Phase 2 zolbetuximab CLDN18.2-directed monoclonal antibody + CAPOX/mFOLFOX6 in BTC

Single-arm Phase 2 at the University of Alabama at Birmingham evaluates zolbetuximab, a CLDN18.2-targeted monoclonal antibody that can drive tumor cell killing via immune effector mechanisms (including ADCC and complement-dependent cytotoxicity), combined with investigator-choice CAPOX (capecitabine + oxaliplatin) every 3 weeks or mFOLFOX6 (5-FU + leucovorin + oxaliplatin) every 2 weeks. The study focuses on second-line locally advanced/unresectable or metastatic biliary tract cancers with high CLDN18.2 expression (≥75% of tumor cells with moderate-to-strong membranous staining by central IHC), and treats until progression (RECIST 1.1), unacceptable toxicity, or up to 2 years. The key scientific bet is that extending a validated gastric/GEJ target (CLDN18.2) into pancreaticobiliary tumors can create a biomarker-defined niche where “chemo backbone + targeted antibody” improves durability versus chemotherapy alone. These patients have received one prior systemic line; after modern first-line gemcitabine/cisplatin-based immunochemotherapy, second-line FOLFOX remains an important chemotherapy benchmark, alongside molecularly targeted therapy for actionable subsets such as FGFR2, IDH1, BRAF V600E, HER2, NTRK, or MSI-H disease. Although this is investigator-sponsored (listed under Midhun Malla on the registry), the drug program itself is associated with Astellas (zolbetuximab/Vyloy), making this a practical “label-to-new-indication” translational move rather than a new-agent de-risking exercise.