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A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer

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Abstract

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m2. Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m2. Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

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Acknowledgments

The authors wish to thank Dr. Pankaj Bhargava and Dr. Joshua Zhang for their contribution to the study conduct. This study was supported by AVEO Oncology and Astellas. AVEO and Astellas are parties to a collaboration agreement for the co-development of tivozanib. Editorial assistance was provided by Jinling Wu, MD, PhD, Chameleon Communications International, and was funded by AVEO and Astellas.

Conflict of interest

E. L. Mayer has served as a consultant for Amgen. M. N. Dickler participated in a compensated advisory board for AVEO Oncology. S. Agarwal and L. Steelman are full-time employees of AVEO Oncology. M. M. Cotreau and A. L. Strahs are full-time employees and stockholders of AVEO Oncology. All remaining authors have declared no conflicts of interest.

Funding

This work was supported by AVEO Oncology and Astellas.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA

    Erica L. Mayer & E. P. Winer

  2. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    M. E. Scheulen & H. Richly

  3. Brigham and Women’s Hospital, Boston, MA, USA

    J. Beckman

  4. AVEO Oncology, Cambridge, MA, USA

    A. Duarte, M. M. Cotreau, A. L. Strahs, S. Agarwal & L. Steelman

  5. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M. N. Dickler

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  1. Erica L. Mayer
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Correspondence to Erica L. Mayer.

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Mayer, E.L., Scheulen, M.E., Beckman, J. et al. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer. Breast Cancer Res Treat 140, 331–339 (2013). https://doi.org/10.1007/s10549-013-2632-9

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  • DOI: https://doi.org/10.1007/s10549-013-2632-9

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