A phase Ib, open-label, multicenter study of urelumab (BMS-663513) in combination with rituximab in subjects with relapsed/refractory B-cell malignancies.

Abstract

TPS3108 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.