Abstract 549P
Background
The anti-cancer activity of 5-FU requires conversion to its active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP) to inhibit thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. Although 5-FU based chemotherapies remain the cornerstone of cancer treatment, their clinical utility is limited by resistance mechanisms including conversion to FUDR-MP, catabolism by DPD and short plasma half-life. NUC-3373, a phosphoramidate transformation of FUDR-MP, is designed to bypass these mechanisms and enhance TS inhibition.
Methods
NuTide:301 was a multi-centre, two-part, phase I dose-escalation study to determine the RP2D and schedule of NUC-3373 in patients (pts) with advanced cancers. Secondary objectives included safety, anti-tumour activity and PK/PD. In Part I, NUC-3373 was given as IV infusion on D1, 8, 15 and 22, Q4w from 125mg/m2-3250mg/m2. In Part II, NUC-3373 was administered on D1,15, Q4w, 1500mg/m2-2500mg/m2.
Results
62 pts enrolled (46 in Part I, 16 in Part II) with colorectal cancer (n=26), cholangiocarcinoma (n=2), oesophago-gastric (n=8) pancreatic (n=4), cervical (n=2) and other (n=20). Patients were 59.7% male, median (IQR) age was 59 (54, 67), median (IQR) prior lines of treatment was 3 (2, 4), including 5-FU (72%). NUC-3373 was well-tolerated. Four DLTs: G3 transaminitis (n=2), G2 headache (n=1), G3 hypotension (n=1) and 3hree G4 AEs were reported. Clinical responses were observed with best responses of durable SD.
Conclusions
NUC-3373 showed a favourable safety profile with encouraging anti-cancer activity, even in 5-FU pre-treated pts. RP2D was 2500mg/m2 D1,8,15 and 28, Q4 weekly. phase II combination studies with irinotecan and oxaliplatin are ongoing.
Clinical trial identification
NCT0272324
Editorial acknowledgement
Legal entity responsible for the study
University of Oxford.
Funding
Nucana PLC.
Disclosure
S. Lord: Financial Interests, Personal, Advisory Role: Eisia Co; Financial Interests, Personal, Advisory Role: Prosignia; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Shinogi; Financial Interests, Institutional, Research Grant: CRUK; Financial Interests, Institutional, Research Grant: Against Breast Cancer; Financial Interests, Institutional, Research Grant: Pathios Therapeutics; Financial Interests, Personal, Stocks/Shares: Mitox Therapeutics; Financial Interests, Personal, Leadership Role: Pfizer. T.R..J. Evans: Financial Interests, Institutional, Advisory Role: Karus Therapeutcis; Financial Interests, Institutional, Speaker’s Bureau: Eisai; Financial Interests, Institutional, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Institutional, Speaker’s Bureau: Nucana PLC; Financial Interests, Institutional, Speaker’s Bureau: United Medical; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Merck Sharp Dohme; Financial Interests, Institutional, Expert Testimony: Medivir; Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Roche Genentech; Financial Interests, Personal, Other, Honoraria: Ascelia; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Beigene; Financial Interests, Institutional, Funding: Basilea; Financial Interests, Institutional, Funding: Celgene; Financial Interests, Institutional, Funding: Nucana. S. Blagden: Financial Interests, Institutional, Research Grant: Nucana PLC; Financial Interests, Personal, Advisory Role: Nucana PLC; Financial Interests, Institutional, Sponsor/Funding: Sierra Oncology; Financial Interests, Institutional, Sponsor/Funding: Nucana PLC; Financial Interests, Institutional, Sponsor/Funding: Astex; Financial Interests, Institutional, Sponsor/Funding: InCyte; Financial Interests, Institutional, Sponsor/Funding: Tesaro; Financial Interests, Institutional, Sponsor/Funding: Redx; Financial Interests, Institutional, Sponsor/Funding: MSD; Financial Interests, Institutional, Sponsor/Funding: Roche; Financial Interests, Institutional, Sponsor/Funding: UCB; Non-Financial Interests, Personal, Ownership Interest: RNA Guardian; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Amphista; Financial Interests, Personal, Advisory Board: Oxford Investment Consultants. All other authors have declared no conflicts of interest.