Preclinical studies have demonstrated synergistic antitumor activity when combining PD-1 blockade and varlilumab, a CD27 agonist antibody. The improved efficacy of the combination treatment was correlated with increases in the number of effector T cells, and the ratio of effector T cells to regulatory T cells (Teff:Treg) within the tumor. Based on these data, a Phase I trial using the approved monotherapy dose of nivolumab (3 mg/kg every 2 weeks) and escalating doses of varlilumab (0.1, 1, or 10 mg/kg every 2 weeks) in patients with advanced cancer was initiated. The primary objective was to assess the safety and tolerability of the combination. Extensive biomarker analysis was implemented to help in selection of the varlilumab dose for the upcoming Phase II portion of the trial, in which preliminary antitumor activity, as measured by ORR, of the combination treatment will be assessed. Varlilumab dose escalation has been completed and a total of 33 patients have been dosed (18 colorectal cancer, 8 ovarian cancer, 4 melanoma and 3 head and neck squamous cell carcinoma). The maximum dose level of 10 mg/kg was reached with no maximum tolerated dose identified. One patient with ovarian cancer in the 10 mg/kg cohort had a dose limiting toxicity of hepatitis (grade 4) and acute kidney injury (grade 3). Another patient with colorectal cancer in the 10 mg/kg cohort had paresthesias (grade 2) and muscle weakness (grade 2), no additional drug related SAEs or DLTs were reported. Toxicity has been consistent with the safety profile of each agent individually and no unexpected toxicities have been seen with the combination. Additional treatment-related AEs have included infusion reactions, lymphopenia, fatigue, nausea, vomiting, rash, and elevated pancreatic enzymes, with the majority of AEs being low grade. Preliminary biomarker analysis suggests a strong immunologic signature in patients across different dose cohorts. In particular, we observed consistent increases in the levels of serum pro-inflammatory cytokines/chemokines including CXCL9, CXCL10, MIP-1b, and MCP that were generally transient and peaking within several hours of dosing. Signficant decreases were found among circulating CD4 T cell (median decrease of 47%; P <0.001) and Treg (median decrease of 51%; P<0.001) populations. In contrast, we found increases in tumor infiltrating lymphocytes (primarily CD8 T cells, and to a lesser extent CD4 T cells and Tregs) in a number of patients with paired pre- and post-treatment biopsies. The frequency and magnitude of these biomarker changes are being evaluated for correlations with varlilumab dose levels, tumor type and patient outcome to help select the Phase II dose.

Citation Format: Rachel E. Sanborn, Michael J. Pishvain, Margaret K. Callahan, Naiyer Rizvi, Harriet Kluger, Michael Yellin, Tracey Rawls, Laura Vitale, Abdel Halim, Tom Davis, Tibor Keler. Phase I results from the combination of an immune-activating anti-CD27 antibody (varlilumab) in combination with PD-1 blockade (nivolumab): activation across multiple immune pathways without untoward immune-related adverse events. [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 CT023.