title: A phase I study of EKB-569 in combination with capecitabine in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer.
  
  
  METHODS
  Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle.
  
  
  RESULTS
  A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037).
  
  
  CONCLUSIONS
  In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. laherda@jhmi.edu
authors.forename: Dan
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authors.lastname: Laheru
authors.forename: Gary
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authors.lastname: Croghan
authors.forename: Ronald
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authors.lastname: Bukowski
authors.forename: Michelle
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authors.lastname: Rudek
authors.forename: Wells
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authors.lastname: Messersmith
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Robert
authors.initials: R
authors.lastname: Pelley
authors.forename: Antonio
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authors.lastname: Jimeno
authors.forename: Ross
authors.initials: R
authors.lastname: Donehower
authors.forename: Joseph
authors.initials: J
authors.lastname: Boni
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Patricia
authors.initials: P
authors.lastname: Martins
authors.forename: Charles
authors.initials: C
authors.lastname: Zacharchuk
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo