Abstract PR005: Primary results of PanCAN-SR1, a phase 1b study evaluating Gemcitabine, nab-Paclitaxel, Canakinumab, and Spartalizumab to target IL-1β and PD-1 in metastatic pancreatic cancer with correlative tissue and blood biomarker analysis

In preclinical work, the inflammatory cytokine IL-1β was shown to be upregulated in pancreatic cancer tumors and to contribute to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We conducted an open-label multicenter Phase Ib study evaluating gemcitabine, nab-paclitaxel, canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a PD-1 mAb. Eligible subjects had previously untreated metastatic PDA and RECIST measurable disease. The primary objective was to confirm recommended phase II dose by evaluating the incidence of dose limiting toxicities (DLTs) in the first 56 days of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. Subjects underwent baseline and on-study tissue and blood collection for correlative translational research. Results: 10 subjects were enrolled between Nov 2020 and Mar 2021. At the primary data cut off of May 23, 2021, 6 subjects were evaluable for DLT. There were no DLTs, the recommended Phase II dose was established as: gemcitabine (1000mg/m2 IV) day 1,8,15; nab-paclitaxel (125mg/m2 IV) day 1,8,15; canakinumab (250mg SC) day 1, spartalizumab (400mg IV) day 1; of each 28 day cycle. At the time of an updated database extraction on June 1, 2022, 2 subjects remain on study. Adverse events were consistent with those typically seen with chemotherapy. The most common Grade 3/4 AEs were neutropenia (60%) and anemia (50%), with no fatal AEs. One patient discontinued spartalizumab due to grade 3 pneumonitis. In preliminary efficacy analysis (n=10), there are 3 confirmed PRs, 5 subjects with stable disease, 2 subjects with progression as best response. Individual site data estimates that the 12 month OS rate is 60%; updated RR, PFS and OS data will be reported. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in both responder and non-responder patients. Using an in vitro suppression assay, we showed that baseline serum from responders could induce myeloid derived suppressor cells, an effect that was abrogated with treatment. Single cell transcriptional profiling, multiplex immunofluorescence and spatial transcriptomics also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical response. Conclusions: PanCAN-SR1 established the Phase II dose of canakinumab and spartalizumab with chemoth