Background: Overall survival remains short for pts with mPDAC despite approved therapies, highlighting the need for more effective treatment options. While TGF-β can act as a tumor suppressor in normal tissue and early-stage PDAC, it is associated with tumorigenic processes (such as enhanced genomic instability, neoangiogenesis, epithelial-to-mesenchymal transition, and metastasis) observed in late-stage PDAC. Within the pancreatic tumor microenvironment (TME), TGF-β activates stellate cells and cancer-associated fibroblasts, thereby promoting fibrotic network development and immune exclusion, maintaining an immunosuppressive TME. Preclinical data in murine models have shown that addition of TGF-β blockade to anti-PD-1 therapy or NG augmented the antitumor activity of those agents, leading to tumor regression. These data provide the rationale for combining TGF-β-targeting agents with chemotherapy and/or immunotherapy. This study investigates NIS793, a human IgG2 mAb that binds TGF-β1 and 2, with and without spartalizumab (PD-1 antagonist) combined with NG in treatment-naïve mPDAC. Methods: This is a phase II open-label, randomized study (NCT04390763) with a safety run-in period followed by randomization. Eligible pts are adults with previously untreated mPDAC with measurable disease as per RECIST 1.1 and ECOG performance status score ≤1. Pts are excluded if they have a microsatellite-unstable tumor. The safety run-in was completed and confirmed a dose of NIS793 (intravenously [IV] 2100 mg Q2W) + spartalizumab (IV 400 mg Q4W) + nab-paclitaxel (IV 125 mg/m² on Days 1, 8, and 15) + gemcitabine (IV 1000 mg/m² on Days 1, 8, and 15). In the randomized part, pts will be randomized 1:1:1 to NIS793 + spartalizumab + NG (n = 50) or NIS793 + NG (n = 50) or NG (n = 50). Treatment will continue until disease progression, unacceptable toxicity, discontinuation by investigator’s/pt’s choice, or withdrawal of consent. The primary objective is to evaluate the progression-free survival per RECIST v1.1 of NIS793 + NG with or without spartalizumab, versus NG alone. Secondary objectives include safety and tolerability, antitumor activity, overall survival, change in tumoral CD8 and PD-L1 status, and characterization of immunogenicity and pharmacokinetics. Efficacy will be assessed by investigator per RECIST v1.1 and iRECIST at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. The study is ongoing and has an estimated enrollment of 161 pts. There are currently 31 sites participating across 14 countries. The study is funded by Novartis. Clinical trial information: NCT04390763.