Abstract CT140: NUC-3373, a targeted inhibitor of thymidylate synthase, in patients with advanced colorectal cancer
Authors: Kazmi Farasat , Ciombor Kristen , Graham Janet , Coveler Andrew , Myers Michelle , Berlin Jordan , Harrison David , Blagden Sarah , Evans TR Jeffry 
Published: July 2021

Background: NUC-3373 is a novel anti-cancer agent developed to replace 5-FU, one of the most widely used anti-cancer drugs globally. Used across a broad range of tumors, including colorectal cancer (CRC), 5-FU (and oral formulation, capecitabine) exerts its main anti-cancer activity via conversion to the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. NUC-3373, a targeted inhibitor of TS, is designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown and avoid the generation of toxic metabolites. NUC-3373 has a longer plasma t1/2 (~10 hours) than 5-FU (8-14 minutes), generating substantially higher intracellular levels of FUDR-MP and lower levels of toxic metabolites FUTP and FBAL. Methods: NuTide:302 is a 3-part, Phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine-containing therapies. Part 1: patients receive NUC-3373 with or without leucovorin (LV). Part 2: NUC-3373 + LV is administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). Part 3: NUFOX and NUFIRI regimens from Part 2 will be combined with biologics targeting VEGF and EGFR pathways. Results: As of 26 November 2020, 37 patients have been treated in Part 1: 21 received 1500 mg/m2 NUC-3373 ± LV q2w; 11 received 1500 mg/m2 NUC-3373 + LV q1w; and 5 received 2500 mg/m2 NUC-3373 + LV q1w. Patients had a median of 4 prior lines of therapy (range: 2-13). NUC-3373 was well tolerated, with 10 patients experiencing Grade 3 treatment-related AEs (2 ALT elevations, 1 AST elevation, 1 ALP elevation, 1 hyponatremia, 1 anemia, 1 fatigue, 1 nausea, 1 fever, 1 bilirubin elevation) and 1 patient experiencing a Grade 4 treatment-related AE (bilirubin elevation). NUC-3373's favorable plasma PK profile was unaffected by LV. Clinical activity observed to date includes a 4th-line patient who achieved a partial response (40% reduction in tumor volume) and a fluoropyrimidine-refractory patient who achieved a 28% reduction in tumor volume and over 5 months disease stabilization. Among the efficacy evaluable population, a disease control rate of 62% was achieved. The RP2D and schedule has not yet been defined. Conclusions: NUC-3373 ± LV (Part 1) has shown encouraging clinical activity in heavily pre-treated CRC patients, including a partial response in a 4th-line patient and a 28% tumor shrinkage and 5-month disease stabilization in a fluoropyrimidine-refractory patient. The safety profile of NUC-3373 ± LV is very encouraging with no NUC-3373 induced neutropenia or hand-foot syndrome of any grade. NUFOX and NUFIRI combinations are currently being investigated in Part 2.Clinical trial information: NCT03428958

Citation Format: Farasat Kazmi, Kristen Ciombor, Janet Graham, Andrew Coveler, Michelle Myers, Jordan Berlin, David Harrison, Sarah Blagden, TR Jeffry Evans. NUC-3373, a targeted inhibitor of thymidylate synthase, in patients with advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT140.