Background: Interleukin-1-alpha (IL-1α) promotes tumor inflammation by shaping the tumor microenvironment, including tumor infiltrating myeloid cell recruitment, angiogenesis, and skewing and suppression of anti-tumor immunity. IL-1a inhibition in cancer subjects increased lean body mass and decreased fatigue, pain, and appetite loss. We report results of a single site phase 1 trial for an IL-1α antagonist (bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: A Bayesian adaptive design based on escalation with overdose control was used. Data are presented as frequency (percentage, %) for categorical variables and mean (± standard deviation) for continuous variables. Lean body mass (LBM) and fat mass were assessed at cycle 1 and 3, and T-test was used to assess changes. Results: Of 21 pts enrolled, 18 were evaluable. Median age was 68. Bermekimab in combination with nanoliposomal irinotecan (70 mg/m2) and 5-fluorouracil (2400mg/m2) was well tolerated at the highest dose level (12mg/kg). 10 pts experienced grade 3/4 toxicities including sepsis, anemia, hypokalemia, neutropenia, or leukopenia. There were no instances of grade 3/4 diarrhea. Ten pts (56%) had weight stability ( < 0.1 kg/BMI). Efficacy results include PR (n = 4, 22%), SD (n = 13, 72%), and PD (n = 1, 6%). PFS 7.7 m (95% CI: 4.34-12.73) and OS 10.5 m (95% CI: 5.79-17.70) were reported. LBM and fat mass change was -1.6 kg (± 2.0; p-value = 0.003) and -1.4 kg (± 1.7; p-value = 0.004). CRP was 20.4 (± 35.6) at cycle 1 and decreased significantly (p-value = 0.005). Serum VEGF decreased from C1 to C3 (p-value = 0.007). QLQ-PAN26 domains improved, particularly hepatic function (p = 0.04). FAACT scores improved for functional well-being (p = 0.02). Average daily step counts increased by 589 steps/day (p = 0.29) and resting heart rate decreased by 2.5 beats per minute (p = 0.005), as assessed by actigraphy. Conclusions: Bermekimab, nano-liposomal irinotecan and 5-fluorouracil in refractory pancreatic cancer patients with cachexia was well-tolerated with promising efficacy and improvements in patient performance. Clinical trial information: NCT03207724.