title: Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors.
abstract: BACKGROUND
  Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin.
  
  
  METHODS
  This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements.
  
  
  RESULTS
  Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90-100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT.
  
  
  CONCLUSIONS
  On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.
authors.affiliation: Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Kunz
authors.forename: Aiwu R
authors.initials: AR
authors.lastname: He
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.forename: Jimmy J
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Clemens
authors.forename: Marianne
authors.initials: M
authors.lastname: Messina
authors.forename: Remigiusz
authors.initials: R
authors.lastname: Kaleta
authors.forename: Fernanda
authors.initials: F
authors.lastname: Abrahao
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; C430592:ixabepilone