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Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma

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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.

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Acknowledgements

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by AVEO Pharmaceuticals, Inc. (to E. G.). The research of R. K. J. and D. G. D. is funded by National Cancer Institute Grant P01CA80124 and the National Foundation for Cancer Research. Funding was also provided by U24CA180918 and U01CA154601 (to J. K. C.) and S10RR023043 and P41RR14075.

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Authors and Affiliations

  1. Martinos Center for Biomedical Imaging, Charlestown, USA

    Jayashree Kalpathy-Cramer, Vyshak Chandra, Xiao Da, Yangming Ou, Kyrre E. Emblem, Xuezhu Cai, Linda Douw, John G. Evans, Stephen Stufflebeam & Bruce Rosen

  2. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA

    Alona Muzikansky, Jorg Dietrich, Dan G. Duda, Rakesh K. Jain, Tracy T. Batchelor & Elizabeth R. Gerstner

  3. The Intervention Centre, Oslo University Hospital, Oslo, Norway

    Kyrre E. Emblem

  4. Department of Anatomy and Neuroscience/VUmc CCA Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Linda Douw

  5. Dana-Farber Cancer Institute, Boston, USA

    Patrick Y. Wen

  6. Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, USA

    Andrew S. Chi

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  1. Jayashree Kalpathy-Cramer
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  2. Vyshak Chandra
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  3. Xiao Da
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Corresponding author

Correspondence to Elizabeth R. Gerstner.

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Conflict of interest

R. K. J. owns equity in Enlight, Ophthotech, SynDevRx, and XTuit and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund, and received grants from MedImmune and Roche. D. G. D. received grants from Merrimack, Bayer and HealthCare Pharmaceuticals.

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Kalpathy-Cramer, J., Chandra, V., Da, X. et al. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol 131, 603–610 (2017). https://doi.org/10.1007/s11060-016-2332-5

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