Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer

摘要: Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy patients metastatic colorectal cancer (mCRC). Methods: Patients previously untreated mCRC received and EKB-569 at doses 10, 25, 50, 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained selected to assess pharmacodynamic effects EGFR signaling alone EKB-569. Complete pharmacokinetic sampling tumor biopsies, when feasible, conducted. Results: Forty-seven enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) observed 1/7 50 mg 2/3 mg. Two additional levels (35 EKB-569/day plus modified FOLFIRI) evaluated. The RD was 25 EKB-569/full FOLFIRI. Grades 4 >10% (30%), neutropenia (21%), asthenia (17%). Twenty-one had objective response [48%; 95% confidence interval (95% CI), 32-65%]. median time progression 7.7 months. At RD, resulted complete inhibition phosphorylated (pEGFR) downstream samples. did not affect pEGFR, but inhibited proliferation activated mitogen-activated protein (MAPK) induced p27 expression skin. Conclusion: is combined results inhibition. Chemotherapy interferes markers, observation be taken into account future studies targeted agents chemotherapy.