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.

Abstract

e16263 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, 5-FU/LV/liposomal irinotecan is currently an FDA-approved regimen in the second-line setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and objective response rate (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 5-FU (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 safety and toxicity. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include ORR, PFS and 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, dose level 1). 2/17 (12%) evaluable patients experienced an objective response (both in dose level 2), one of which was confirmed. Disease control rate (DCR) was 65%. Median follow up was 6.15 months. At the time of analysis, mPFS of all patients is 3.57 months (95% CI 1.28 – 8.12) and mOS is 6.14 months (95% CI 2.43 – 11.77). The mPFS is 3.55 months (0.79-6.21) for dose level 1 and 4.83 months (0.62-9.96) for dose level 2. The mOS is 6.15 months (0.79-8.12) for dose level 1 and 6.66 months (1.78-14.53) for dose level 2. Correlative analysis shows increased tumor vascularity (via CD31) and a trend toward decreased stromal fibrosis (via Sirius Red) in dose level 2. Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer and survival outcomes were comparable to liposomal irinotecan plus 5-FU/ LV. Clinical trial information: NCT03883919 .