title: Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial.
abstract: BACKGROUND
  Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors.
  
  
  METHODS
  Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response.
  
  
  RESULTS
  The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for >8 weeks, with the maximum duration of 245 days. Mean drug exposure (±SD) was generally higher with 400 mg qd (area under the curve [AUC(0-∞)] of 7.75 ± 2.79 μM h on Day 1 post-dose) compared with 300 mg bid (AUC(0-∞) of 3.94 ± 1.56 μM h on Day 1 post-dose).
  
  
  CONCLUSIONS
  Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.
authors.affiliation: National Cancer Center Hospital East, Chiba, Japan. doi.toshi3@gmail.com
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Kensho
authors.initials: K
authors.lastname: Chin
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.forename: Kazuo
authors.initials: K
authors.lastname: Noguchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Otsuki
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat