title: Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.
abstract: OBJECTIVE
  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/m(2) 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 p21(Waf1/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.
authors: Division of Oncology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10467, USA. mhaigent@montefiore.org
authors: Missak
authors: M
authors: Haigentz
authors: Mimi
authors: M
authors: Kim
authors: Catherine
authors: C
authors: Sarta
authors: Juan
authors: J
authors: Lin
authors: Roger S
authors: RS
authors: Keresztes
authors: Bruce
authors: B
authors: Culliney
authors: Anu G
authors: AG
authors: Gaba
authors: Richard V
authors: RV
authors: Smith
authors: Geoffrey I
authors: GI
authors: Shapiro
authors: Lucian R
authors: LR
authors: Chirieac
authors: John M
authors: JM
authors: Mariadason
authors: Thomas J
authors: TJ
authors: Belbin
authors: John M
authors: JM
authors: Greally
authors: John J
authors: JJ
authors: Wright
authors: Robert I
authors: RI
authors: Haddad
mesh_terms: D000107:Acetylation; D000368:Aged; D019175:DNA Methylation; D047630:Depsipeptides / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin