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Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo

Breast Cancer Research and Treatment volume 132, pages 1063–1072 (2012)Cite this article

Abstract

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1–3, 8–10, and 15–17, plus paclitaxel (90 mg/m2) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel–bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

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Acknowledgments:

This study was supported by United States Department of Health and Human Service contract N01-CM-62204 (P.I. Joseph A. Sparano, MD) and N01-CM-62207 (PI: Miguel Villalona, MD), and N01 CM62205 (PI: Charles Erlichman MD).

Disclosures

The authors have no relevant disclosures except Dr. Vered Stearns who has received research funding from Merck.

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Authors and Affiliations

  1. The Ohio State University, Columbus, OH, USA

    B. Ramaswamy & C. L. Shapiro

  2. The University of Kansas Cancer Center, Kansas City, KS, USA

    W. Fiskus & K. Bhalla

  3. Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA

    B. Cohen, C. Pellegrino & J. A. Sparano

  4. New York Presbyterian Hospital, New York, NY, USA

    D. L. Hershman

  5. Weill Cornell Medical College, New York, NY, USA

    E. Chuang & P. Christos

  6. City of Hope Medical Center, Duarte, CA, USA

    Thehang Luu & G. Somlo

  7. Mayo Clinic, Rochester, MN, USA

    M. Goetz

  8. Fox Chase Cancer Center, Philadelphia, PA, USA

    R. Swaby

  9. Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA

    V. Stearns

  10. NCI, Bethesda, MD, USA

    I. Espinoza-Delgado

Authors
  1. B. Ramaswamy
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  2. W. Fiskus
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  3. B. Cohen
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  4. C. Pellegrino
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  5. D. L. Hershman
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  6. E. Chuang
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  8. G. Somlo
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  9. M. Goetz
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  10. R. Swaby
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  11. C. L. Shapiro
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  12. V. Stearns
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  13. P. Christos
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  14. I. Espinoza-Delgado
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  15. K. Bhalla
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  16. J. A. Sparano
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Corresponding author

Correspondence to B. Ramaswamy.

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Ramaswamy, B., Fiskus, W., Cohen, B. et al. Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. Breast Cancer Res Treat 132, 1063–1072 (2012). https://doi.org/10.1007/s10549-011-1928-x

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  • DOI: https://doi.org/10.1007/s10549-011-1928-x

Keywords

  • Metastatic breast cancer
  • Paclitaxel
  • Bevacizumab
  • Vorinostat
  • HDAC inhibitors