title: A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†.
abstract: BACKGROUND
  A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway.
  
  
  METHODS
  SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods.
  
  
  RESULTS
  Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity.
  
  
  CONCLUSIONS
  This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population.
  
  
  BACKGROUND
  NCT01112384.
authors: Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton. Electronic address: quincy.chu@albertahealthservices.ca.
authors: Q S-C
authors: QS
authors: Chu
authors: Department of Pathology, British Columbia Cancer Agency, Vancouver.
authors: T O
authors: TO
authors: Nielsen
authors: Division of Medical Oncology, Department of Oncology, McGill University, Montreal.
authors: T
authors: T
authors: Alcindor
authors: Division of Medical Oncology, Department of Oncology, Mount Sinai Hospital/Princess Margaret Hospital, University of Toronto, Toronto, Canada.
authors: A
authors: A
authors: Gupta
authors: Department of Orthopedic Surgery, Kyushu University, Fukuoka, Japan.
authors: M
authors: M
authors: Endo
authors: Department of Pathology, British Columbia Cancer Agency, Vancouver.
authors: A
authors: A
authors: Goytain
authors: Investigational New Drug Program, NCIC-Clinical Trials Group, Kingston.
authors: H
authors: H
authors: Xu
authors: Department of Medical Oncology, Ottawa Cancer Centre, University of Ottawa, Ottawa.
authors: S
authors: S
authors: Verma
authors: Division of Medical Oncology, Department of Oncology, Jurvinski Cancer Centre, McMaster University, Hamilton.
authors: R
authors: R
authors: Tozer
authors: Department of Pathology, British Columbia Cancer Agency, Vancouver.
authors: M
authors: M
authors: Knowling
authors: Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Canada.
authors: V B
authors: VB
authors: Bramwell
authors: Investigational New Drug Program, NCIC-Clinical Trials Group, Kingston.
authors: J
authors: J
authors: Powers
authors: Investigational New Drug Program, NCIC-Clinical Trials Group, Kingston.
authors: L K
authors: LK
authors: Seymour
authors: Investigational New Drug Program, NCIC-Clinical Trials Group, Kingston.
authors: E A
authors: EA
authors: Eisenhauer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000600:supply & distribution / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000600:supply & distribution / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002170:Canada; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000600:supply & distribution / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D013997:Time Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: histone deacetylase inhibitor; phase II; translocation-associated sarcoma