LAUSR

Background CD40 is a member of the TNFR superfamily that is broadly expressed by immune, vascular, epithelial, and tumor cells. Interaction between CD40 and its ligand CD40L plays an important role in innate and adaptive immunity. APCs such as dendritic cells can be primed by CD4+ T cells by interaction between CD40 and CD40L. Several studies have confirmed that CD40 is broadly expressed on multiple solid tumor types. Thus, further evaluation of investigational agents and combination immunotherapies targeting the CD40 pathway is warranted across multiple cancer indications. MEDI5083 is a homodimeric fusion protein consisting of 3 scCD40L domains and an IgG4P Fc domain. MEDI5083 agonizes CD40 on APCs and bridges the innate and adaptive immune systems by promoting potent antitumor T cell mediated immune responses. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, allowing T cells to recognize and kill tumor cells. In clinical studies durvalumab has shown a manageable and consistent tolerability profile across multiple tumor types. The combination of MEDI5083 and durvalumab has the potential to activate the adaptive immune system through potentially complementary mechanisms, leading to enhanced targeting of tumor cells. Methods This Phase 1 first in human study evaluates the safety, pharmacokinetics, and immunogenicity of MEDI5083 alone and in combination with durvalumab in select advanced solid tumors. The primary objective is to evaluate the safety and tolerability, describe dose-limiting toxicity, and determine the maximum tolerated dose or the highest protocol-defined dose for MEDI5083 when administered as monotherapy and when administered concurrently in combination with durvalumab. Key secondary objectives include describing PK, systemic pharmacodynamics, immunogenicity and preliminary clinical activity of MEDI5083 administered alone or concurrently with durvalumab. This is a 3-part study; Part 1 is dose escalation of MEDI5083 monotherapy followed by either durvalumab monotherapy or potential reinduction with MEDI5083. Part 2 is dose escalation of MEDI5083 with concurrent durvalumab therapy, followed by durvalumab monotherapy restricted to selected tumor types. Part 3 is MEDI5083 with concurrent durvalumab, followed by durvalumab monotherapy in tumor specific expansion cohorts. Recruitment is ongoing (NCT03089645). Citation Format: Ben Tran, Johanna Bendell, Martin Gutierrez, Jie Yang, Natasha Angra, Victoria L. Chiou, Mark Voskoboynik. A phase I first time in human study to evaluate the safety, pharmacokinetics, and immunogenicity of MEDI5083 alone and in combination with durvalumab in selected advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT126.