{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:33:46Z","timestamp":1783420426870,"version":"3.54.6"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cisplatin\/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0\u20131 received NUC-1031 (625 or 725 mg\/m2) and cisplatin (25 mg\/m2) on days 1 and 8, every 21\u2009days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Twenty-one patients (median age 61\u2009years, n =\u200913 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg\/m2 (n =\u20098 and expansion n =\u20097; median six cycles) or 725 mg\/m2 (n =\u20096; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3\u20134 adverse events occurring in more than one patient with 625 mg\/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg\/m2, increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg\/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3\u201310.1), and median OS was 9.6 months (95% CI, 6.7\u201313.1). The median estimates of area under the plasma concentration\u2013time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218\u2013324 \u03bcg\u2022h\/mL and 309\u2013889 \u03bcg\/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47\u20131.56 \u03bcg\u2022h\/mL and 0.284\u20130.522 \u03bcg\/mL, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg\/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Implications for Practice<\/jats:title>\n                  <jats:p>The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin\/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg\/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/onco.13598","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T20:25:11Z","timestamp":1605817511000},"page":"e669-e678","source":"Crossref","is-referenced-by-count":22,"title":["A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08)"],"prefix":"10.1093","volume":"26","author":[{"given":"Mair\u00e9ad G.","family":"McNamara","sequence":"first","affiliation":[{"name":"Division\u2009of Cancer Sciences, University of Manchester, Manchester, United Kingdom"},{"name":"Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bridgewater","sequence":"additional","affiliation":[{"name":"University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Clatterbridge Cancer Centre and Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olusola","family":"Faluyi","sequence":"additional","affiliation":[{"name":"Clatterbridge Cancer Centre and Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet","family":"Wasan","sequence":"additional","affiliation":[{"name":"Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alkesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Christie NHS Foundation Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D.","family":"Ryder","sequence":"additional","affiliation":[{"name":"Manchester Clinical Trials Unit, University of Manchester, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safia","family":"Barber","sequence":"additional","affiliation":[{"name":"Manchester Clinical Trials Unit, University of Manchester, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chathunissa","family":"Gnanaranjan","sequence":"additional","affiliation":[{"name":"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essam","family":"Ghazaly","sequence":"additional","affiliation":[{"name":"Barts Cancer Institute, Queen Mary University of London, London, United Kingdom"},{"name":"Beatson West of Scotland Cancer Centre, University of Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.R. 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