Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC)

Abstract

3579 Background: EKB-569 is an orally active, low molecular weight, selective, irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase. In animal models, EKB-569 in combination with different chemotherapy agents shows at least additive effects on growth inhibition of colorectal and other tumors. Methods: This open-label, dose-escalation study evaluates the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-tumor activity of EKB-569 in combination with the FOLFOX-4 regimen in patients (pts) with previously untreated advanced CRC. Pts (3–6 per cohort) were to receive EKB-569 (25, 35, 50, or 75 mg/day orally) starting on day 3 in combination with the FOLFOX-4 regimen (day 1: oxaliplatin 85 mg/m2 and leucovorin [LV] 200 mg/m2, 120 min, simultaneously, followed by 5-fluorouracil [FU] 400 mg/m2, bolus, and FU 600 mg/m2, 22-h continuous infusion; day 2: LV and FU as on day 1). Dose escalation was based on safety evaluations after 2 treatment cycles (14 days/cycle). Treatment continues until evidence of disease progression or unacceptable toxicity. Results: Twenty nine pts were enrolled; enrollment is complete. Median age was 61 yrs (range, 46–70); ECOG performance status was 0: 71% and 1: 29%. Dose-limiting toxicities within the first 2 treatment cycles were grade 3 diarrhea (1 pt) and grade 3 febrile neutropenia (1 pt) in the 35-mg cohort. Thus, the MTD was 25 mg EKB-569, FOLFOX-4. For 25 pts, treatment-emergent adverse events (TEAEs), all grades, with frequency ≥ 30% were diarrhea (76%), paresthesia (60%), nausea (48%), and neutropenia (40%). Grade 3 or 4 TEAEs with frequency ≥ 5% were neutropenia (32%) and diarrhea (8%). Of 11 pts who completed ≥ 4 treatment cycles, 4 had partial response (PR), 6 had stable disease (2 pts for ≥ 6 mos, 1 pt with unconfirmed PR), and 1 had progressive disease (RECIST guidelines). Conclusions: EKB-569 at an oral dose of 25 mg in combination with the FOLFOX-4 regimen is generally well tolerated and shows promising antitumor activity in pts with previously untreated advanced CRC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Research Wyeth-Lederle