fosifloxuridine nafalbenamide (NUC-3373)

P1/2, N=107, Completed, NuCana plc | Recruiting --> Completed | N=225 --> 107 | Trial completion date: Nov 2023 --> Mar 2024 | Trial primary completion date: Nov 2023 --> Mar 2024

P2, N=182, Active, not recruiting, NuCana plc | Recruiting --> Active, not recruiting

P2, N=171, Recruiting, NuCana plc | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Sep 2024

P1/2, N=225, Recruiting, NuCana plc | Trial completion date: Jun 2023 --> Nov 2023 | Trial primary completion date: Jun 2023 --> Nov 2023

P1/2, N=91, Recruiting, NuCana plc | Not yet recruiting --> Recruiting

P2, N=171, Recruiting, NuCana plc | Initiation date: Jan 2023 --> Apr 2023

Taken together, these results highlight key differences between NUC-3373 and 5-FU that are driven by the anti-cancer metabolites generated. NUC-3373 is a potent inhibitor of TS that also causes DNA-directed damage. These data support the preliminary clinical evidence that suggest NUC-3373 has a favorable safety profile in patients.

P1/2, N=225, Recruiting, NuCana plc | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

P2, N=171, Recruiting, NuCana plc

Background: NUC-3373 is a phosphoramidate modification of fluorodeoxyuridine-monophosphate (FUDR-MP), the active anti-cancer metabolite of fluorouracil (5-FU), which binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair...At the time of co-culture, cells were treated with 10 υg/ml nivolumab to assess the effect of an anti-PD-1 antibody being combined with NUC-3373... NUC-3373 induces DAMPs and PD-L1 expression in CRC cells and promotes pro-immune cytokine production from PBMCs resulting in ICD in vitro. Furthermore, the addition of anti-PD-1 antibody to co-cultures of NUC-3373-treated CRC cells and PMBCs enhanced this ICD. With an improved clinical safety profile (NCT03428958), including less haematologic toxicity, and a more convenient dosing regimen than 5-FU, NUC-3373 is an attractive combination partner for immune checkpoint inhibitors.

P1/2, N=225, Recruiting, NuCana plc | Phase classification: P1 --> P1/2 | N=118 --> 225 | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Fluoropyrimidines, such as 5-FU and capecitabine, exert their main anti-cancer activity via FUDR-MP, which binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair...In Part 1, patients receive NUC-3373 ± leucovorin (LV). In Part 2, NUC-3373 + LV with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). Selected NUFOX and NUFIRI regimens will then be combined with bevacizumab or cetuximab in Part 3. As of 25 January 2021, 38 heavily pre-treated patients (median of 4 prior lines; range: 2-13) had been treated with NUC-3373 ± LV (Part 1)... Part 1 is complete with 38 patients. NUC-3373 ± LV was well tolerated and has a favourable PK profile that is not affected by LV. Encouraging efficacy signals have been observed in heavily pre-treated CRC patients.

P1, N=62, Completed, University of Oxford | Recruiting --> Completed | Trial completion date: Jun 2020 --> Feb 2021

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...The negative control was DMSO in medium, and the positive controls were oxaliplatin, a known inducer of ICD, and PMA/ionomycin, which causes NK cell degranulation... NUC-3373 induces endoplasmic reticulum stress in CRC cells, followed by release of DAMPs. This promotes NK activation as shown by increased degranulation and upregulation of IFNγ. In an in vivo system, activation of NK cells can recruit and activate other immune cell subtypes to create a more immunogenic environment.

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...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)... 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

Funding: NuCana plc. Clinical trial identification: NCT03428958.

NUC-3373, a potent inhibitor of TS activity, also induces ER stress, upregulates cell surface CRT, and decreases nuclear HMGB1 in CRC cells. The aforementioned DAMPs have been shown to cause ICD. In addition to being an effective cytotoxic agent, these findings suggest that NUC-3373 has the potential to evoke a host immune response and enhance the clinical utility of immunotherapy.

In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI)...Clinical trial information: NCT03428958. Research Funding: NuCana