{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T19:44:43Z","timestamp":1788291883044,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T00:00:00Z","timestamp":1539043200000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD). Because hypercalcemia has been the most worrisome calcitriol\u2010related adverse event, the less hypercalcemic agent paricalcitol may be preferred for further investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>The authors undertook a phase 1 study of gemcitabine in combination with escalating doses of paricalcitol administered weekly intravenously in patients with advanced cancers. A standard 3+3 dose escalation schema was used. Pharmacokinetic assessment of gemcitabine and its metabolite 2\u2019,2\u2019\u2010difluorodeoxyuridine (dFdU) was performed. Pharmacodynamic assessment of paricalcitol was performed by measurement of CDD activity in peripheral blood mononuclear cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>A total of 44 patients were enrolled. Somnolence was the main dose\u2010limiting toxicity. The highest dose of paricalcitol administered was 10.5 \u00b5g\/kg. Hypercalcemia was infrequent and mild in severity. Paricalcitol did not appear to affect the pharmacokinetics of gemcitabine and dFdU. Evaluation of CDD activity was available for 9 patients; no clear trend for CDD activity after treatment with paricalcitol was established. The overall response rate was 4%; the rate of disease control was 67% in patients who were pretreated with gemcitabine. Progression\u2010free and overall survival were 3.4 months and 6.5 months, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Paricalcitol can be administered safely in doses up to 7 \u00b5g\/kg weekly with fixed dose rate gemcitabine without dose\u2010limiting hypercalcemia. To the best of the authors\u2019 knowledge, the maximum tolerated dose has not been formally established to date. Preliminary clinical activity deserves further exploration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.31676","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T13:07:50Z","timestamp":1539090470000},"page":"3890-3899","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A phase 1, open\u2010label, dose escalation study of intravenous paricalcitol in combination with gemcitabine in patients with advanced malignancies"],"prefix":"10.1002","volume":"124","author":[{"given":"Christos","family":"Fountzilas","sequence":"first","affiliation":[{"name":"Department of Medicine  Roswell Park Comprehensive Cancer Center Buffalo New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milind","family":"Javle","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center  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