title: A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).
  
  
  METHODS
  In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clinical efficacy were evaluated at each schedule.
  
  
  RESULTS
  Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs observed were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 months).
  
  
  CONCLUSIONS
  The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule.
authors.affiliation: University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Balaji
authors.initials: B
authors.lastname: Venugopal
authors.forename: Richard
authors.initials: R
authors.lastname: Baird
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Kristeleit
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Richard
authors.initials: R
authors.lastname: Cowan
authors.forename: Adam
authors.initials: A
authors.lastname: Stewart
authors.forename: Nele
authors.initials: N
authors.lastname: Fourneau
authors.forename: Peter
authors.initials: P
authors.lastname: Hellemans
authors.forename: Yusri
authors.initials: Y
authors.lastname: Elsayed
authors.forename: Steve
authors.initials: S
authors.lastname: McClue
authors.forename: Johan W
authors.initials: JW
authors.lastname: Smit
authors.forename: Ann
authors.initials: A
authors.lastname: Forslund
authors.forename: Charles
authors.initials: C
authors.lastname: Phelps
authors.forename: John
authors.initials: J
authors.lastname: Camm
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C541788:quisinostat