A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)
Abstract Purpose 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 fluorodeoxyurid...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-03010-1 |
| _version_ | 1797219538839797760 |
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| author | Pavlina Spiliopoulou Farasat Kazmi Francesca Aroldi Thomas Holmes David Thompson Lucinda Griffiths Cathy Qi Matthew Parkes Simon Lord Gareth J. Veal David J. Harrison Vicky M. Coyle Jill Graham Thomas R. Jeffry Evans Sarah P. Blagden |
| author_facet | Pavlina Spiliopoulou Farasat Kazmi Francesca Aroldi Thomas Holmes David Thompson Lucinda Griffiths Cathy Qi Matthew Parkes Simon Lord Gareth J. Veal David J. Harrison Vicky M. Coyle Jill Graham Thomas R. Jeffry Evans Sarah P. Blagden |
| author_sort | Pavlina Spiliopoulou |
| collection | DOAJ |
| description | Abstract Purpose 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. Patients and methods 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 cycles 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. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) 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 < 10% 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. Conclusion 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 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 . |
| first_indexed | 2024-04-24T12:35:15Z |
| format | Article |
| id | doaj.art-8de199adb6da4ff4b44e74190f835493 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-24T12:35:15Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-8de199adb6da4ff4b44e74190f8354932024-04-07T11:34:21ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-04-0143111610.1186/s13046-024-03010-1A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)Pavlina Spiliopoulou0Farasat Kazmi1Francesca Aroldi2Thomas Holmes3David Thompson4Lucinda Griffiths5Cathy Qi6Matthew Parkes7Simon Lord8Gareth J. Veal9David J. Harrison10Vicky M. Coyle11Jill Graham12Thomas R. Jeffry Evans13Sarah P. Blagden14School of Cancer Sciences, University of GlasgowEarly Phase Clinical Trials Unit, Churchill Hospital, Oxford University HospitalsEarly Phase Clinical Trials Unit, Churchill Hospital, Oxford University HospitalsDepartment of Oncology, Oncology Clinical Trials Office, University of OxfordDepartment of Oncology, Oncology Clinical Trials Office, University of OxfordDepartment of Oncology, Oncology Clinical Trials Office, University of OxfordCentre for Statistics in Medicine and Oxford Clinical Trials Research Unit (OCTRU)Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit (OCTRU)Early Phase Clinical Trials Unit, Churchill Hospital, Oxford University HospitalsTranslational and Clinical Research Institute, Newcastle University Centre for CancerSchool of Medicine, University of St AndrewsPatrick G. Johnston Centre for Cancer Research, Queens University BelfastBeatson West of Scotland Cancer CentreSchool of Cancer Sciences, University of GlasgowEarly Phase Clinical Trials Unit, Churchill Hospital, Oxford University HospitalsAbstract Purpose 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. Patients and methods 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 cycles 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. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) 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 < 10% 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. Conclusion 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 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .https://doi.org/10.1186/s13046-024-03010-1NUC-33735-FU5-fluorouracilFluoropyrimidinesThymidylate synthaseResistant cancer |
| spellingShingle | Pavlina Spiliopoulou Farasat Kazmi Francesca Aroldi Thomas Holmes David Thompson Lucinda Griffiths Cathy Qi Matthew Parkes Simon Lord Gareth J. Veal David J. Harrison Vicky M. Coyle Jill Graham Thomas R. Jeffry Evans Sarah P. Blagden A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) Journal of Experimental & Clinical Cancer Research NUC-3373 5-FU 5-fluorouracil Fluoropyrimidines Thymidylate synthase Resistant cancer |
| title | A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) |
| title_full | A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) |
| title_fullStr | A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) |
| title_full_unstemmed | A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) |
| title_short | A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) |
| title_sort | phase i open label dose escalation study of nuc 3373 a targeted thymidylate synthase inhibitor in patients with advanced cancer nutide 301 |
| topic | NUC-3373 5-FU 5-fluorouracil Fluoropyrimidines Thymidylate synthase Resistant cancer |
| url | https://doi.org/10.1186/s13046-024-03010-1 |
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