Phase II study of E7820 in combination with cetuximab in subjects (pts) with metastatic and refractory colorectal cancer (CRC).

Abstract

3537 Background: In vitro,E7820, inhibits α2-integrin expression, endothelial cell proliferation, and vascular tube formation. In colorectal cancer xenograft models, the combination of E7820 and cetuximab demonstrated additive antitumor activity. Methods: This phase II study evaluates the combination of E7820 and cetuximab in subjects with refractory mCRC. A phase Ib study established the maximum tolerated dose of E7820 (100 mg qd po) with cetuximab (400 mg/m2 iv Day 8/Cycle 1, followed by 250 mg/m2 weekly) to be administered in this study (JCO. 2008;26[May 20 suppl]; Abstr 3568). There were 28 evaluable subjects (ECOG 0-1) who relapsed following ≤ 3 prior regimens including 5 subjects from the phase Ib study. The primary endpoint was objective response rate. Results: A mean of 3 cycles (range, 1-13+) were administered. One case each of grade 4 pleuritic pain and pulmonary embolism were observed. E7820 related-grade 3 toxicities included increased AST (3/28, 11%), increased ALT (2/28, 7%), and diarrhea, hypomagnesemia, decreased glomerular filtration rate and elevated creatinine (1/28, 3% in each). E7820-related grade 2 toxicities (> 2 subjects) included anorexia, fatigue, dermatitis acneiform, diarrhea, increased ALT and headache. There were no treatment-related deaths. α2-Integrin levels (18 subjects) decreased over the first month to 81.5% of baseline levels (p = 0.0074) without significant changes in platelet function. Treatment outcomes: objective response rate (ORR = 3.6%), clinical benefit rate (CBR = 14.3%), median progression-free survival (PFS=1.9 mo) and median overall survival (OS = 9.6 mo). Kras mutations were detected in 7/15 (47%) tumor samples available for analysis; among this group, one PR was observed and continues for > 13 cycles. Conclusions: E7820 combined with cetuximab is well-tolerated in subjects with refractory mCRC. This study did not meet its primary endpoint. The single prolonged PR observed in a subject with mutated Kras may indicate possible activity of the E7820 and cetuximab combination in this subset of patients and will require additional confirmatory studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai