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, B.
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, J. A.
N1 - Funding Information:
The trial was reviewed, approved, and sponsored by the Cancer Therapy Evaluation Program of the National cancer Institute (Clinicaltrails.gov, identifier NCT00368875). The local institutional review board at each individual participating center approved the protocol. All patients were required to sign a written, voluntary, informed consent.
Funding Information:
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 Vil-lalona, MD), and N01 CM62205 (PI: Charles Erlichman MD).
Funding Information:
Disclosures The authors have no relevant disclosures except Dr. Vered Stearns who has received research funding from Merck.
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
C2 - 22200869
AN - SCOPUS:84865168464
SN - 0167-6806
VL - 132
SP - 1063
EP - 1072
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -