Abstract
BACKGROUND: Bevacizumab, a monoclonal antibody against VEGF-A, is approved for recurrent glioblastoma (GBM) but must be administered as an intravenous infusion twice a month. We designed a Phase II study of oral tivozanib, a VEGFR tyrosine kinase inhibitor, to determine if an oral substitute could be found. METHODS: A two-stage, Phase II study of tivozanib monotherapy was conducted in patients with recurrent GBM. Standard eligibility criteria were included and all patients had at least 1 cm of residual disease to assess radiographic tumor response. The primary endpoint was the proportion of patients progression-free at 6 months (PFS6). Secondary endpoints included median PFS, OS, toxicity, radiographic response (RR), and exploratory analyses of perfusion, permeability, diffusion MRI as well as blood biomarkers of angiogenesis. RESULTS: Ten patients were enrolled in stage 1 with a median age of 62 (51-73). Best MacDonald criteria responses were: CR (1), PR (1), SD (4), PD (4). By volume measurements, 8 patients exhibited a >20% decrease in tumor size. Median duration of response was 3.6 mo (1.7-3.8mo). One patient was taken off study for skin toxicity/fatigue and 8 patients were taken off study for PD. There were no patients progression-free at 6 months although 1 patient remains on treatment at 5 months. Since it was not possible to achieve the pre-specified PFS6 the study was terminated after stage 1. One patient experienced grade 3 hypertension probably related to tivozanib. Two of 4 patients who were on steroids at the start of treatment were able to decrease or discontinue steroids. CONCLUSION: Tivozanib was well tolerated but the PFS6 did not meet the pre-specified efficacy threshold for further analysis. Ongoing analysis of the correlative imaging (perfusion, diffusion, permeability) and blood biomarkers may shed light on why this oral VEGFR inhibitor was ineffective in this patient population.