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

B. Ramaswamy, W. Fiskus, Bruce C. Cohen, C. Pellegrino, D. L. Hershman, E. Chuang, Thehang Luu, G. Somlo, M. Goetz, R. Swaby, C. L. Shapiro, V. Stearns, P. Christos, I. Espinoza-Delgado, K. Bhalla, Joseph A. Sparano

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulinpolymerizing 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/m 2) 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.

Original languageEnglish (US)
Pages (from-to)1063-1072
Number of pages10
JournalBreast Cancer Research and Treatment
Volume132
Issue number3
DOIs
StatePublished - Apr 2012

Fingerprint

Tubulin
Acetylation
Paclitaxel
Breast Neoplasms
Bevacizumab
vorinostat
Histone Deacetylase Inhibitors
Histones
Vascular Endothelial Growth Factor A
Diarrhea
Confidence Intervals
Biopsy
Safety
Drug Therapy
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Ramaswamy, B.; Fiskus, W.; Cohen, Bruce C.; Pellegrino, C.; Hershman, D. L.; Chuang, E.; Luu, Thehang; Somlo, G.; Goetz, M.; Swaby, R.; Shapiro, C. L.; Stearns, V.; Christos, P.; Espinoza-Delgado, I.; Bhalla, K.; Sparano, Joseph A.

In: Breast Cancer Research and Treatment, Vol. 132, No. 3, 04.2012, p. 1063-1072.

Research output: Contribution to journalArticle

Ramaswamy, B, Fiskus, W, Cohen, BC, Pellegrino, C, Hershman, DL, Chuang, E, Luu, T, Somlo, G, Goetz, M, Swaby, R, Shapiro, CL, Stearns, V, Christos, P, Espinoza-Delgado, I, Bhalla, K & Sparano, JA 2012, '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, vol. 132, no. 3, pp. 1063-1072. https://doi.org/10.1007/s10549-011-1928-x
Ramaswamy, B. ; Fiskus, W. ; Cohen, Bruce C. ; Pellegrino, C. ; Hershman, D. L. ; Chuang, E. ; Luu, Thehang ; Somlo, G. ; Goetz, M. ; Swaby, R. ; Shapiro, C. L. ; Stearns, V. ; Christos, P. ; Espinoza-Delgado, I. ; Bhalla, K. ; Sparano, Joseph A. / 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. In: Breast Cancer Research and Treatment. 2012 ; Vol. 132, No. 3. pp. 1063-1072.
@article{cc12eb2d99854eed9eba1e1545f3fe60,
title = "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",
abstract = "In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulinpolymerizing 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/m 2) 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.",
keywords = "Bevacizumab, HDAC inhibitors, Metastatic breast cancer, Paclitaxel, Vorinostat",
author = "B. Ramaswamy and W. Fiskus and Cohen, {Bruce C.} and C. Pellegrino and Hershman, {D. L.} and E. Chuang and Thehang Luu and G. Somlo and M. Goetz and R. Swaby and Shapiro, {C. L.} and V. Stearns and P. Christos and I. Espinoza-Delgado and K. Bhalla and Sparano, {Joseph A.}",
year = "2012",
month = "4",
doi = "10.1007/s10549-011-1928-x",
language = "English (US)",
volume = "132",
pages = "1063--1072",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer

T2 - Evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo

AU - Ramaswamy, B.

AU - Fiskus, W.

AU - Cohen, Bruce C.

AU - Pellegrino, C.

AU - Hershman, D. L.

AU - Chuang, E.

AU - Luu, Thehang

AU - Somlo, G.

AU - Goetz, M.

AU - Swaby, R.

AU - Shapiro, C. L.

AU - Stearns, V.

AU - Christos, P.

AU - Espinoza-Delgado, I.

AU - Bhalla, K.

AU - Sparano, Joseph A.

PY - 2012/4

Y1 - 2012/4

N2 - In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulinpolymerizing 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/m 2) 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.

AB - In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulinpolymerizing 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/m 2) 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.

KW - Bevacizumab

KW - HDAC inhibitors

KW - Metastatic breast cancer

KW - Paclitaxel

KW - Vorinostat

UR - http://www.scopus.com/inward/record.url?scp=84865168464&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865168464&partnerID=8YFLogxK

U2 - 10.1007/s10549-011-1928-x

DO - 10.1007/s10549-011-1928-x

M3 - Article

VL - 132

SP - 1063

EP - 1072

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 3

ER -