title: Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).
abstract: BACKGROUND
  Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10).
  
  
  RESULTS
  Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity.
  
  
  CONCLUSIONS
  At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.
authors.affiliation: Drug Development Unit, Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.forename: G
authors.initials: G
authors.lastname: Attard
authors.forename: P C
authors.initials: PC
authors.lastname: Fong
authors.forename: V
authors.initials: V
authors.lastname: Karavasilis
authors.forename: A H M
authors.initials: AH
authors.lastname: Reid
authors.forename: S
authors.initials: S
authors.lastname: Patterson
authors.forename: C E
authors.initials: CE
authors.lastname: Riggs
authors.forename: C
authors.initials: C
authors.lastname: Higano
authors.forename: W M
authors.initials: WM
authors.lastname: Stadler
authors.forename: W
authors.initials: W
authors.lastname: McCulloch
authors.forename: D
authors.initials: D
authors.lastname: Dearnaley
authors.forename: C
authors.initials: C
authors.lastname: Parker
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D002369:Castration; D047630:Depsipeptides / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D017430:Prostate-Specific Antigen