A phase I/IIA pharmacokinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients (pts) with advanced colorectal cancer (ACC)

Abstract

3543 Background: In preclinical models, EKB-569 has shown growth inhibition of EGFR-expressing colorectal tumor cell lines with at least additive inhibition when combined with chemotherapy. Methods: We have conducted a phase I/IIA study with EKB-569 used in combination with the FOLFIRI regimen as first-line treatment in pts with ACC. The objectives were to determine its safety, MTD, PK profile, antitumor activity and correlation with EGFR-signalling pathways in skin and tumors before and after treatment. Oral EKB-569 was given daily starting on day 3 of cycle 1 (28 days per cycle) with IV infusion of FOLFIRI on days 1–2 and 15–16 (CPT-11 180 mg/m2 90 min, simultaneously with LV 400 mg/m2 120 min, followed by 5FU 400 mg/m2 bolus and 2400 mg/m2 46-h continuous infusion). Pts were enrolled to receive 10, 25, 50 or 75 mg EKB-569 (3–6 pts per cohort). Dose escalation was based on safety evaluation of pt cohorts within the first 28 days. After the initial escalation, 2 cohorts were added: 35 mg EKB-569, FOLFIRI and 50 mg EKB-569, modified FOLFIRI (5FU 300 mg/m2 bolus and 2000 mg/m2 46-h continuous infusion). Results: 47 pts were included, median age 62 yrs (range 19–77) and ECOG PS 0 in 64% and 1 in 33%. DLTs were grade 3 diarrhea (2 pts in the 75-mg cohort and 2 in the 50-mg/modified FOLFIRI cohort) and grade 3 fatigue (1 in the 50-mg cohort and 1 in the 50-mg/modified FOLFIRI cohort). Limiting grade 2 diarrhea was observed in the 50-mg cohort. Thus, the MTD was selected as 25-mg EKB-569. Of 39 pts evaluable so far, the response rate is 38% and the clinical benefit rate is 85%. EKB-569 treatment resulted in complete inhibition of pEGFR and significant inhibition of pMAPK in both skin samples (11 pts) and tumor samples (3 pts) with no change in pAKT activity. Conclusions: EKB-569 combined with FOLFIRI was generally well-tolerated and showed encouraging evidence of antitumor activity and inhibition of the EGFR pathway. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth; Wyeth Research Wyeth Research