Antiangiogenic exclusion rules in glioma trials: Historical perspectives and guidance for future trial design

Despite lack of proven therapies for recurrent high-grade glioma (HGG), only 8-11% of patients with glioblastoma participate in clinical trials, partly due to stringent eligibility criteria. Prior bevacizumab treatment is a frequent exclusion criterion, due to difficulty with response assessment and concerns for rebound edema following antiangiogenic discontinuation. There are no standardized trial eligibility rules related to prior antiangiogenic use. We reviewed ClinicalTrials.gov listings for glioma studies starting between May 2009 and July 2022 for eligibility rules related to antiangiogenics. We also reviewed the literature pertaining to bevacizumab withdrawal. Two-hundred-ninety-seven studies for patients with recurrent glioma were reviewed. Most were phase 1 (n=145, 49%), non-randomized (n=257, 87%), evaluated a drug-only intervention (n=223, 75%), and had a safety and tolerability primary objective (n=181, 61%). Fifty-one (17%) excluded participants who received any antiangiogenic, one (0.3%) excluded participants who received any non-temozolomide systemic therapy. Fifty-nine (20%) outlined washout rules for bevacizumab (range 2-24 weeks, 4-week washout n=35, 12% most common). Seventy-eight required a systemic therapy washout (range 1-6 weeks, 4-week washout n=34, 11% most common). Nine permitted prior bevacizumab use with limitations, 18 (6%) permitted any prior bevacizumab, 5 (2%) were for bevacizumab-refractory disease, 76 (26%) had no rules regarding antiangiogenic use. A literature review is then presented to define standardized eligibility criteria with a six-week washout period proposed for future trial design. Interventional clinical trials for patients with HGG have substantial heterogeneity regarding eligibility criteria pertaining to bevacizumab use, demonstrating a need for standardizing clinical trial design.