Targeting tumor angiogenesis is a potential therapeutic strategy for 
glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF 
receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma 
angiogenesis. We conducted a phase II study to test the effectiveness of 
tivozanib in patients with recurrent glioblastoma. Ten adult patients were 
enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 
28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at 
baseline, within 24-72 h of treatment initiation, and monthly thereafter. 
Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel 
architecture imaging were used to assess vascular effects. Resting state MRI was 
used to assess brain connectivity. Best RANO criteria responses were: 1 complete 
response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). 
Two patients were taken off study for toxicity and 8 patients were taken off 
study for PD. Median progression-free survival was 2.3 months and median overall 
survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood 
flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma 
PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of 
tivozanib. However, there were no clear structural changes in vasculature as 
vessel caliber and enhancing tumor volume did not significantly change. Despite 
functional changes in tumor vasculature, tivozanib had limited anti-tumor 
activity, highlighting the limitations of anti-VEGF monotherapy. Future studies 
in glioblastoma should leverage the anti-vascular activity of agents targeting 
VEGF to enhance the activity of other therapies.