A phase I/IIa study to evaluate the safety and tolerability, activity, and PK of a potential novel CNTN4-targeted checkpoint inhibitor, EP0089, in patients with advanced solid tumors.

Abstract

TPS2688 Background: Contactin 4 (CNTN4) has recently been identified as a novel cancer target which is overexpressed across a range of tumor types, including gastrointestinal, genitourinary, melanoma, breast and lung. Preclinical data shows that CNTN4 functions as an immune checkpoint through its binding to the T-cell transmembrane protein APP (Amyloid Precursor Protein). The interaction between CNTN4 on the surface of tumor cells and APP diminishes T cell receptor signaling cascades, inhibiting the activation and proliferation of CD4+ and CD8+ T cells. Tumor upregulation of CNTN4 may facilitate tumor immune evasion. Elevated CNTN4 levels have been associated with poorer outcomes for patients treated with anti-PD-1 checkpoint inhibitors. Therapeutic agents that block the interaction of CNTN4 with APP therefore have the potential to address significant unmet medical needs across a range of tumor types. EP0089 is a humanized IgG4 monoclonal antibody which specifically binds CNTN4 and inhibits the interaction between CNTN4 and APP, thereby enabling an immune response within the tumor microenvironment. In vitro and i n vivo studies demonstrated that EP0089 neutralized CNTN4-mediated suppression of T cell activation and promoted killing of CNTN4 over-expressing tumors. Methods: This is a first-in-human, open-label, phase I/IIa study (NCT07030478). Eligible patients will have a confirmed diagnosis of an advanced solid tumor with no available standard therapy or for whom standard therapy has failed, ECOG performance status of 0-1, life expectancy greater than 3 months, and measurable disease per RECIST v1.1 (or specified disease-specific guidelines). The population will be enriched for tumor types known to express CNTN4, including gastric, gastro-esophageal, esophageal adenocarcinoma, hepatocellular, bladder, gallbladder, endometrial, melanoma, and prostate. The primary objective is to determine the maximum tolerated dose and recommended phase II dose of EP0089. The secondary objectives are to characterize the PK and immunogenicity profile of EP0089 and assess preliminary antitumor activity. Exploratory objectives are to evaluate biomarkers of response, including the impact of CNTN4 expression and other PD biomarkers. Part A consists of dose-escalation, utilizing a 3+3 design, and dose expansion to further evaluate dose levels/regimens of interest. Part B will be determined based on review of Part A data and may include further dose optimization, and/or evaluation of specific populations of interest. Patients will initially receive EP0089 by IV infusion once every 2 weeks, subject to ongoing Safety Monitoring Committee review throughout dose escalation. The study is being conducted in the Republic of Korea, Australia and United States and later in Europe. Target recruitment is approximately 250 patients. Clinical trial information: NCT07030478 .