The anti-cancer activity of 5-FU, and its other forms: floxuridine and capecitabine, is largely attributable to its active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP) that inhibits the enzyme thymidylate synthase (TS) and depletes the dTMP pool essential for cancer cell replication. Although 5-FU based agents remain the cornerstone of treatment for many tumour types, key cellular resistance mechanisms of breakdown, activation and transport limit their effectiveness. NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass these resistance pathways. It efficiently inhibits TS and depletes the dTMP pool within 2-4 hours. NUC-3373 is resistant to dihydropyrimidine dehydrogenase-mediated degradation and does not generate the toxic metabolite dhFU. NUC3373 has an advantageous PK/PD profile compared to 5-FU, with plasma t1/2=9.7 h vs 8-14 mins, enabling the study of a more convenient alternate weekly dose-scheduling (Ghazaly et al ESMO, 2017).
The primary study objective is to determine the RP2D and schedule of NUC3373 in patients with advanced cancers. Secondary objectives include safety, anti‐tumour activity and PK/PD. In Part I, NUC‐3373 was administered as an IV infusion on days 1, 8, 15 and 22 of a 28‐day cycle. In Part II, NUC-3373 was administered on days 1 and 15 of a 28‐day cycle. For PK analyses, blood samples were collected at 12 timepoints up to 48 h post‐dose during cycle 1. Plasma and intracellular metabolites were measured by UPLC-MS/MS. Levels of free and bound TS were measured in PBMCs by western blotting. To date, thirty-six patients have been enrolled: Part I n = 29; Part II n = 7. Dose escalation is ongoing to establish the RP2D. Cohorts in Part I received NUC-3373 at 125, 250, 500, 750, 1125 and 1500 mg/m2 and cohorts in Part II at 1500 and 1875 mg/m2.
Clinical trial identification
Legal entity responsible for the study
S. Blagden: Advisor: Ellipses, Director of RNA Guardian Ltd.; Advisory boards: Clovis and Novartis; Research funding Nucana plc (unrelated to NUC-3373). T.R.J. Evans: Institution receives financial support for the costs of conducting this clinical trial and other studies with another of Nucana's compounds. Institution has also been reimbursed for time in a one-off advisory board for Nucana for another of their compounds. All other authors have declared no conflicts of interest.