Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m²)/LV (400mg/m²)/liposomal irinotecan (70mg/m²) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Between 8/29/2019 to 5/6/2021, a total of 20 patients were enrolled in the study. No DLTs or grade 4 adverse events were observed in either paricalcitol cohort. The most common toxicities were gastrointestinal (nausea, diarrhea), fatigue and anemia and were similar in both cohorts. Only one grade 3 adverse event was possibly due to paricalcitol (spinal fracture). 2/10 patients experienced an objective response, one of which was confirmed. Median follow up was 6.1 months. At the time of analysis, one patient remains on liposomal irinotecan and 5-FU/LV and mPFS of all patients is 3.57 months and mOS is 6.15 months. The mPFS is 3.55 months for dose level 1 and 5.34 months for dose level 2 (p = 0.3). The mOS is 6.15 months for dose level 1 and 6.66 months for dose level 2 (p = 0.4). Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer, however does not appear to improve response rate or survival outcomes. Correlative analyses are ongoing. Clinical trial information: NCT03883919.