Breast Cancer Research and Treatment

, Volume 140, Issue 2, pp 331–339 | Cite as

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

  • Erica L. MayerEmail author
  • M. E. Scheulen
  • J. Beckman
  • H. Richly
  • A. Duarte
  • M. M. Cotreau
  • A. L. Strahs
  • S. Agarwal
  • L. Steelman
  • E. P. Winer
  • M. N. Dickler
Clinical Trial


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.


Metastatic breast cancer Paclitaxel Tivozanib VEGFR inhibitor 



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.


This work was supported by AVEO Oncology and Astellas.


  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18PubMedGoogle Scholar
  3. 3.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 29:669–676CrossRefGoogle Scholar
  4. 4.
    Nakamura K, Taguchi E, Miura T et al (2006) KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 66:9134–9142PubMedCrossRefGoogle Scholar
  5. 5.
    Eskens FA, de Jonge MJ, Bhargava P et al (2011) Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res 17:7156–7163PubMedCrossRefGoogle Scholar
  6. 6.
    Nosov DA, Esteves B, Lipatov ON et al (2012) Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol 30:1678–1685PubMedCrossRefGoogle Scholar
  7. 7.
    Motzer RJ, Nosov D, Eisen T et al (2012) Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: results from a phase III randomized, open-label, multicenter trial. J Clin Oncol 30:277s (abstract 4501)CrossRefGoogle Scholar
  8. 8.
    Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  9. 9.
    Rugo H, Barry WT, Moreno-Aspitia A (2012) Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 30(18 suppl):abstract CRA1002Google Scholar
  10. 10.
    O’Shaughnessy J, Miles D, Gray R et al (2010) A meta-analysis of overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC). J Clin Oncol 28(15 suppl):abstract 1005Google Scholar
  11. 11.
    Robert NJ, Dieras V, Glaspy J et al (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. J Clin Oncol 29:1252–1260PubMedCrossRefGoogle Scholar
  12. 12.
    Miles D, Chan A, Romieu G et al (2008) Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol 26(20 suppl):abstract LBA1011Google Scholar
  13. 13.
    Brufsky A, Bonarenko I, Smirnov V et al (2009) RIBBON-2: A randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. Cancer Res 69(24 suppl):abstract 42Google Scholar
  14. 14.
    Baselga J, Segalla JG, Roche H et al (2012) Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol 30:1484–1491PubMedCrossRefGoogle Scholar
  15. 15.
    Shishehbor MH, Aviles RJ, Brennan ML et al (2003) Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 289:1675–1680PubMedCrossRefGoogle Scholar
  16. 16.
    Corretti MC, Anderson TJ, Benjamin EJ et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 239:257–265CrossRefGoogle Scholar
  17. 17.
    Mross K, Hauns B, Haring B et al (1998) Clinical phase I study with one-hour paclitaxel infusion. Ann Oncol 9:569–572PubMedCrossRefGoogle Scholar
  18. 18.
    Mross K, Haring B, Hollander N et al (2002) Comparison of 1-hour and 3-hours paclitaxel infusion pharmacokinetics: results from a randomized trial. Onkologie 25:503–508PubMedCrossRefGoogle Scholar
  19. 19.
    Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  20. 20.
    Foulkes WD, Brunet JS, Stefansson IM et al (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64:830–835PubMedCrossRefGoogle Scholar
  21. 21.
    Nalwoga H, Arnes JB, Stefansson IM et al (2011) Vascular proliferation is increased in basal-like breast cancer. Breast Cancer Res Treat 130:1063–1071PubMedCrossRefGoogle Scholar
  22. 22.
    Brufsky A, Valero V, Tiangco B et al (2011) Bevacizumab (BEV) plus second-line taxane (TAX) or other chemotherapy (CT) for triple-negative breast cancer (TNBC): subgroup analysis of RIBBON-2. J Clin Oncol 29(82 suppl):abstract 1010Google Scholar
  23. 23.
    von Minckwitz G, Eidtmann H, Rezai M et al (2012) Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299–309CrossRefGoogle Scholar
  24. 24.
    Bear HD, Tang G, Rastogi P et al (2012) Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310–320PubMedCrossRefGoogle Scholar
  25. 25.
    Cameron D, Brown J, Dent R et al (2012) Primary results of BEATRICE, a randomized Phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Cancer Res 272:abstract S6-5Google Scholar
  26. 26.
    Dowlati A, Gray R, Sandler AB et al (2008) Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res 14:1407–1412PubMedCrossRefGoogle Scholar
  27. 27.
    Miles DW, de Haas SL, Dirix LY et al (2013) Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 108:1052–1060PubMedCrossRefGoogle Scholar
  28. 28.
    Gianni L, Romieu GH, Lichinitser M et al (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31:1719–1725PubMedCrossRefGoogle Scholar
  29. 29.
    Schneider BP, Wang M, Radovich M et al (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672–4678PubMedCrossRefGoogle Scholar
  30. 30.
    Bertolini F, Shaked Y, Mancuso P et al (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6:835–845PubMedCrossRefGoogle Scholar
  31. 31.
    Dahlberg SE, Sandler AB, Brahmer JR et al (2010) Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 28:949–954PubMedCrossRefGoogle Scholar
  32. 32.
    Rini BI, Cohen DP, Lu DR et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103:763–773PubMedCrossRefGoogle Scholar
  33. 33.
    Goodwin R, Seymour L, Ding K et al (2009) Hypertension (HTN) in National Cancer Institute of Canada Clinical Trials Group study BR.24: a randomized, double-blind phase II trial of carboplatin (C) and paclitaxel (P) with either daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo, in patients with advanced non-small cell lung cancer. J Clin Oncol 27(152 suppl):abstract 3527Google Scholar
  34. 34.
    O’Connor JP, Jackson A, Parker GJ et al (2007) DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96:189–195PubMedCrossRefGoogle Scholar
  35. 35.
    Gatza ML, Kung HN, Blackwell KL et al (2011) Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. Breast Cancer Res 13:abstract R62CrossRefGoogle Scholar
  36. 36.
    Jubb AM, Miller KD, Rugo HS et al (2011) Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res 17:372–381PubMedCrossRefGoogle Scholar
  37. 37.
    Jin ZG, Ueba H, Tanimoto T et al (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363PubMedCrossRefGoogle Scholar
  38. 38.
    Mayer EL, Dallabrida SM, Rupnick MA et al (2011) Contrary effects of the receptor tyrosine kinase inhibitor vandetanib on constitutive and flow-stimulated nitric oxide elaboration in humans. Hypertension 58:85–92PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Erica L. Mayer
    • 1
    Email author
  • M. E. Scheulen
    • 2
  • J. Beckman
    • 3
  • H. Richly
    • 2
  • A. Duarte
    • 4
  • M. M. Cotreau
    • 4
  • A. L. Strahs
    • 4
  • S. Agarwal
    • 4
  • L. Steelman
    • 4
  • E. P. Winer
    • 1
  • M. N. Dickler
    • 5
  1. 1.Dana-Farber Cancer InstituteBostonUSA
  2. 2.Department of Medical Oncology, West German Cancer Center, University Hospital EssenUniversity of Duisburg-EssenEssenGermany
  3. 3.Brigham and Women’s HospitalBostonUSA
  4. 4.AVEO OncologyCambridgeUSA
  5. 5.Memorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations