Gordon
Jerome J. Graber
Todd L. Graves
Jethro Hu
Emma Maria Viktoria Hyddmark
Fabio Iwamoto
Columbia University Irving Medical Center, New York, NY
Kurt A. Jaeckle
Mayo Clinic Florida, Jacksonville, FL
Adam Johnson
Massachusetts General Hospital, Boston, Massachusetts, United States
Marija Kalabic
Mustafa Khasraw
Lyndon Kim
Icahn School of Medicine at Mount Sinai, New York, NY
Heather M. Kling
Global Coalition for Adaptive Research, Larkspur, CA
Andrew B. Lassman
Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, New York-Presbyterian, New York, NY
Eudocia Q. Lee
Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA
Glenn J. Lesser
Michael Lim
Megan Mantica
University of Pittsburgh Medical Center, Pittsburgh, PA
Joe Marion
Anna McGlothlin
Ingo Mellinghoff
3Memorial Sloan Kettering Cancer Center, New York, United States
Tom Mikkelsen
Burt Nabors
University of Alabama at Birmingham, Birmingham, AL
Herbert B. Newton
University Hospitals Cleveland Medical Center & Seidman Cancer Center, Cleveland, OH
Jeffrey J. Olson
Emory University School of Medicine, Atlanta, GA
Scott Owen
Department of Medical Oncology, McGill University Health Centre, Montreal
James R Perry
Katherine B. Peters
Ashley Powell
Christina T. Saunders
Berry Consultants, Austin, TX
David Schiff
31Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA
Erik P. Sulman
Kirk Tanner
Sarah Untch
Tobias Walbert
Henry Ford Health, Michigan State and Wayne State University, Detroit, MI
Shiao-Pei Weathers
Michael Weller
Patrick Y. Wen
Emma Wilcox
W. K. Alfred Yung