Abstract | PURPOSE: EXPERIMENTAL DESIGN: 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). CONCLUSION: 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.
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Authors | Dan Laheru, Gary Croghan, Ronald Bukowski, Michelle Rudek, Wells Messersmith, Charles Erlichman, Robert Pelley, Antonio Jimeno, Ross Donehower, Joseph Boni, Richat Abbas, Patricia Martins, Charles Zacharchuk, Manuel Hidalgo |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 14
Issue 17
Pg. 5602-9
(Sep 01 2008)
ISSN: 1078-0432 [Print] United States |
PMID | 18765554
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Aminoquinolines
- Aniline Compounds
- Deoxycytidine
- Capecitabine
- Fluorouracil
- EKB 569
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Aminoquinolines
(administration & dosage, adverse effects, pharmacokinetics)
- Aniline Compounds
(administration & dosage, adverse effects, pharmacokinetics)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Capecitabine
- Colorectal Neoplasms
(drug therapy)
- Deoxycytidine
(administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
- Drug Administration Schedule
- Female
- Fluorouracil
(administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
- Humans
- Male
- Middle Aged
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