Background: Pancreas adenocarcinoma (PDAC) is an aggressive cancer projected to be the second leading cause of cancer-related death in the United Statesby 2030 for which improved treatment options are desperately needed. Immune checkpoint blockade (ICB) for PDAC has failed as monotherapy in early phase clinical trials likely due to a highly immunosuppressive tumor microenvironment. The CXCR4/CXCL12 axis is a key immune evasion mechanism thought to deter CD8+ T-cells (CTLs) from infiltrating the tumor. We performed a large seven arm survival and biopsy/necropsy study in KPC mice (Kras^LSL.G12D/+;p53^R172H/+;Pdx1Cre^tg/+) where we demonstrate that addition of gemcitabine to CXCR4 inhibition in combination with ICB, enhanced tumor stabilization and neoplastic cell death, and improved survival by 50 percent. Multiplex immunofluorescence indicated an increased CTL to regulatory T-cell ratio and clustering of CTLs around neoplastic cells. Presented here is a trial-in progress that will evaluate combination of a CXCR4 inhibitor, ICB, and chemotherapy in treatment naïve patients with PDAC. Methods: This is a multicenter, single arm, open-label phase 2 study of combination motixafortide 1.25mg/kg SC monotherapy for 5 days during priming followed by twice weekly, cemiplimab 350mg IV once every 21 days, gemcitabine 1000mg/m2 IV with nab-paclitaxel 125mg/m2 IV on days 1, 8, and 15 every 28 days. Patients with histologically confirmed metastatic PDAC who have not received prior therapy will be enrolled. The primary endpoint is overall response rate by 16 weeks. A response rate greater than 45% by 16 weeks is considered promising, whereas a response rate of less than 23% is considered not promising. We will use a Simon optimal 2-stage design, where we will enroll 10 patients in the first stage. If 3 or more patients meet the endpoint in the first stage, the study will be expanded to a total of 40 patients. If a total of 14 or more patients achieve CR or PR by 16 weeks, the agent will be considered promising and worthy of further study. Secondary endpoints include safety, mPFS, disease control rate (DCR), and mOS. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, and generation of patient derived organoids for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the stage I portion of the study. Clinical trial information: NCT04543071