A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Downloads (Pure)

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.
Original languageEnglish
Number of pages16
JournalJournal of Experimental & Clinical Cancer Research
Volume43
DOIs
Publication statusPublished - 2 Apr 2024

Keywords

  • NUC-3373
  • 5-FU
  • 5-fluorouracil
  • Fluoropyrimidines
  • Thymidylate synthase
  • Resistant cancer

Fingerprint

Dive into the research topics of 'A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)'. Together they form a unique fingerprint.

Cite this