title: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer.
abstract: OBJECTIVE
  To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer.
  
  
  METHODS
  Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition.
  
  
  RESULTS
  Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months.
  
  
  CONCLUSIONS
  Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Joan and Sanford Weill Medical College of Cornell University, New York, NY 10021, USA. kellyw@mskcc.org
authors.forename: William Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: Judy H
authors.initials: JH
authors.lastname: Chiao
authors.forename: Mark
authors.initials: M
authors.lastname: Heaney
authors.forename: Tracy
authors.initials: T
authors.lastname: Curley
authors.forename: Barbara
authors.initials: B
authors.lastname: MacGregore-Cortelli
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: Stacy
authors.initials: S
authors.lastname: Richardson
authors.forename: Elaina
authors.initials: E
authors.lastname: Chu
authors.forename: Semra
authors.initials: S
authors.lastname: Olgac
authors.forename: Paul A
authors.initials: PA
authors.lastname: Marks
authors.forename: Howard
authors.initials: H
authors.lastname: Scher
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat