title: A phase I/II trial of vorinostat in combination with 5-fluorouracil  in patients with metastatic colorectal cancer who previously failed  5-FU-based chemotherapy.
abstract: OBJECTIVE
  We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).
  
  
  METHODS
  Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.
  
  
  RESULTS
  Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.
  
  
  CONCLUSIONS
  The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.
authors.affiliation: Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wilson
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: Syma
authors.initials: S
authors.lastname: Iqbal
authors.forename: William
authors.initials: W
authors.lastname: Fazzone
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: LaBonte
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: Sarah
authors.initials: S
authors.lastname: Cole
authors.forename: Margaret
authors.initials: M
authors.lastname: Kornacki
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ladner
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D017211:Treatment Failure; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; D013940:Thymidylate Synthase; D051548:Histone Acetyltransferases; D002955:Leucovorin; D005472:Fluorouracil