557 Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy that is refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was shown to be upregulated in pancreatic cancer tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We hypothesize that blockade of IL-1β and PD-1 will result in alterations in myeloid, lymphoid, and fibroblast subsets within the pancreatic cancer microenvironment and add therapeutic benefit in combination with chemotherapy in PDA. Methods: We are conducting an open-label multicenter Phase Ib study evaluating a 4 drug regimen including gemcitabine and nab-paclitaxel with the addition of canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1). Eligible subjects have metastatic PDA without prior anti-cancer therapy for metastatic disease and RECIST measurable disease. The primary objective was to identify a recommended phase II/III dose of combination therapy by evaluating the incidence of dose limiting toxicities in the first 56 days (8 weeks) of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability of quadruple therapy and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021, and the first 6 subjects to complete 8 weeks of therapy were included in the dose confirmation analysis. There were no dose limiting toxicities and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) on day 1,8,15; nab-paclitaxel (125 mg/m2 IV) on day 1,8,15, canakinumab (250 mg via subcutaneous injection) on day 1, spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. The majority of subjects completed the on-treatment blood and tissue collection for correlative analysis. The study is ongoing with subjects remaining on therapy and all subjects will be evaluated for efficacy. Conclusions: In this Phase Ib study, we demonstrated the feasibility and safety of adding canakinumab and spartalizumab to standard of care chemotherapy in first line metastatic PDA and established the recommended Phase II/III dose. This novel 4 drug combination will be tested in a randomized Phase II/III study through the Precision Promise clinical trial network. Preliminary correlative and efficacy data will be reported. Clinical trial information: NCT04581343.