title: Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.
abstract: BACKGROUND
  SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours.
  
  
  METHODS
  Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels.
  
  
  RESULTS
  In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response.
  
  
  CONCLUSIONS
  SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.
authors.affiliation: Drug Development Program, Department of Medical Oncology and Haematology, Princess Margaret Hospital, Suite 5-718 (5th Floor), 610 University Avenue, Toronto, Ontario, M5G 2M9 Canada.
authors.forename: A R A
authors.initials: AR
authors.lastname: Razak
authors.forename: S J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: E X
authors.initials: EX
authors.lastname: Chen
authors.forename: H W
authors.initials: HW
authors.lastname: Hirte
authors.forename: J
authors.initials: J
authors.lastname: Powers
authors.forename: W
authors.initials: W
authors.lastname: Walsh
authors.forename: L-A
authors.initials: LA
authors.lastname: Stayner
authors.forename: A
authors.initials: A
authors.lastname: Laughlin
authors.forename: V
authors.initials: V
authors.lastname: Novotny-Diermayr
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: E A
authors.initials: EA
authors.lastname: Eisenhauer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound