Background: 5-FU and its other forms, floxuridine and capecitabine, exert their anti-cancer activity mainly due to the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which inhibits the enzyme thymidylate synthase (TS). Although these agents remain the cornerstone of combination treatments for colorectal cancer (CRC), key cancer resistance mechanisms of breakdown, activation and transport limit their effectiveness. NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass the key resistance mechanisms associated with 5-FU. NuTide 301 is an ongoing first-in-human study of NUC-3373 in patients with advanced solid tumors. PK/PD data obtained to date demonstrate NUC-3373 has a long plasma t_1/2 (9.7 h v 8-14 mins for 5-FU) and generates high levels of the active intracellular anti-cancer metabolite, FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes (TS-T), depleting the pool of dTMP within 2-4 hours. Methods: NuTide:302 is a two-part, Phase Ib study in patients with CRC who have relapsed after ≥2 prior lines of therapy. The primary objective is to identify a recommended NUC-3373 dose when administered every 2 weeks in combination with standard agents used in CRC treatment. Secondary objectives included safety, PK/PD and anti‐tumor activity. In Part 1, NUC-3373 is being administered with leucovorin (LV) to determine if the folate is beneficial in the formation of TS-T. Approximately 12 patients will be enrolled in Part 1 of the study. If LV augments TS-T formation, it will be administered in Part 2. In Part 2, the following combination agents will be administered with NUC-3373 (±LV): oxaliplatin; oxaliplatin + bevacizumab; oxaliplatin + panitumumab; irinotecan; and irinotecan + cetuximab. In Part 2, patients will be enrolled in cohorts of 3-6, in a modified 3+3 design. Up to 62 patients will be recruited, depending on cohort expansion. Clinical trial information: NCT03428958