Run-in phase trial of gemcitabine plus nab-paclitaxel with or without paricalcitol for metastatic pancreatic cancer

In preclinical models of pancreatic cancer, vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy. A run-in phase trial at Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Women’s Hospital (all in Boston, MA) evaluated the addition of the VDR agonist paricalcitol to first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol, of GA plus oral paricalcitol. The primary endpoint was safety. Paricalcitol was safely administered with GA, although five patients (42%) receiving oral paricalcitol had grade 2-4 hypercalcemia and required dose reduction. Nuclear VDR protein expression was heterogeneous across patients, and VDR was expressed in tumor, immune, and stromal cells. Compared to pretreatment specimens, on-treatment biopsies had decreased proportion of αSMA⁺ fibroblasts, altered fibroblast VDR activation signature, and greater density and spatial colocalization of CD8⁺ T cells with tumor cells in the GA-plus-paricalcitol arms. The authors conclude that paricalcitol can be safely adminstered with chemotherapy to patients with metastatic pancreatic cancer, with on-treatment biopsies indicating favorable modulation of the tumor microenvironment as predicted by preclinical models.