A Phase 1b, Open-Label, Multicenter Study of Urelumab (BMS-663513) in Combination with Cetuximab in Subjects with Advanced/Metastatic Colorectal Cancer or Advanced/Metastatic Squamous Cell Carcinoma of the Head and Neck
To determine the safety, tolerability, DLT and combination maximum tolerated dose (combination MTD) of urelumab in combination with cetuximab in subjects with advanced/metastatic colorectal cancer (CRC) or advanced/metastatic squamous cell carcinoma of the head and neck (SCCHN). Background of Cetuximab Cetuximab (ERBITUX®) is a chimeric mouse/human monoclonal antibody (MAb) of the immunoglobulin G (IgG1) subclass. Cetuximab binds specifically to the human tyrosine kinase epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor and other ligands. Background of CD137 (4-1BB) and Urelumab CD137 (4-1BB or TNFRSF9), a TNF superfamily Type 1 membrane glycoprotein receptor, is expressed on the surface of lymphoid organs and can be detected on activated T cells (CD4+ and CD8+), activated NK cells, natural killer T (NKT) cells, regulatory T cells, activated thymocytes,intraepithelial lymphocytes and eosinophils. Urelumab (BMS-663513) is a fully human agonistic mAb specific to the human CD137 receptor 4-1BB). Urelumab activates the CD137 pathway and provides a strong costimulatory signal to T cells and NK cells, resulting in enhanced cytokine production (chiefly IFN?), survival and proliferation. Consequently, urelumab can enhance the function of antigen-specific T cells and mediate clinical antitumor activity by enhancing the host antitumor immune response. Urelumab is the first agonistic anti CD137 antibody studied in humans. By the end of 2008, four studies in humans had been conducted using urelumab: 2 monotherapy studies (a Phase 1 study, CA186001, in subjects with solid malignancies and a Phase 2 study, CA186006, in subjects with advanced melanoma) and 2 phase 1 combination therapy studies [CA186004 (which combined urelumab with carboplatin and paclitaxel in subjects with solid malignancies) and CA186005(which combined urelumab with radiation and carboplatin plus paclitaxel in subjects with nonsmall cell lung cancer)]. In total, 291 subjects including 273 subjects treated with monotherapy and 18 subjects treated on the combination trials have received urelumab treatment in these 4 studies.
Metastatic Colorectal Cancer. Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
Study Design and Duration This is a Phase 1b, open-label study consisting of a dose escalation and a dose expansion. Dose escalation will assess the safety and tolerability of urelumab (BMS-663513) administered with cetuximab in subjects with advanced/metastatic WT KRAS CRC or advanced/metastatic SCCHN. Subjects will complete up to three periods of the study: Screening, Treatment, and Clinical Follow-up. Screening (up to 28 days). Treatment (up to a maximum of 96 weeks of study therapy). Clinical Follow-up (60 days). One cycle is 3 weeks. The Treatment Period will consist of up to 32 treatment cycles.
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