title: A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose.
  
  
  METHODS
  Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing.
  
  
  RESULTS
  CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics.
  
  
  CONCLUSIONS
  It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA. lgarland@azcc.arizona.edu
authors.forename: Linda L
authors.initials: LL
authors.lastname: Garland
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Banu K
authors.initials: BK
authors.lastname: Arun
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lovalvo
authors.forename: Irene A
authors.initials: IA
authors.lastname: Eiseman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Olson
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lenehan
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D009025:Morpholines; D043823:Taxoids; D000077143:Docetaxel; C420268:Canertinib