{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:35:09Z","timestamp":1791326109512,"version":"4.3.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T00:00:00Z","timestamp":1712016000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T00:00:00Z","timestamp":1712016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100018536","name":"NuCana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018536","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and methods<\/jats:title>\n                    <jats:p>NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day\u2009cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200943) and 3 alternate-weekly dosing cohorts in Part 2 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200916). They had received a median of 3 prior lines of treatment (range: 0\u201311) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in &lt;\u200910% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500\u2009mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015.\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT02723240\">https:\/\/clinicaltrials.gov\/study\/NCT02723240<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-024-03010-1","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T01:01:39Z","timestamp":1712019699000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)"],"prefix":"10.1186","volume":"43","author":[{"given":"Pavlina","family":"Spiliopoulou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farasat","family":"Kazmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Aroldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucinda","family":"Griffiths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Parkes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth J.","family":"Veal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky M.","family":"Coyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Jeffry Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah P.","family":"Blagden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,2]]},"reference":[{"key":"3010_CR1","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1023\/A:1006416410198","volume":"18","author":"JL Grem","year":"2000","unstructured":"Grem JL. 5-fluorouracil: forty-plus and still ticking. 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Ann Oncol. 2017;28:v128.","journal-title":"Ann Oncol"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-024-03010-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-024-03010-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-024-03010-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T01:02:57Z","timestamp":1712019777000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-024-03010-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,2]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3010"],"URL":"https:\/\/doi.org\/10.1186\/s13046-024-03010-1","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3593277\/v1","asserted-by":"object"}]},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,2]]},"assertion":[{"value":"9 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was reviewed and given a favourable opinion by the South-Central Oxford C Research Ethics Committee [Ref 15\/SC\/0644] and authorised by the Medicines and Healthcare products Regulatory Agency. It was conducted under the oversight of the Independent Early Phase Trial Oversight Committee (IEPTOC) acting as the Trial Steering Committee and as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit (OCTRU) at the University of Oxford. It has followed their Standard Operating Procedures ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. All participants signed a consent form before commencing study participation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"SPB discloses institutional funding as PI or CI to support clinical trials from: NuCana plc, Redx Pharma plc, UCB (Union Chimique Belge), Nurix Therapeutics, BioNTech, Moderna, Regeneron, Theolytics and Medannex. Consulting agreements with Ellipses, Theolytics, Oxford Drug Design, Pathios, UCB and Immunocore. Director and founder of RNA Guardian Ltd., patent application WO2016075455A1. TRJE discloses Honoraria (payable to employing institution): Ascelia, AstraZeneca, Bicycle Therapeutics, BMS, Eisai, Medivir, MSD, Nucana, Roche\/Genentech, Seagen; Speakers\u2019 Bureau (payable to employing institution): AstraZeneca, BMS, Eisai, Ewopharma, Medivir, MSD, Nucana, Roche\/Genentech, United Medical; Research Funding (payable to employing institution): Adaptimmune, Astellas Pharma, AstraZeneca, Athenex, Avacta, Basilea, Beigene, Berg Pharma, Bicycle Therapeutics, BiolineRx, Boehringer Ingelheim, BMS, Celgene, Clovis Oncology, Codiak, CytomX Therapeutics, Eisai, GlaxoSmithKline, Halozyme, Immunocore, iOnctura, Iovance Biotherapeutics, Janssen, Johnson & Johnson, Lilly, Medivir, Merck Serono, MSD, MiNA Therapeutics, Modulate Pharma, Novartis, Nucana, Plexxikon, Roche\/Genentech, Sanofi\/Aventis, Sapience Therapeutics, Seattle Genetics, Sierra Pharma, Starpharma, Seagen, UCB, Verastem, Vertex; Expert Testimony (payable to employing institution): Medivir; Support to attend national \/ international conferences (personal): BMS, Eisai, MSD, Nucana, Pierre Fabre. VMC discloses institutional support from NuCana plc, personal honoraria from Servier, membership of MSD UK Advisory board and NIHR committee. FA discloses current employment by Astra Zeneca but not at the time of this study. PS, FK, SL, TH, DT, LG, CQ, MP, VMC and GJV report no competing interests to disclose. DJH discloses funding of translational research and personal salary and stock interests from NuCana plc.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"100"}}