Vitamin D receptor agonist paricalcitol plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer

Perez, K, Cleary, J. M., Karasic, T. B., Raghaven, S., Rahma, O. E., Nowak, J. A., Borazanci, E. H., Downes, Michael, Drebin, Jeffrey A, Tuveson, D. A., Ting, D. T., Moffitt, R. A., Yeh, J. J., Aguirre, A. J., Evans, R., Von Hoff, D. D., Odwyer, P. J., Wolpin, B. M. (February 2020) Vitamin D receptor agonist paricalcitol plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer. Journal of Clinical Oncology, 38 (4). ISSN 0732-183X



Background: Patients(pts) with metastatic pancreatic cancer (PC) have a median survival of less than one year even with use of multiagent chemotherapy programs. Pancreatic tumors are composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration (Sherman. Cell, 2014). Paricalcitol is a synthetic VDR agonist used in patients with secondary hyperparathyroidism due to chronic kidney disease. A prior pilot study evaluated IV paricalcitol with gemcitabine (G) and nab-paclitaxel (A) before surgical resection in patients with resectable PC (NCT02030860). Methods: Pts with previously-untreated metastatic PC will be enrolled in a two-stage study consisting of a safety run-in and a randomized phase 2 study (NCT03520790). In the run-in stage, 36 pts will be randomized 1:1:1 to G (1000 mg/m2) and A (125 mg/m2) given 3 weeks on and 1 week off plus: (a) paricalcitol 25mcg IV thrice weekly, (b) paricalcitol 16mcg oral daily, or (c) placebo oral daily. Grade 3/4 hypercalcemia or genitourinary stones will be considered dose limiting toxicities.Pts will undergo paired pre- and on-treatment tumor biopsies to examine pharmacodynamic (PD) markers by bulk and single cell RNA sequencing and multiplex immunofluoresence.Assuming safety and supportive PD assessments, the phase 2 study will randomize an additional 76 pts to two treatment arms with GA plus: (a) paricalcitol or (b) placebo.Paricalcitol formulation (IV or oral) will be determined based on data from the run-in stage.The primary endpoint of the phase 2 study is overall survival, with a total of 100 pts needed to identify a hazard ratio of 0.6 with 80% power and one-sided alpha of 0.10.Secondary endpoints include safety, response rate, and progression free survival.Trial funding provided by SU2C, CRUK,Lustgarten Foundation, and AACR. Clinical trial information: NCT03520790.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Vitamin D receptor
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matthew Dunn
Date: 1 February 2020
Date Deposited: 06 Jul 2020 18:26
Last Modified: 29 Sep 2020 16:51

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