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Background & Aims: To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids. Methods: In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 μg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1. Results: Eight patients received 15 μg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 μg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-μg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4+ T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections. Conclusions: Visilizumab had an acceptable safety profile at the 10-μg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid–refractory ulcerative colitis. Abbreviations used in this paper: DLT, dose-limiting toxicity, EBV, Epstein–Barr virus, MTWSI, Modified Truelove and Witts Severity Index ⁎ Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina ‡ Atlanta Gastroenterology Associates, Atlanta, Georgia § Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium ∥ Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania ¶ Leiden University Medical Center, Leiden, The Netherlands # Mayo Clinic, Rochester, Minnesota ⁎⁎ Gastroenterology Clinic, University of Chicago Medical Center, Chicago, Illinois ‡‡ Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California §§ Mount Sinai School of Medicine, New York, New York ∥∥ Mt Zion Hospital, University of California, San Francisco, San Francisco, California ¶¶ PDL BioPharma, Inc, Fremont, California
Supported by the sponsor, PDL BioPharma, Fremont, CA. The authors declare the following conflicts of interest: consultant, PDL BioPharma (S.P., G.V., M.R., D.H., W.S., S.H., S.T., L.M., U.M.); research support for clinical trial, PDL BioPharma (S.P., B.S., G.V., M.R., D.H., W.S., S.H., S.T., L.M., U.M.); speaker at continuing medical education symposia sponsored by PDL BioPharma (S.P., W.S., S.H., D.H.). ClinicalTrials.gov identifier: NCT00032305. PII: S0016-5085(07)01491-6 doi:10.1053/j.gastro.2007.08.035 © 2007 AGA Institute. Published by Elsevier Inc. All rights reserved. | ||||||||||||||||||||||||||||