Abstract B049: Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323)
Authors: Wilson Richard H , Ciombor Kristen K , Coveler Andrew L , Graham Janet S , Schlechter Benjamin L , George Thomas J , Élez Elena , Evans TR Jeffry , Berlin Jordan , de Gramont Aimery , McKissock Fiona G , Oelmann Elisabeth , Bloss Jeffrey D , Martini Giulia , Bennouna Jaafar , Modest Dominik P , Taieb Julien , Tabernero Josep 
Published: December 2023

Abstract
Background: NUC-3373 is a phosphoramidate transformation of fluorodeoxyuridine monophosphate (FUDR-MP) designed to replace fluoropyrimidines, such as 5-FU. Fluoropyrimidines predominantly exert their activity via FUDR-MP, which inhibits thymidylate synthase (TS). NUC-3373 has been designed to overcome the shortcomings that limit the clinical utility of 5-FU, such as inefficient conversion to FUDR-MP, generation of toxic metabolites, and a lengthy administration schedule due to poor pharmacokinetic (PK) properties. Promising data have been observed in the NuTide:302 study where heavily pre-treated patients (pts) received NUC-3373 (± leucovorin, LV) or NUC-3373 + LV + irinotecan (NUFIRI), and second-line pts received NUFIRI + bevacizumab (NUFIRI-bev). NUC-3373 was well-tolerated in all combinations. Prolonged stable disease was observed in heavily pre-treated pts, with tumour shrinkages as well as periods of progression-free survival (PFS) longer than those achieved on prior lines.
Methods: NuTide:323 is a Phase II, open-label, randomised study of NUFIRI-bev vs FOLFIRI-bev in pts with advanced/metastatic CRC who have previously received ≥2 months of a first-line fluoropyrimidine and oxaliplatin-containing regimen or have relapsed within 6 months of completing adjuvant fluoropyrimidine and oxaliplatin. Pts with measurable disease, ECOG 0-1 and wildtype BRAF are eligible. Pts with MSI-H or dMMR are ineligible. 171 pts will be randomised (1:1:1) to either 1500 mg/m2 NUC-3373 + LV Q1W or 1500 mg/m2 NUC-3373 + LV Q2W, both with 180 mg/m2 irinotecan and 5 mg/kg bevacizumab Q2W or FOLFIRI-bev Q2W. NUC-3373 will be administered over 2 h (vs 46 h for 5-FU). Randomisation is stratified by RAS status, prior bevacizumab and duration of prior line of therapy. Primary objectives are to compare the PFS of NUFIRI-bev to FOLFIRI-bev and determine the optimal NUFIRI-bev dosing schedule. Secondary objectives are to compare the efficacy and safety of NUFIRI-bev to FOLFIRI-bev, and assess the PK of NUFIRI-bev. NuTide:323 is being conducted at 65 sites in Europe and the USA. Clinical trial information: NCT05678257
Citation Format: Richard H Wilson, Kristen K Ciombor, Andrew L Coveler, Janet S Graham, Benjamin L Schlechter, Thomas J George, Elena Élez, TR Jeffry Evans, Jordan Berlin, Aimery de Gramont, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Giulia Martini, Jaafar Bennouna, Dominik P Modest, Julien Taieb, Josep Tabernero. Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B049.