PROJECT SUMMARY/ABSTRACT A Phase 1b clinical trial of dual myeloid blockade in metastatic pancreatic adenocarcinoma (PDAC) is planned. Patients will be treated with standard chemotherapy (FOLFIRINOX) and 2 orally available, small molecule allosteric chemokine receptor inhibitors to CCR2 (CXC872) and CXCR1/2 (SX682). The primary endpoint of the trial is safety and tolerability, and the secondary endpoint is clinical effectiveness as measured by progression free survival at 24 weeks. Baseline and on treatment tumor biopsies will be subjected to genomic analysis as well as sophisticated immune monitoring using mass cytometry. Genetic and immunologic biomarkers of treatment resistance and response will be explored. Preclinical studies will also be performed throughout the study to inform and perfect subsequent clinical translation of the most effective ways to immunologically reprogram the immunosuppressive tumor microenvironment that is characteristic of PDAC.