title: A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine.
abstract: BACKGROUND
  This study was conducted to determine the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetics of the putative histone deacetylase inhibitor CI-994 in combination with capecitabine.
  
  
  METHODS
  Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks.
  
  
  RESULTS
  At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (C(max)) of CI-994.
  
  
  CONCLUSIONS
  The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Undevia
authors.forename: H L
authors.initials: HL
authors.lastname: Kindler
authors.forename: L
authors.initials: L
authors.lastname: Janisch
authors.forename: S C
authors.initials: SC
authors.lastname: Olson
authors.forename: R L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: K A
authors.initials: KA
authors.lastname: Kimmel
authors.forename: T A
authors.initials: TA
authors.lastname: Macek
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil; C081895:tacedinaline