Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in PDAC. The IL-1 pathway is active in the pancreatic tumor microenvironment and upregulated in response to chemotherapy. IL1RAP interacts with IL-1R1 and modulates downstream factors (e.g. IL-6, IL-8) and CRP level. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α and IL-1β signaling. Here, results are reported from the phase 1/2a clinical trial CANFOUR evaluating nadunolimab combined with GN in PDAC. Methods: Patients (pts) with previously untreated, unresectable, locally advanced or metastatic PDAC received nadunolimab at 1 (n=20) 2.5 (n=20), 5 (n=28) or 7.5 mg/kg (n=8) Q2W with standard GN. Primary objective was safety; secondary objectives included ORR, iPFS per iRECIST and OS, and exploratory objectives included effects on serum and tumor tissue biomarkers. Results: In total, 76 pts were enrolled: median age 63 years (43-89), 42% female, 93% stage IV, 45% PS=0, 9% received adjuvant chemotherapy. Treatment-related adverse events (AE) of grade≥3 were reported in 72% with neutropenia being most frequent. G-CSF prophylaxis was useful in managing neutropenic events. The 7.5 mg/kg dose was above MTD due to neutropenia. Infusion-related reactions were reported in 29% (grade 3 in 3%). Peripheral sensory neuropathy was rare (only two grade 2 events). Common treatment-related grade 3/4 AE are shown below. Seventy-three pts received combination therapy and were included in the efficacy analysis. Three pts did not receive chemotherapy due to consent withdrawal (n=2) or clinical deterioration (n=1). Median iPFS was 7.3 months (95% CI 5.6-8.9) with 15 pts still on treatment, median OS was 13.2 months (10.0-19.1) with 62% of pts alive and 1-year survival of 59% (42-72%). ORR was 33% (22-45), disease control rate 63% (51-74%) and duration of response 5.7 months (3.9-11.1). ORR was similar for all dose levels. Low baseline CRP was favorable for OS; reduction of serum IL-8 and CRP during Cycle 1 correlated with positive impact on OS. Also, neutrophil-lymphocyte ratio was reduced throughout the trial, driven by the reduction in circulating neutrophils. IL1RAP expression on cancer and stromal cells was confirmed in tumor biopsies. Conclusions: Nadunolimab combined with GN shows promising iPFS and OS and manageable safety in PDAC pts. A phase 2/3 trial of nadunolimab combined with chemotherapy in PDAC is planned and nadunolimab is also currently evaluated in additional combination trials with chemotherapy or IO. Clinical trial information: NCT03267316.