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)

• Published in: Molecular cancer therapeutics 2023-12, Vol.22 (12_Supplement), p.B049-B049
• Main 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
• Format: Article
• Language: English
• ISSN: 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.TARG-23-B049

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, i