title: Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma.
abstract: 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.
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Kalpathy-Cramer
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Vyshak
authors.initials: V
authors.lastname: Chandra
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Da
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Yangming
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.|The Intervention Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Kyrre E
authors.initials: KE
authors.lastname: Emblem
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Cai
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.|Department of Anatomy and Neuroscience/VUmc CCA Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Douw
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Evans
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.affiliation: Dana-Farber Cancer Institute, Boston, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Stufflebeam
authors.affiliation: Martinos Center for Biomedical Imaging, Charlestown, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Rosen
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA. egerstner@partners.org.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Anti-angiogenesis; Glioblastoma; MRI; Overall survival; Progression-free survival; Tivozanib