Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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.

People
Spiliopoulou, Pavlina
Author

Cartwright, Douglas and Kidd, Andrew C. and Ansel, Sonam and Ascierto, Maria Libera and Spiliopoulou, Pavlina (2025) Oncogenic signalling pathways in cancer immunotherapy: leader or follower in this delicate dance? International Journal of Molecular Sciences, 26 (9): 4393. ISSN 1661-6596

Genta, S. and Araujo, D.V. and Hueniken, K. and Pipinikas, C. and Ventura, R. and Rojas, P. and Jones, G. and Butler, M.O. and Saibil, S.D. and Yu, C. and Easson, A. and Covelli, A. and Sauder, M.B. and Fournier, C. and Saeed Kamil, Z. and Rogalla, P. and Arteaga, D.P. and Vornicova, O. and Spiliopoulou, Pavlina and Muniz, T.P. and Siu, L.L. and Spreafico, A. (2024) Bespoke ctDNA for longitudinal detection of molecular residual disease in high-risk melanoma patients. ESMO Open, 9 (11): 103978. ISSN 2059-7029

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Kazmi, Farasat
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Aroldi, Francesca
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Holmes, Thomas
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Thompson, David
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Griffiths, Lucinda
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Qi, Cathy
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Parkes, Matthew
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Lord, Simon
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

Henriksen, Peter A. and Hall, Peter and MacPherson, Iain R. and Joshi, Shruti S. and Singh, Trisha and Maclean, Morag and Lewis, Steff and Rodriguez, Aryelly and Fletcher, Alexander and Everett, Russell J. and Stavert, Harriet and Broom, Angus and Eddie, Lois and Primrose, Lorraine and McVicars, Heather and McKay, Pam and Borley, Annabel and Rowntree, Clare and Lord, Simon and Collins, Graham and Radford, John and Guppy, Amy and Williams, Michelle C. and Japp, Alan and Payne, John R. and Newby, David E. and Mills, Nick L. and Oikonomidou, Olga and Lang, Ninian N. (2023) Multicenter, prospective, randomized controlled trial of high-sensitivity cardiac troponin I–guided combination angiotensin receptor blockade and beta-blocker therapy to prevent anthracycline cardiotoxicity: The Cardiac CARE trial. Circulation, 148 (21). pp. 1680-1690. ISSN 0009-7322

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Veal, Gareth J.
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Harrison, David J.
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Coyle, Vicky M.
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Graham, Jill
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Jeffry Evans, Thomas R.
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Blagden, Sarah P.
Author

Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P. (2024) 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 and Clinical Cancer Research, 43 (1): 100. ISSN 1756-9966

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Title:
A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)
Creators:
Spiliopoulou, Pavlina and Kazmi, Farasat and Aroldi, Francesca and Holmes, Thomas and Thompson, David and Griffiths, Lucinda and Qi, Cathy and Parkes, Matthew and Lord, Simon and Veal, Gareth J. and Harrison, David J. and Coyle, Vicky M. and Graham, Jill and Jeffry Evans, Thomas R. and Blagden, Sarah P.
Identification Number:
10.1186/s13046-024-03010-1
Date:
2 April 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
BioMed Central
Additional Information:
The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The Glasgow Experimental Cancer Medicine Centre (ECMC) is funded by Cancer Research UK and The Chief Scientist’s Office, Scotland (grant award A25174).
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URI:
https://pub.demo35.eprints-hosting.org/id/eprint/304
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
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Users 37347 not found.
Date Deposited:
11 Jun 2025 16:36
Revision:
14
Last Modified:
12 Jun 2025 10:48
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