Background: Pancreatic cancer is biologically aggressive, and the majority of pts was diagnosed as locally advanced or metastatic disease. Nab-paclitaxel and gemcitabine is a frequently used regimen for advanced pancreatic cancer, but chemoresistance is unavoidable. The combination of immunotherapy with chemotherapy have shown efficacy for certain types of cancer, but no similar results have been obtained in pancreatic cancer. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. In a phase Ⅱ clinical trial (NCT04324307), as of August 10, 2021, 53 pts with unresectable advanced pancreatic cancer had received one cycle KN046 combined AG regimen treatment and 31 subjects had received post-baseline tumor assessment at least once. Objective response rate (ORR) was 45.2% (95% CI: 27.3%, 64.0%) and disease control rate (DCR) was 93.5% (95% CI: 78.6%, 99.2%)，excellent preliminary results have been achieved. Based on this, a phase III pivotal study (ENREACH-PDAC-01) is conducting now in China to verify the efficacy and safety of KN046 plus nab-paclitaxel and gemcitabine as first-line treatment for advanced pancreatic cancer (NCT05149326). Methods: This nationwide multicenter phase III clinical trial enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinomas with a WHO performance score of 0 or 1 and expected survival period of more than 3 months. Eligible pts will be randomized 1:1 to intervention group or control group and receive 4-6 cycles of KN046 (5mpk Q2W) or placebo combined with nab-paclitaxel (initial dose: 125mg/m² D1,8,15 Q4W) and gemcitabine (initial dose: 1000mg/m² D1,8,15 Q4W) followed by KN046 (5mpk Q2W) or placebo with gemcitabine（QW × 3, 1 week off） maintenance therapy. Treatment will continue until disease progression or intolerable toxicity, withdrawal of consent, loss to follow-up or death, end of study, whichever occurs first. The primary endpoint is overall survival (OS). Key secondary endpoints are ORR and progression free survival (PFS). PFS and ORR will be assessed independently per RECIST v1.1 at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. Tumor and blood samples will be collected at baseline and during study treatment for pharmacokinetic, immunogenicity and biomarker assessment. The first patient was enrolled in early February 2022. Clinical trial information: NCT05149326.