A first-in-human phase I study of ATG-031, anti-CD24 antibody, in patients with advanced solid tumors or B-cell non-Hodgkin lymphomas (PERFORM).

Abstract

TPS2691 Background: ATG-031 is a first-in-class humanized cluster of differentiation 24 (CD24) antibody. By disrupting the interaction between CD24, a ‘do not eat me’ signal on cancer cells, and the inhibitory receptor Siglec-10 on tumor-associated macrophages (TAMs), it enhances macrophage-mediated phagocytosis of cancer cells and promotes cytotoxic T cell function in the tumor microenvironment. ATG-031 also triggers antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) towards target tumor cells through its immunoglobulin gamma 1 (IgG1) Fc-dependent effects. Preclinical studies indicated that ATG-031-induced phagocytosis transforms macrophages from a tumor-tolerant M2 phenotype to an antitumor M1 phenotype, significantly inhibiting tumor growth both as monotherapy and synergistically with immune checkpoint inhibitors (ICI) and/or chemotherapies in mouse models. Methods: ATG-031 is undergoing evaluation for safety and preliminary antitumor efficacy in a Phase I, multi-center, open-label clinical study, PERFORM (NCT04986865), in patients with advanced solid tumors or B-cell non-Hodgkin’s lymphoma. The study includes a dose escalation phase and a dose expansion phase. The dose escalation phase enrolls patients with advanced solid tumors (preferred tumor types: lung cancer, breast cancer, ovarian cancer, urothelial cancer, and liver cancer) using a Bayesian Optimal Interval (BOIN) design with 3 to 9 patients at each dose level. A priming dose, defined as an initial lower dose followed by escalation to the full treatment dose, will be applied if Grade ≥2 cytokine release syndrome (CRS) is observed during the dose-limiting toxicity (DLT) period. The dose expansion phase will enroll patients with specific tumor types and will randomize patients into two or more dose levels to determine the recommended Phase II dose (RP2D). The PERFORM study explores an intravenous dose of ATG-031 once every 21 days (1 cycle) to assess DLT during the first two treatment cycles in dose escalation. Key inclusion criteria include histological or cytological confirmation of a solid tumor that has relapsed or has been refractory to standard therapy, at least one measurable lesion per RECIST, and an ECOG performance status of 0 to 1. The study excludes patients with CNS malignancies and those who have experienced Grade ≥3 immune-related adverse events (irAEs) or irAEs leading to prior immunotherapy discontinuation. As of January 2024, 2 sites in the United States have initiated the study, and 4 patients have received ATG-031 treatment at 0.03mg/kg (dose level 1). Clinical trial information: NCT04986865 .