title: A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer.
abstract: OBJECTIVE
  We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX).
  
  
  METHODS
  Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied.
  
  
  RESULTS
  Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR.
  
  
  CONCLUSIONS
  The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.
authors.affiliation: Department of Medicine, Pharmacology, and Radiology, Roswell Park Cancer Institute, Buffalo, NY, USA. marwan.fakih@roswellpark.org
authors.forename: Marwan G
authors.initials: MG
authors.lastname: Fakih
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pendyala
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.forename: Karoli
authors.initials: K
authors.lastname: Toth
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Alan
authors.initials: A
authors.lastname: Litwin
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Ross
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Holleran
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077337:Vorinostat; D002955:Leucovorin; D005472:Fluorouracil