354P - NUC-3373, a ProTide transformation of 5-FU, in combination with oxaliplatin (NUFOX) or irinotecan (NUFIRI) in patients with advanced colorectal cancer (CRC) (NuTide:302)

Background

Fluoropyrimidines predominantly exert anti-cancer activity via fluorodeoxyuridine-monophosphate (FUDR-MP; FdUMP). 5-FU has multiple limitations: inefficient conversion to FUDR-MP; generation of toxic metabolites; and a short half-life leading to challenging administration schedules (46 hour infusions). NUC-3373, a ProTide transformation of FUDR-MP, is designed to overcome these limitations by: generating high levels of FUDR-MP; avoiding toxic metabolite generation; and increasing the half-life to enable more convenient administration schedules (2-4 hour infusions).

Methods

NuTide:302 is a phase Ib/II study in patients with advanced CRC who relapsed on prior fluoropyrimidine-containing regimens. Primary objective is to determine MTD of NUC-3373 in combination with other agents. Secondary objectives include safety, PK and efficacy. Part 1, NUC-3373 ± leucovorin (LV), is complete (n=38). In Part 2, NUC-3373 + LV is administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). Part 3 will explore NUFOX and NUFIRI + bevacizumab in 2^nd-line advanced CRC.

Results

As of March 2022, 38 patients (median 4 prior lines; range: 2-10) received either NUFOX (n=19; NUC-3373 1500-2250 mg/m²) or NUFIRI (n=19 ; NUC-3373 1500-1875 mg/m²) in Part 2. Most frequent treatment-related AEs (TRAEs) are below in table. Grade 3 TRAEs occurring in more than 1 patient were: NUFOX (ALT elevation, nausea; 2 patients each (11%) and NUFIRI (ALT elevation; 2 patients (11%). No patients had Grade 4 or 5 TRAEs. Encouraging signs of anti-cancer activity were observed. Available data, including MTDs, from Parts 2 and 3 will be presented. Table: 354P

Conclusions

NUFOX and NUFIRI combinations have been well tolerated with encouraging signs of anti-cancer activity in heavily pre-treated patients. NUFIRI + bevacizumab will be compared to FOLFIRI + bevacizumab in 2^nd-line CRC in a randomised phase II study.

Clinical trial identification

NCT03428958.

Editorial acknowledgement

Legal entity responsible for the study

NuCana.

Funding

NuCana.

Disclosure

A. Coveler: Financial Interests, Institutional, Invited Speaker: Seagen, AbGenomics, Novocure, Amgen, Actuate Therapeutics, Surface Oncology, Nucana, Nextrast. A. Skolariki: Financial Interests, Personal, Training: Roche. K.K. Ciombor: Financial Interests, Personal, Advisory Board: Pfizer, Merck, Lilly/Loxo, Replimune, Personalis; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Genentech, Merck, Incyte, Seagen, BMS, Nucana, Daiichi Sankyo, Calithera, Array. J. Graham: Financial Interests, Personal, Advisory Role: Merck KGA; Financial Interests, Personal, Funding: NuCana; Financial Interests, Personal, Other: Merck Serono, BMS, NuCana, Bayer. M.L. Peters: Financial Interests, Personal, Advisory Role: Agios; Financial Interests, Personal, Stocks/Shares: Lilly, Medtronic, Procter & Gamble, Merck, Agios; Financial Interests, Institutional, Funding: Taiho, AZ, Exelixis, BeiGene, Berg, Merck, Bayer, NuCana, Helsinn Therapeutics. S.A. Cohen: Financial Interests, Personal, Advisory Role: Natera, Pfizer, Taiho, Istari oncology, Kallyope, ACCC; Financial Interests, Personal, Expert Testimony: Robins Kaplan; Financial Interests, Institutional, Funding: Boston Biomedical, Polaris, Isofol Medical, EMD Serono/Merck. M. Myers: Financial Interests, Personal, Full or part-time Employment: NuCana. E.M. Oelmann: Financial Interests, Personal, Full or part-time Employment: NuCana. J. Bloss: Financial Interests, Personal, Full or part-time Employment: NuCana. S.P. Blagden: Financial Interests, Personal, Advisory Role: UCB, Oxford investment consultants; Financial Interests, Personal, Ownership Interest: RNA Guardian; Financial Interests, Personal, Other: Amphista Therapeutics , Theolytics, UCB, Rapport Global; Financial Interests, Institutional, Funding: NuCana, Redx, UCB, Mina, Astex, Nurix, BerGenBio, MSD Oncology. J.D. Berlin: Financial Interests, Personal, Advisory Role: Bayer Health, qed therapeutics, Clovis, Mirati Therapeutics, Insmed; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Other: Boston Biomedical, Novocure, pancreatic cancer action network, Karyopharm; Financial Interests, Institutional, Research Grant: Bayer, Incyte, Karyopharm , EMD Serono, Boston Biomed, Macrogenetics, PsiOxus, Pfizer, Lilly, Dragonfly Therapeutics, AbbVie, I-MAB, Astellas, Atreca, Day One Biopharmaceuticals, BMS/Celgene. T.R.J. Evans: Financial Interests, Institutional, Advisory Board, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol-Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol-Myers Squibb; Financial Interests, Institutional, Advisory Board, Advisory Boards - GI cancers, melanoma: Roche / Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche / Genentech; Financial Interests, Institutional, Advisory Board, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board, advisory board: MSD, AstraZeneca, Medivir, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board, Advisory board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol-Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Invited Speaker, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Invited Speaker, reimbursement of study costs for commercial studies: Astellas, Bayer, Adaptimmune, Bristol-Myers Squibb, Basilea, Celgene, GSK, Eisai, MSD, Roche, Medivir, Nucana, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, Beigene, Pfizer, Johnson & Johnson, iOnctura, UCB, Sanofi, Codiak; Financial Interests, Institutional, Invited Speaker, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Invited Speaker, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, reimbursement of costs of commercial study: Seagen; Non-Financial Interests, Other, Member of Clinical Experts Review Panel / Clinical Research Committee: Cancer Research UK; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Other, Clinical Subjects Editor: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase I trial - honorarium payable to the employing institution: Genmab. All other authors have declared no conflicts of interest.