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Breast Cancer Research and Treatment

, Volume 136, Issue 1, pp 169–178 | Cite as

Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics

  • Erica L. MayerEmail author
  • Steven J. Isakoff
  • Giannoula Klement
  • Sean R. Downing
  • Wendy Y. Chen
  • Keri Hannagan
  • Rebecca Gelman
  • Eric P. Winer
  • Harold J. Burstein
Clinical Trial

Abstract

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0–4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1–2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ≥24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.

Keywords

Angiogenesis inhibition Breast cancer Metronomic chemotherapy Proteomics Vandetanib 

Notes

Acknowledgments

This research was supported by a grant from the Investigator-Sponsored Study Program of AstraZeneca, Wilmington, DE

Conflict of interest

None.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Erica L. Mayer
    • 1
    • 2
    Email author
  • Steven J. Isakoff
    • 3
  • Giannoula Klement
    • 4
  • Sean R. Downing
    • 5
  • Wendy Y. Chen
    • 1
    • 2
  • Keri Hannagan
    • 1
  • Rebecca Gelman
    • 1
  • Eric P. Winer
    • 1
    • 2
  • Harold J. Burstein
    • 1
    • 2
  1. 1.Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  2. 2.Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  4. 4.Tufts University School of MedicineBostonUSA
  5. 5.Foundation MedicineCambridgeUSA

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