Background: OX40 (CD134) belongs to the tumor necrosis factor receptor (TNFR) family, and transduces a costimulatory signal during T-cell activation. In the periphery, OX40 expression is limited to recently activated CD4+ and CD8+ cells. In tumors, infiltrating T lymphocytes are enriched for OX40, where it augments T-cell activation, proliferation and survival. OX40 is also expressed on tumor infiltrating regulatory T cells (Tregs). Intratumoral Treg depletion is critical for the in vivo antitumor activity of immune checkpoint antibodies. OX40 can also be found on natural killer (NK) cells, mediating antibody-dependent cellular cytotoxicity. Together, these mechanisms make stimulation of OX40 with agonistic agents an attractive target for a novel anti-cancer immunotherapy. GSK3174998 is a humanized IgG1 anti-OX40 agonistic monoclonal antibody identified through collaboration with MD Anderson Cancer Center and is currently in phase I development.

Methods: The primary objective of this open-label non-randomized multicenter phase I study is to evaluate the safety of GSK3174998, as monotherapy in escalating doses every 3 weeks IV for up to 48 weeks (Part 1) or

in combination with 200 mg pembrolizumab administered every 3 weeks IV for up to 2 years (Part 2). Secondary objectives include assessment of antitumor activity, pharmacokinetics, pharmacodynamics and immunogenicity. Adverse events will be monitored using NCI CTCAE v. 4.0. Radiographic imaging will be obtained every 12 weeks to assess clinical response defined by immune-related RECIST. Exploratory objectives include examination of changes in genomic DNA, RNA, protein, measures of immune function in tumor, and the association of these with antitumor activity. The study will enroll up to approximately 180 pts; eligible pts will have measurable disease with documentation of metastatic non-small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma, bladder, soft tissue sarcoma, triple-negative breast cancer, and colorectal carcinoma displaying microsatellite instability that has progressed after standard therapy, or for which standard therapy is ineffective, intolerable, or inappropriate. A pre-treatment biopsy is requested of all pts. Matched pre-treatment and on-treatment biopsies will be performed in expansion cohorts to allow investigation of candidate biomarkers which may predict clinical response. As of Feb 1, 2016, monotherapy cohorts 1 and 2 have completed without DLT and enrollment to Cohort 3 is ongoing. This study (NCT02528357) is funded by GlaxoSmithKline.

Citation Format: Jeffrey Infante, Christoph M. Ahlers, F Stephen Hodi, Sopie Postel-Vinay, Jan HM Schellens, John V. Heymach, Karen Autio, Mary Barnette, Herbert Struemper, Maura Watmuff, Elaine M. Paul, David R. Kaufman, Jeffrey S. Weber, Axel Hoos. A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1). [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 CT027.