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

Abstract

Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3).Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogenactivated protein kinase (MAPK) and induced p27 expression in the skin. Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.Colorectal cancer is the second most frequent cause of cancerrelated death worldwide, and patients with metastatic colorectal cancer (mCRC) have a median survival of 8.5 months without chemotherapy (1). Current standard chemotherapy regimens such as FOLFIRI [irinotecan/5-fluorouracil (5-FU)/ leucovorin (LV)] or FOLFOX (oxaliplatin/5-FU/LV) induce response rates of about 50%, prolong progression-free survival to about 8 months, and increase the median overall survival to 20 months (2 -5). Despite these advances, the long-term prognosis of patients with mCRC remains poor, with <5% surviving 5 years. Therefore, new treatment strategies have to be explored to improve the prognosis of this disease.The epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in a variety of cancers including mCRC. Two different approaches have been clinically developed to target the EGFR: monoclonal antibodies (i.e., cetuximab and panitumumab) directed to the ectodomain of the receptor that have shown meaningful clinical activity in patients with mCRC refractory to standard chemotherapy (6); and small-molecule tyrosine kinase inhibitors (TKI).

A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer

“…EKB-569 has also been tested in combination with Irinotecan and infusional 5-FU and has been shown to be safe and active. At the 25 mg EKB-569/full-dose Irinotecan and infusional 5-FU, complete inhibition of phosphorylated EGFR as well as downstream signaling pathways in skin and tumor samples was identified (14). …”

“…At 50 mg EKB-569 per day, sustained plasma concentrations above the enzyme inhibitory target concentration were achieved (6). EKB-569 in combination with Irinotecan and infusional 5-FU has been recently shown to be safe, and at the 25 mg, EKB-569/full-dose Irinotecan and infusional 5-FU resulted in complete inhibition of phosphorylated EGFR as well as downstream signaling pathways in skin and tumor samples (14). …”

Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer

“…25–28 We analyzed activation of EGFR pathway components in skin biopsies, a previously employed technique that appears to correlate with tumor EGFR analysis and clinical outcomes. 29,30 Detailed methods of these analyses are provided in the Supplemental Text.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Preclinical and Phase I studies suggest that pelitinib has greater activity in inhibiting EGFR/HER1, is capable of overcoming resistance to other EGFR-targeted TKIs due to acquired mutations, and also inhibits signaling through HER2/neu [198][199][200]. Phase I studies have been reported establishing a maximum-tolerated dose of 75 mg/day with gastrointestinal toxicity (diarrhea) being limiting [200][201][202][203][204]. AST1306 is another recently developed dual HER1 and HER2 TKI, which has yet to progress to earlyphase clinical studies [205].…”