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<p>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 run-in phase trial 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 pretreatment and on-treatment tumor biopsies. 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<sup>+</sup> fibroblasts, altered fibroblast VDR activation signature and greater density and spatial colocalization of CD8<sup>+</sup> 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. ClinicalTrials.gov identifier: <a href="http://clinicaltrials.gov/ct2/show/NCT03520790">NCT03520790</a>.</p>

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Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Kimberly J. Perez,
  • Andressa Dias Costa,
  • Alexander Jordan,
  • Thomas B. Karasic,
  • Dalia Elganainy,
  • Suryun Kim,
  • Chen Yuan,
  • Dan Y. Gui,
  • Runzi Tan,
  • Sung Chul Hong,
  • Xi Wang,
  • Simona Cristea,
  • Emma Coleman,
  • Morgan Truitt,
  • Tae Gyu Oh,
  • Hui Zheng,
  • C. Sloane Furniss,
  • Lauren Brais,
  • Alexandra Bird,
  • Josh Remland,
  • Vasilena Gocheva,
  • Jennifer S. Thalappillil,
  • Mark Anderson,
  • James M. Cleary,
  • Andrea Enzinger,
  • Marios Giannakis,
  • Kimmie Ng,
  • Douglas A. Rubinson,
  • Benjamin Schlechter,
  • Rishi Surana,
  • Harshabad Singh,
  • Thomas Abrams,
  • Ursina Teitelbaum,
  • Natallia Izgur,
  • Eliezer Allen,
  • Peter S. Winter,
  • Srivatsan Raghavan,
  • Jen Jen Yeh,
  • Daniel Von Hoff,
  • Christopher Liddle,
  • Michael Downes,
  • Ronald M. Evans,
  • Peter O’Dwyer,
  • Andrew Aguirre,
  • Jonathan A. Nowak,
  • Brian M. Wolpin

摘要

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 run-in phase trial 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 pretreatment and on-treatment tumor biopsies. 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. 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. ClinicalTrials.gov identifier: NCT03520790.