Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer

Missak Haigentz, Mimi Kim, Catherine Sarta, Juan Lin, Roger S. Keresztes, Bruce Culliney, Anu G. Gaba, Richard V. Smith, Geoffrey I. Shapiro, Lucian R. Chirieac, John M. Mariadason, Thomas J. Belbin, John M. Greally, John J. Wright, Robert I. Haddad

Research output: Contribution to journalArticle

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Abstract

Objectives: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. Methods: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m2 as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. Results: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21Waf1/Cip1 characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. Conclusions: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

Original languageEnglish (US)
Pages (from-to)1281-1288
Number of pages8
JournalOral Oncology
Volume48
Issue number12
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

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Histone Deacetylase Inhibitors
Head and Neck Neoplasms
Histone Deacetylases
Therapeutics
Neoplasms
romidepsin
Mouth Mucosa
DNA Methylation
Microarray Analysis
Electron Transport
Cell Cycle Checkpoints
Intravenous Infusions
Fatigue
Signal Transduction
Staining and Labeling
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oral Surgery
  • Oncology
  • Cancer Research

Cite this

Haigentz, Missak ; Kim, Mimi ; Sarta, Catherine ; Lin, Juan ; Keresztes, Roger S. ; Culliney, Bruce ; Gaba, Anu G. ; Smith, Richard V. ; Shapiro, Geoffrey I. ; Chirieac, Lucian R. ; Mariadason, John M. ; Belbin, Thomas J. ; Greally, John M. ; Wright, John J. ; Haddad, Robert I. / Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. In: Oral Oncology. 2012 ; Vol. 48, No. 12. pp. 1281-1288.
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title = "Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer",
abstract = "Objectives: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. Methods: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m2 as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. Results: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21Waf1/Cip1 characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. Conclusions: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.",
author = "Missak Haigentz and Mimi Kim and Catherine Sarta and Juan Lin and Keresztes, {Roger S.} and Bruce Culliney and Gaba, {Anu G.} and Smith, {Richard V.} and Shapiro, {Geoffrey I.} and Chirieac, {Lucian R.} and Mariadason, {John M.} and Belbin, {Thomas J.} and Greally, {John M.} and Wright, {John J.} and Haddad, {Robert I.}",
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Haigentz, M, Kim, M, Sarta, C, Lin, J, Keresztes, RS, Culliney, B, Gaba, AG, Smith, RV, Shapiro, GI, Chirieac, LR, Mariadason, JM, Belbin, TJ, Greally, JM, Wright, JJ & Haddad, RI 2012, 'Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer', Oral Oncology, vol. 48, no. 12, pp. 1281-1288. https://doi.org/10.1016/j.oraloncology.2012.05.024

Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. / Haigentz, Missak; Kim, Mimi; Sarta, Catherine; Lin, Juan; Keresztes, Roger S.; Culliney, Bruce; Gaba, Anu G.; Smith, Richard V.; Shapiro, Geoffrey I.; Chirieac, Lucian R.; Mariadason, John M.; Belbin, Thomas J.; Greally, John M.; Wright, John J.; Haddad, Robert I.

In: Oral Oncology, Vol. 48, No. 12, 01.12.2012, p. 1281-1288.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer

AU - Haigentz, Missak

AU - Kim, Mimi

AU - Sarta, Catherine

AU - Lin, Juan

AU - Keresztes, Roger S.

AU - Culliney, Bruce

AU - Gaba, Anu G.

AU - Smith, Richard V.

AU - Shapiro, Geoffrey I.

AU - Chirieac, Lucian R.

AU - Mariadason, John M.

AU - Belbin, Thomas J.

AU - Greally, John M.

AU - Wright, John J.

AU - Haddad, Robert I.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Objectives: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. Methods: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m2 as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. Results: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21Waf1/Cip1 characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. Conclusions: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

AB - Objectives: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. Methods: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m2 as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. Results: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21Waf1/Cip1 characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. Conclusions: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

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