title: A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.
abstract: OBJECTIVE
  This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.
  
  
  METHODS
  CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.
  
  
  RESULTS
  Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.
  
  
  CONCLUSIONS
  Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.
authors.affiliation: The Drug Development Unit, Sycamore House, Division of Cancer Therapeutics/Division of Clinical Studies, The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, United Kingdom. udai.banerji@icr.ac.uk
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: Leni
authors.initials: L
authors.lastname: van Doorn
authors.forename: Dionysis
authors.initials: D
authors.lastname: Papadatos-Pastos
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.forename: Phillip
authors.initials: P
authors.lastname: Debnam
authors.forename: Matthew
authors.initials: M
authors.lastname: Tall
authors.forename: Adam
authors.initials: A
authors.lastname: Stewart
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Michelle Dawn
authors.initials: MD
authors.lastname: Garrett
authors.forename: Martin
authors.initials: M
authors.lastname: Toal
authors.forename: Leon
authors.initials: L
authors.lastname: Hooftman
authors.forename: Johann Sebastian
authors.initials: JS
authors.lastname: De Bono
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Ferry Alm
authors.initials: FA
authors.lastname: Eskens
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D005500:Follow-Up Studies; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: C555225:2-(6-(((6-fluoroquinolin-2-yl)methyl)amino)bicyclo(3.1.0)hex-3-yl)-N-hydroxypyrimidine-5-carboxamide; D053961:Azabicyclo Compounds; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; D006655:Histone Deacetylases