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.
The TME in PDAC is immunologically ?cold? due to the high prevalence of immunosuppressive myeloid cells (both macrophages and neutrophils) that infiltrate tumors; in the parent R01 we have shown that these cells are actively recruited to the TME by known chemokine/receptor pathways that can be blocked with small molecule allosteric chemokine receptor inhibitors. We propose a clinical trial (based on promising results from our previous studies) of dual myeloid inhibition that blocks both TAM and TAN in combination with standard chemotherapy in PDAC. Correlative immune and genetic studies are planned on baseline and on-treatment biopsies that will help us elucidate mechanisms of treatment resistance and discover biomarkers that predict response.
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