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

Ugur Sener; Mahnoor Islam; Mason Webb; Sani H Kizilbash

doi:10.1093/noajnl/vdae039

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

Neurooncol Adv. 2024 Mar 15;6(1):vdae039. doi: 10.1093/noajnl/vdae039. eCollection 2024 Jan-Dec.

Authors

Ugur Sener¹, Mahnoor Islam², Mason Webb³, Sani H Kizilbash³

Affiliations

¹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
² Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
³ Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

Background: Despite the 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.

Methods: 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.

Results: Two hundred and 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, and 76 (26%) had no rules regarding antiangiogenic use. A literature review is then presented to define standardized eligibility criteria with a 6-week washout period proposed for future trial design.

Conclusions: 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.

Keywords: antiangiogenic; bevacizumab; clinical trial; glioma; study design.