title: A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.
abstract: BACKGROUND
  SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC.
  
  
  METHODS
  Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed.
  
  
  RESULTS
  Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %).
  
  
  CONCLUSIONS
  Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada, bernie.eigl@bccancer.bc.ca.
authors.forename: B J
authors.initials: BJ
authors.lastname: Eigl
authors.forename: S
authors.initials: S
authors.lastname: North
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.forename: D
authors.initials: D
authors.lastname: Finch
authors.forename: L
authors.initials: L
authors.lastname: Wood
authors.forename: S S
authors.initials: SS
authors.lastname: Sridhar
authors.forename: J
authors.initials: J
authors.lastname: Powers
authors.forename: J
authors.initials: J
authors.lastname: Good
authors.forename: M
authors.initials: M
authors.lastname: Sharma
authors.forename: J A
authors.initials: JA
authors.lastname: Squire
authors.forename: J
authors.initials: J
authors.lastname: Bazov
authors.forename: T
authors.initials: T
authors.lastname: Jamaspishvili
authors.forename: M E
authors.initials: ME
authors.lastname: Cox
authors.forename: P A
authors.initials: PA
authors.lastname: Bradbury
authors.forename: E A
authors.initials: EA
authors.lastname: Eisenhauer
authors.forename: K N
authors.initials: KN
authors.lastname: Chi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007610:Kallikreins; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C072312:ERG protein, human; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen