A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated CD8+t CELLS in patients with advanced solid tumors.

Abstract

TPS4196 Background: PD-1/PD-L1-targeted immunotherapies have become critical roles in the treatment for many tumors. However, there is limited progress in pancreatic ductal adenocarcinoma (PDAC). PDAC is low immunogenicity. PDAC microenvironment is immunosuppressive. More than 70% PDACs have few or no CD8+ T cells around the tumor cell or in the tumor microenvironment (TME). Therefore, immunotherapy like PD-1/PD-L1 antibody alone is rarely effective for PDACs. Some cytokine or analogs may activate CD8+ T cells. An analog specifically activating tumor antigen associated (TAA) CD8+ T cells was designed and fused to anti-CLDN18.2 antibody. This specific bi-functional molecule LB4330 has high affinity to human anti-CLDN18.2 (14pM) and CD8+T cells. LB4330, as a novel, first-in-class molecule, may activate TAA CD8+ T cells in TME and has potential in alone or in combination with PD-1/PD-L1 mAb, for the treatment of advanced solid tumors, especially for Claudin 18.2 positive PDAC. Methods: This is a FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001). The planned sample size is approximately 66 patients in two parts: part 1 dose escalation, will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in advanced gastric and gastroesophageal junction adenocarcinoma and PDAC with Claudin 18.2 expression. In dose escalation stage, patients will be recruited with advanced solid tumors who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage. Exclusion criteria include a greater risk for gastric bleeding, irritable bowel syndrome with symptoms, active virus infections. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB4330. Tumor response will be assessed per RECIST and iRECIST every 2 cycles. The Phase I study in advanced solid tumors is ongoing. Enrollment in cohort 1 began in Nov 2022. Clinical trial information: NCT05707676 .