title: Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer.
abstract: OBJECTIVE
  The purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine.
  
  
  METHODS
  This was a dose escalation trial in which gemcitabine (1,000 mg/m2) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating doses of 2, 4, 6, and 8 mg/m2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment.
  
  
  RESULTS
  Twenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limitingtoxicity occurred at the 8-mg/ m2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable.
  
  
  CONCLUSIONS
  The 6-mg/m2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.
authors.affiliation: US Oncology, Baylor University Medical Center, Dallas, Texas, USA. John.Nemunaitis@USOncology.com
authors.forename: John J
authors.initials: JJ
authors.lastname: Nemunaitis
authors.forename: Douglas
authors.initials: D
authors.lastname: Orr
authors.forename: Rob
authors.initials: R
authors.lastname: Eager
authors.forename: C Casey
authors.initials: CC
authors.lastname: Cunningham
authors.forename: Adrienne
authors.initials: A
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Mennel
authors.forename: William
authors.initials: W
authors.lastname: Grove
authors.forename: Stephen
authors.initials: S
authors.lastname: Olson
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D010655:Phenylenediamines; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; C081895:tacedinaline; D000093542:Gemcitabine