A randomized phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody EMD 72000 in subjects with advanced gastrointestinal cancers

Abstract

3018 Background: Growth factor signaling through EGFR drives tumor proliferation, motility, angiogenic stimulation, and protects the cells from stress induced apoptosis. EMD 72000 is a humanized monoclonal anti-EGFR IgG1 antibody that blocks ligand binding, EGFR signaling, induces receptor downregulation, and potentially participates in antibody-dependent cell-mediated tumor cell killing. Methods: A phase I study was conducted to assess the safety and anti-tumor activity of EMD 72000 in 24 patients with advanced refractory gastrointestinal tumors. Antitumor activity was assessed using CT and 18FDG PET dual-modality tomography. Subjects were randomized in groups of 6 to receive absolute doses of 100, 200, 400, or 800 mg EMD 72000 weekly for 4 wks followed by treatment with 400 mg per wk until disease progression. EMD 72000 was administered by 1-hr IV infusion without routine premedication. CT and 18FDG PET images were obtained before treatment and in wks 4 and 8. Skin and tumor biopsies were obtained before treatment and at wks 4 (skin only) and 8. Blood samples for pharmacokinetics were obtained weekly for 8 wks. Results: Patient population: 21 colorectal, 2 cholangiocellular, and 1 gastric cancer; median age was 58 (range 29–70) years with a median of 3 prior chemotherapy protocols (range 0–6) and 2 sites of metastatic disease (range 1–4). Tumors were EGFR+ by immunohistochemistry. No NCI-CTC grade 3 or 4 drug-related toxicities were observed; grade 1/2 skin reaction was seen in > 80% of subjects with doses ≥ 200 mg. Assessment of metabolic response by PET-CT using EORTC criteria in 18 patients after 4 wks on study showed 1 CR (800 mg), 6 PR (2 each at 400 and 800 mg, 1 each at 100 and 200 mg), and 9 SD. One patient who did not show 18FDG uptake at baseline achieved a CR during follow up with magnetic resonance imaging. Median time to progression was 13 wks. Conclusions: In this study administration of EMD 72000 was associated with no grade 3 or 4 toxicities. Preliminary evidence of metabolic response by PET and antitumor activity by CT and MRI was seen in heavily pretreated subjects with gastrointestinal cancers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany