First-in-human phase 1/2 trial evaluating TAC01-CLDN18.2 autologous T cells in CLDN18.2-positive solid tumors.

TPS419 Background: CLDN18.2 is a tight junction protein expressed in differentiated gastric epithelial cells and is abnormally expressed in various solid tumor types, serving as a promising target for therapy. To date, there are no approved therapies directed against this target, but compelling data exist using monoclonal antibodies and conventional CAR T therapy. The T Cell Antigen Coupler (TAC) technology is an approach to modifying T cells ex vivo, which allows recognition and cytotoxicity of tumor cells by co-opting the natural T cell receptor. The TAC technology has a safer profile than conventional CAR T therapies and is used to create an autologous TAC01-CLDN18.2 T cell product targeting CLDN18.2. Methods: This first in-human trial (NCT05862324) is designed to assess both the safety profile and preliminary antitumor activity of TAC01-CLDN18.2 in patients with CLDN18.2+/HER2- solid tumors after ≥ 2 lines of therapy. The phase 1 dose escalation segment employs a traditional 3+3 dose-escalation design to evaluate increasing doses of TAC01-CLDN18.2 with estimated enrollment numbers of 9 to 24 subjects. The subsequent phase 2 will further evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose. With 3 cohorts, Group A will enroll up to 57 subjects with gastric and esophageal adenocarcinoma, Group B aims to enroll 10 subjects with pancreatic ductal adenocarcinoma (PDAC) while Group C will examine up to 22 subjects with ovarian and non-small cell lung cancer (NSCLC). Groups A and C will leverage a Simon 2-stage design to assess whether the treatment achieves efficacy, while Group B will be exploratory with an opportunity for cohort enrichment based on clinical data. Prior to TAC01-CLDN18.2 infusion, subjects will undergo leukapheresis and may receive bridging anticancer therapy as appropriate during cell manufacturing. CLDN18.2 expression levels will be determined centrally using a clinical trial assay validated across relevant indications. Subjects will then undergo low intensity lymphodepletion chemotherapy. A second dose of TAC01-CLDN18.2 may be administered based on prespecified safety and clinical criteria. Evaluation of DLTs will take place within a 28-day window following the first infusion. In both phases, CLDN18.2+/HER2- solid tumor patients must have completed at least two prior therapy lines except for PDAC patients who may qualify after one prior antineoplastic regimen. For phase 2, up to four prior treatment lines is permissible and definitions of eligible CLDN18.2 expression levels will be based on retrospective analysis of data from Phase 1 in association with clinical efficacy. The trial is currently in the open-enrollment stage, awaiting the inclusion of the inaugural patient. No data analysis is available as of the submission deadline. Clinical trial information: NCT05862324 .

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