title: Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients with refractory cancer.
abstract: OBJECTIVE
  To determine the tolerability and pharmacokinetics of CI-1033 given daily for 7 days of a 21-day cycle. Tumor response and changes in erbB receptor tyrosine kinase activity in tumor and skin tissue were examined, and modulation of potential biomarkers in plasma was explored.
  
  
  METHODS
  This was a dose-finding phase I study in patients with advanced solid malignancies. Patients were evaluated for safety, pharmacokinetics, and tumor response. Pharmacodynamic markers, such as Ki67, p27, and erbB receptor status, were assessed in tumor and skin tissue using immunohistochemical and immunoprecipitation methodologies. Plasma biomarkers HER2, vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 were evaluated using immunologic techniques.
  
  
  RESULTS
  Fifty-three patients were enrolled in the study. Dose-limiting toxicity (emesis, persistent rash, and mouth ulcer) was observed at 750 mg. The maximum tolerated dose was 650 mg. There were no confirmed objective responses. CI-1033 treatment showed down-regulation of epidermal growth factor receptor, HER2, and Ki67 in a variety of tumor tissues and up regulation of p27 in skin tissue. Plasma HER2 was reduced following CI-1033 administration, but no consistent change in vascular endothelial growth factor, interleukin-8, or matrix metalloproteinase-9 was noted. CI-1033 plasma concentrations were proportional to dose.
  
  
  CONCLUSIONS
  The safety and pharmacokinetic profile of CI-1033 was favorable for multidose oral administration. Evidence of modulation of erbB receptor activity in tumor and skin tissue was accompanied by changes in markers of proliferation and cell cycle inhibition. Additional clinical trials are warranted in defining the role of CI-1033 in the treatment of cancer and further assessing the utility of antitumor markers.
authors.affiliation: M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Zinner
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Irene
authors.initials: I
authors.lastname: Eiseman
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Olson
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lenehan
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009025:Morpholines; C420268:Canertinib