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Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: A randomized, multi-arm, phase I trial

ABSTRACT: Vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy in preclinical models of pancreatic cancer. We conducted a phase I trial (NCT03520790) with primary endpoint of safety when the VDR agonist paricalcitol is given with first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Secondary endpoints included pharmacodynamic analyses. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol or GA plus oral paricalcitol with pre-treatment and on-treatment tumor biopsies. Paricalcitol was safely administered with GA, although 5 (42%) patients 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 pre-treatment 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. VDR expression was predictive of tumor response in the GA plus paricalcitol arms. Paricalcitol can be safely administered with chemotherapy to patients with metastatic pancreatic cancer, and on-treatment biopsies indicated favorable modulation of the tumor microenvironment by paricalcitol as predicted by preclinical models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313748 | GEO | 2025/12/21

REPOSITORIES: GEO

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