Phase I study of EMD 525797 (DI17E6), an antibody targeting ανβ integrins, in combination with cetuximab and irinotecan, as a second-line treatment for patients with k-ras wild-type metastatic colorectal cancer
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Media type:
E-Article
Title:
Phase I study of EMD 525797 (DI17E6), an antibody targeting ανβ integrins, in combination with cetuximab and irinotecan, as a second-line treatment for patients with k-ras wild-type metastatic colorectal cancer
Description:
<jats:p> 3539 </jats:p><jats:p> Background: EMD 525797 is a humanized monoclonal antibody that specifically targets all αν integrins, including ανβ1, ανβ3, ανβ5, ανβ6, and ανβ8. In colorectal cancer (CRC), ανβ3 is highly expressed on tumor-associated vessels, and ανβ5 is strongly expressed on tumor cells, vessels, and stromal cells. Overexpression of ανβ6 is associated with a significant reduction in median overall survival. Methods: Safety, tolerability, and anti-tumor activity of escalating doses of EMD525797 in combination with irinotecan and cetuximab were assessed in patients (pts) with metastatic CRC who had failed first-line fluoropyrimidine/oxaliplatin-containing chemotherapy. Pts received IV infusions over 1 hour of 250, 500, 750, and 1,000 mg EMD 525797 every 2 weeks in combination with irinotecan at 180 mg/m<jats:sup>2 </jats:sup>IV every 2 weeks and cetuximab at 400 mg/m<jats:sup>2</jats:sup> on Cycle 1, Day 1 and then 250 mg/m<jats:sup>2</jats:sup> IV weekly. A standard 3+3 trial design was used. Three pts were enrolled at each dose level and if no dose limiting toxicities (DLTs) were observed, pts were enrolled at the next dose level. An additional 3 pts were added if 1 of the initial 3 pts in the cohort experienced a DLT. Results: A total of 16 pts received treatment.No DLTs were observed at any dose of EMD 525797 in combination with irinotecan and cetuximab. Serious adverse events related to EMD 525797 included Grade 3 hypokalemia and tachyarrhythmia. Dosing was well tolerated over treatment intervals as long as 18 months. Objective responses included 1 partial response (PR) at 250 mg; 1 complete response and 1 PR at 750 mg; and 2 PRs at 1,000 mg. Two pts had prolonged stable disease lasting longer than 11 weeks at 750 mg. Anti-tumor activity was observed in pts who had failed anti-VEGF therapy in combination with first-line chemotherapy. Conclusions: The combination of EMD 525797 with irinotecan and cetuximab was well tolerated and has anti-tumor activity. Further evaluation of this regimen is warranted and is underway in an open-label, randomized phase II study of two doses of EMD 525797 (500 and 1,000 mg) combined with irinotecan and cetuximab that are compared with standard irinotecan and cetuximab. </jats:p>