Abstract CT034: A phase I study of GSK2857916, a BCMA-directed monoclonal antibody conjugated to microtubule-disrupting agent in patients with relapsed, refractory multiple myeloma and other BCMA-expressing hematologic malignancies

Abstract Background: Expression of B cell maturation antigen (BCMA), a cell surface receptor belonging to the tumor necrosis factor receptor superfamily, is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells [Darce, 2007; O’Connor, 2004]. BCMA is also expressed on multiple myeloma (MM) cells and at various frequencies on cells from other B cell malignancies. GSK2857916 is a humanized, afucosylated IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F (MMAF) via a stable, protease resistant maleimidocaproyl linker. Upon binding to BCMA, GSK2857916 is rapidly internalized and active drug is released within the cell. In addition, GSK2857916 exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation which increases the affinity of the antibody's Fc domain to FCγRIIIa expressed on immune effector cells. The rationale for the investigation of GSK2857916 in MM and other BCMA-positive hematologic malignancies is supported by the restricted pattern of BCMA expression, and by evidence from preclinical studies [Tai, 2015]. Methods: BMA117159 is a Phase I, open-label, study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity in adult patients with relapsed/refractory MM or select, BCMA-expressing hematologic malignancies. Seventeen MM patients have been enrolled as of 26 January 2016 into the ongoing dose escalation phase with the once every 3 weeks intravenous dosing schedule. A continual reassessment method applied to dose limiting toxicity findings guide dose escalation decisions and maximum tolerated dose determination. Expansion cohorts will include patients with MM and other BCMA-expressing hematologic malignancies. Eligible MM patients are required to have undergone stem cell transplant or be considered transplant ineligible, to have received prior treatment with alkylators, proteosome inhibitors and immunomodulators, and to have documented disease progression on or within 60 days of completion of last therapy. Documented BCMA expression is required for patients with other hematologic malignancies. ClinicalTrials.gov identifier: NCT02064387 Study is funded by GlaxoSmithKline Citation Format: Larry D. Anderson, James Cavet, Adam D. Cohen, Yan Y. Degenhardt, Catherine E. Ellis, Fiona Germaschewski, Nikoletta Lendvai, Edward Libby, Joanna Opalinska, Rakesh Popat, Isabelle Pouliquen, Paul G. Richardson, Keith E. Stockerl-Goldstein, Heather J. Sutherland, Suzanne Trudel, Peter M. Voorhees, Jeffrey Wetherington. A phase I study of GSK2857916, a BCMA-directed monoclonal antibody conjugated to microtubule-disrupting agent in patients with relapsed, refractory multiple myeloma and other BCMA-expressing hematologic malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT034.

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