A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer whose disease progressed on gemcitabine-based therapy

TPS793 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m2 IV over 90 minutes, LV at 400 mg/m2 IV over 30 minutes, and 5-FU at 2400 mg/m2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.