Abstract 475P
Background
NUC-3373 is a novel phosphoramidate nucleotide analogue that generates high intracellular levels of the anti-cancer metabolite fluorodeoxyuridine-monophosphate (FUDR-MP). 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. Fluoropyrimidines also result in the generation of the toxic metabolites FBAL and FUTP. NUC-3373, a targeted TS inhibitor, is designed to bypass the 5-FU and capecitabine resistance mechanisms associated with transport, activation and breakdown and to reduce the generation of toxic metabolites such as FBAL and FUTP.
Methods
NuTide:302 is a phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine-containing therapies. The primary objective is to determine the RP2D and schedule of NUC-3373. Secondary objectives include safety, PK and anti-tumour activity of NUC-3373. 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.
Results
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). Interim data from these patients demonstrated that NUC-3373 was well-tolerated with no NUC-3373-induced neutropaenia or hand-foot syndrome of any grade. Encouraging anti-cancer signals were observed with a disease control rate of 62% (efficacy evaluable population). To date, 16 patients have been treated in Part 2 of the study. Data from Part 2 of the study will be shared at the conference.
Conclusions
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. Part 2 is ongoing.
Clinical trial identification
NCT03428958.
Editorial acknowledgement
Legal entity responsible for the study
NuCana plc.
Funding
NuCana plc.
Disclosure
J. Berlin: Financial Interests, Personal, Advisory Role: Celgene; EMD Serono; Cornerstone Pharmaceuticals; AbbVie; Bayer Health; qed therapeutics; Clovis Oncology; Ipsen; Financial Interests, Personal, Other, travel, Accommodations, Expenses: EMD Serono; Bayer; Boston Biomedical; Financial Interests, Personal, Other: novocure; Pancreatic Cancer Action Network; Financial Interests, Institutional, Research Grant: Bayer; Incyte; Pharmacyclics; Karyopharm Therapeutics; EMD Serono; Boston Biomedical; Macrogenics; PsiOxus Therapeutics; Pfizer; Lilly; Dragonfly Therapeutics; AbbVie; I-MAB. A.L. Coveler: Financial Interests, Personal, Advisory Role: Halozyme; Seattle Genetics; Merrimack; AbbVie; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Halozyme; AbbVie; Financial Interests, Institutional, Research Grant: XBiotech; Newlink Genetics; Taiho Pharmaceutical; Immunomedics; Onconova Therapeutics; Lilly; Gilead Sciences; Genentech; Seattle Genetics; AbGenomics International; Halozme; Novocure; MedImmune; Amgen; Amgen; ActuateTherapeutics. K.K. Ciombor: Financial Interests, Personal, Advisory Role: Bayer; Foundation Medicine; Taiho Pharmaceutical; Natera; Array BioPharma; Research to Practice; i3 Health; Merck; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Array BioPharma; Financial Interests, Institutional, Research Grant: Pfizer; Boston Biomedical; MedImmune; Onyx; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Merck; Novartis; Incyte; Amgen; Sanofi; Bristol-Myers Squibb; Array BioPharma; Incyte; Daiichi Sankyo; NuCana; AbbVie; Merck; Pfizer/Calithera. J. Graham: Financial Interests, Personal, Advisory Role: Merck KGaA; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: NuCana; Financial Interests, Personal, Other, Honoraria: Merck Serono; Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: NuCana; Financial Interests, Personal, Other, Honoraria: Bayer. M.L. Peters: Financial Interests, Institutional, Funding: Ambry Genetics; BeiGene; Berg; Financial Interests, Personal, Other, Honoraria and Consulting: Agios; Exelixis; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Halozyme; AstraZeneca; Exelisis; Financial Interests, Personal, Research Grant, K08CA248743: National Cancer Institute. M. Myers: Financial Interests, Personal, Full or part-time Employment: NuCana plc.T.R..J. Evans: Financial Interests, Institutional, Advisory Role: Karus Therapeutics; Financial Interests, Institutional, Speaker’s Bureau: Eisai; Bristol-Myers Squibb; Merck Sharp & Dohme; NuCana; United Medical; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol-Myers Squibb; Merck Sharp & Dohme; Pierre Fabre; Eisai; NuCana; Financial Interests, Institutional, Expert Testimony: Medivir; Financial Interests, Institutional, Other: Genmab; Financial Interests, Institutional, Other, Honoraria: Eisai; Merck Sharp & Dohme; Bristol-Myers Squibb; NuCana; Roche/Genentech; Ascelia; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: AstraZeneca; Beigene; Financial Interests, Institutional, Research Grant: Basilea; Celgene; Eisai; Merck Sharp & Dohme; MiNA Therapeutics; Bicycle Therapeutics; Lilly; Merck Serono; Financial Interests, Institutional, Research Grant: Janssen; Johnson & Johnson; Verastem; Roche/Genentech; Novartis; Iovance Biotherapeutics; Medivir; Sanofi/Aventis; Clovis Oncology; Plexxikon; NuCana; Sierra Pharma; GlaxoSmithKline; Halozyme; CytomX Therapeutics; Vertex; Athenex; Adaptimmine; Immunocore; Modulate Pharma; Berg; Starpharma; BiolineRx; iOncologi; UCB. S. Blagden: Financial Interests, Personal, Other, Honoraria: NuCana; Financial Interests, Personal, Advisory Role: Ellipses Pharma; Financial Interests, Institutional, Research Grant: NuCana; Sierra Oncology; Astex Pharmaceuticals; Incyte; Octimet; Tesaro; Redx Pharma; MSD; Roche; UCB; Financial Interests, Personal, Royalties: RNA Guardian; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: NuCana; Tesaro. All other authors have declared no conflicts of interest.