title: A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors.
  
  
  METHODS
  Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels.
  
  
  RESULTS
  Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. I.v. belinostat displayed linear pharmacokinetics with respect to C(max) and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for > or =4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease.
  
  
  CONCLUSIONS
  I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.
authors.affiliation: The Beatson West of Scotland Cancer Centre, Glasgow, UK. nicola.steele@northglasgow.scot.nhs.uk
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Steele
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Poul
authors.initials: P
authors.lastname: Knoblauch
authors.forename: Annie
authors.initials: A
authors.lastname: Rasmussen
authors.forename: Chean Eng
authors.initials: CE
authors.lastname: Ooi
authors.forename: Peter
authors.initials: P
authors.lastname: Buhl-Jensen
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.forename: Johann S
authors.initials: JS
authors.lastname: DeBono
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D007262:Infusions, Intravenous; D008017:Life Expectancy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018579:Patient Selection; D013449:Sulfonamides
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases; C487081:belinostat