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Lookup NU author(s): Professor Gareth Veal
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Spiliopoulou P, Kazmi F, Aroldi F, Holmes T, Thompson D, Griffiths L, Qi C, Parkes M, Lord S, Veal GJ, Harrison DJ, Coyle VM, Graham J, Evans TRJ, Blagden SP
Publication type: Article
Publication status: Published
Journal: Journal of Experimental and Clinical Cancer Research
Year: 2024
Volume: 43
Issue: 1
Online publication date: 02/04/2024
Acceptance date: 11/03/2024
Date deposited: 08/04/2024
ISSN (electronic): 1756-9966
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13046-024-03010-1
DOI: 10.1186/s13046-024-03010-1
Data Access Statement: The data generated in this study are available upon request to researchers who provide a methodologically sound proposal to the corresponding author. To gain access, data requestors will need to sign a data access agreement.
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