NUC-3373 Demonstrates Promising Anti-Tumor Activity and Safety in Combination with Oxaliplatin (NUFOX) and Irinotecan (NUFIRI) in Heavily Pre-Treated Colorectal Cancer Patients
Randomized Study of NUFIRI vs. FOLFIRI in Second-Line Colorectal Cancer Patients Initiated
Poster 345P: NUC-3373, a ProTide transformation of 5-FU, in combination with oxaliplatin (NUFOX) or irinotecan (NUFIRI) in patients with advanced colorectal cancer (NuTide:302)
NUC-3373, a phosphoramidate transformation of 5-FU, that was designed to overcome the key limitations and challenges associated with 5-FU has previously demonstrated promising anti-tumor activity and a favorable safety and pharmacokinetic profile as a single agent and in combination with leucovorin in heavily pre-treated patients with advanced colorectal cancer (CRC). Data presented at ESMO describe NUC-3373 plus leucovorin in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in the dose-finding part of the study.
Both NUFOX and NUFIRI demonstrated encouraging anti-tumor activity in heavily pre-treated CRC patients with progressive disease who had all previously received regimens containing 5-FU, oxaliplatin and irinotecan. Of the 46 patients who received either NUFOX or NUFIRI, twelve (six from each cohort) achieved progression-free survival (PFS) of greater than three months, including three patients who achieved PFS of six months or longer. The disease control rates for the NUFOX and NUFIRI regimens were 80% and 55%, respectively. Data presented also indicate that NUFOX and NUFIRI have favorable safety profiles when compared to historical data for the 5-FU-containing regimens FOLFOX and FOLFIRI, with lower rates of toxicities such as neutropenia and gastrointestinal disturbances that limit their clinical utility. With these data, NuCana has established the recommended Phase 2 dose for NUC-3373 as part of NUFOX and NUFIRI regimens.
“These data are highly supportive of our strategy to develop NUC-3373 as a replacement for 5-FU, one of the most widely used medicines for the treatment of patients with cancer,” said
About NUC-3373
NUC-3373 is a phosphoramidate transformation of 5-fluorouracil, or 5-FU, which is designed to overcome the key limitations and pharmacologic challenges that hinder the clinical utility of 5-FU, with the aim of improving 5-FU's efficacy, safety and administration challenges.
5-FU (and its other forms including capecitabine) is an inactive prodrug and its anti-cancer activity is dependent on its conversion to the active anti-cancer metabolite (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. TS is required to convert uridine (specifically dUMP) to thymidine (specifically dTMP), one of the four nucleotides that comprise DNA. The inhibition of TS results in an imbalance in the ratio of dUMP and dTMP, thereby disrupting DNA synthesis and repair, ultimately leading to cancer cell death. However, due to multiple limitations, 5-FU is not efficiently converted to FUDR-MP.
NUC-3373 generates much higher concentrations of FUDR-MP in patients’ cells. It also has a more convenient administration schedule and does not produce toxic levels of metabolites such as FBAL or FUTP (which are associated with hand-foot syndrome, neutropenia, mucositis and diarrhea) resulting in an improved safety profile.
In addition to preventing the synthesis of thymidine via TS inhibition, NUC-3373 treatment also results in the release of Damage Associate Molecular Patterns (DAMPs) and pro-inflammatory cytokines by cancer cells. These act as molecular signals to the immune system, encouraging them to kill cancer cells. Furthermore, NUC-3373 has been shown to induce the expression of PD-L1 on treated cells. In vitro experiments using NUC-3373 treated CRC cells co-cultured with immune cells have shown that NUC-3373 is able to potentiate the effects of PD-1 inhibitors, thus providing a strong scientific rationale for combining NUC-3373 and PD-1/PD-L1 inhibitors in patients.
About NuCana
NuCana is a clinical-stage biopharmaceutical company focused on significantly improving treatment outcomes for patients with cancer by applying our ProTide technology to transform some of the most widely prescribed chemotherapy agents, nucleoside analogs, into more effective and safer medicines. While these conventional agents remain part of the standard of care for the treatment of many solid and hematological tumors, they have significant shortcomings that limit their efficacy and they are often poorly tolerated. Utilizing our proprietary technology, we are developing new medicines, ProTides, designed to overcome the key limitations of nucleoside analogs and generate much higher concentrations of anti-cancer metabolites in cancer cells. NuCana’s pipeline includes NUC-3373 and NUC-7738. NUC-3373 is a new chemical entity derived from the nucleoside analog 5-fluorouracil, a widely used chemotherapy agent. NUC-3373, in combination with other agents, is in a Phase 1b/2 study in patients with metastatic colorectal cancer. NuCana has also initiated a randomized Phase 2 study of NUC-3373, in combination with other agents, for the second-line treatment of patients with advanced colorectal cancer. In addition, NuCana has initiated a Phase 1b/2 modular study of NUC-3373 in combination with other agents, including a PD-1 inhibitor, in patients with advanced solid tumors to identify additional indications for development. NUC-7738 is a transformation of 3’-deoxyadenosine, a novel anti-cancer nucleoside analog. NUC-7738 is in the Phase 2 part of a Phase 1/2 study in patients with advanced solid tumors which is evaluating NUC-7738 as a monotherapy and in combination with a PD-1 inhibitor.
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For more information, please contact:
Chief Executive Officer
T: +44 131-357-1111
E: info@nucana.com
ICR Westwicke
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E: chris.brinzey@westwicke.com
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E: mjanic@rooneyco.com
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