title: A phase I study of oral ixabepilone in patients with advanced solid tumors.
abstract: BACKGROUND
  Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors.
  
  
  METHODS
  Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects.
  
  
  RESULTS
  The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine.
  
  
  CONCLUSIONS
  The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.
authors.affiliation: Inova Comprehensive Cancer and Research Center, 3300 Gallows Road, Falls Church, VA, 22042, USA, John.Deeken@inova.org.
authors.forename: John F
authors.initials: JF
authors.lastname: Deeken
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Ahlers
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Clemens
authors.forename: Susan M
authors.initials: SM
authors.lastname: Parker
authors.forename: Lisa
authors.initials: L
authors.lastname: Iacono
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034261:Epothilones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; C430592:ixabepilone