Background: GN is a first-line treatment option for patients (pts) with mPC. Poor prognosis and low 5-year survival rate ( < 5%) with mPC highlight the need for new therapeutics. Claudin 18.2 (CLDN18.2), a tight junction protein expressed exclusively on normal gastric epithelial cells, is maintained during malignant transformation in gastric cancers and is frequently expressed in some carcinomas from organs that do not normally express it, such as pancreatic cancer. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase 2 study (NCT03816163) will assess safety and efficacy of GN alone or with zolbetuximab in CLDN18.2-positive mPC. Methods: The study was expanded to enroll approximately 369 pts with histologically confirmed mPC and high CLDN18.2 expression (moderate-to-strong IHC staining intensity in ≥75% of tumor cells). The study included a safety lead-in that enrolled 3-12 pts to assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m² on Cycle 1 Day 1 then 600 mg/m² Q2W, then expand/de-escalate using a 3+3 design) plus GN. Dose-limiting toxicities (DLTs, defined as a specified zolbetuximab-related toxicity that occurs during DLT assessment period) will be assessed after Cycle 1 (28 days). Based on the recommended phase 2 dose (RP2D), confirmed during the safety lead-in, approximately 357 pts will be randomized 2:1 to zolbetuximab Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle (Arm 1), or GN alone on Days 1, 8, and 15 of each cycle (Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). At sites in Japan, DLTs (assessed from Cycle 1 Day 1 to Cycle 2 Day 1) will be evaluated in ≤6 pts randomized to the RP2D in Arm 1. Pts will undergo imaging (CT/MRI) at baseline and Q8W until investigator-assessed disease progression (RECIST v1.1) or the start of another systemic anticancer treatment, whichever comes earlier. In addition to confirming the RP2D during the safety lead-in, primary objectives are to assess whether treatment with zolbetuximab plus GN, versus GN alone, improves overall survival (randomization phase) and to establish the safety/tolerability profile of zolbetuximab plus GN (across the study). Secondary endpoints include progression-free survival, objective response rate, disease control rate, duration of response, pharmacokinetics, and health-related quality of life (per protocol amendment). Descriptive statistics will be used for continuous endpoints and frequency and percentage for categorical endpoints. Original protocol enrollment completion was in October 2021. Under the expanded protocol amendment, 95 of ~140 sites in North America, Latin America, Europe, and Asia Pacific were activated. Clinical trial information: NCT03816163.