Abstract 600TiP
Background
Nucleoside analogues form the backbone of systemic therapy for both solid and haematological malignancies. However, their clinical effectiveness is limited by cancer resistance mechanisms including transportation, intracellular activation and breakdown. NUC-7738 is a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA, cordycepin), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, inhibiting DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumour activity in non-clinical studies, it has not been successful in clinical studies due to its rapid breakdown by adenosine deaminase (ADA). With the addition of the phosphoramidate moiety, NUC-7738 can bypass the key resistance pathways associated with 3’-dA, including breakdown by ADA.
Trial design
NuTide:701 is a two-part, first-in-human phase I study in patients with advanced solid tumours who have exhausted all available treatment options. The primary objective is to determine the recommended Phase 2 dose (RP2D) and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumour activity. Part 1, in patients with advanced solid tumours, will establish the RP2D and schedule of NUC-7738. Part 2 will further evaluate NUC-7738 in an expansion cohort of patients with advanced solid tumours or lymphoma. To date, 11 patients have been dosed in Part 1.
Clinical trial identification
NCT03829254.
Editorial acknowledgement
Legal entity responsible for the study
NuCana plc.
Funding
NuCana plc.
Disclosure
S. Symeonides: Advisory/Consultancy: Vaccitech; Advisory/Consultancy: Bicycle Therapeutics; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: EUSA Pharma; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Pfizer/EMD Serono; Advisory/Consultancy: MedAnnex; Speaker Bureau/Expert testimony: Novartis; Travel/Accommodation/Expenses: Ipsen; Research grant/Funding (institution): Verastem; Research grant/Funding (institution): Boston Pharmaceuticals; Research grant/Funding (institution): Sierra Oncology; Research grant/Funding (institution): NuCana; Research grant/Funding (institution): BioNTech AG; Research grant/Funding (institution): BiolineRx; Research grant/Funding (institution): Nouscom; Research grant/Funding (institution): Sapience Therapeutics. F. Aroldi: Travel/Accommodation/Expenses: NuCana. R. Plummer: Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Novartis; Advisory/Consultancy: Astex Pharmaceuticals; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Bayer; Advisory/Consultancy: Octimet; Advisory/Consultancy: Biosceptre; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Karus Therapeutics; Advisory/Consultancy: Cybrexa Therapeutics; Advisory/Consultancy: Sanofi/Aventis; Advisory/Consultancy: CV6 Therapeutics; Travel/Accommodation/Expenses: MSD Oncology; Honoraria (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Licensing/Royalties, Named on patent of use of PARP inhibitor rucaparib: Clovis Oncology; Spouse/Financial dependant, immediate family member receives honorarium: Pfizer; Spouse/Financial dependant, immediate family member receives honorarium: Amgen; Honoraria (self): Tesaro; Honoraria (self): Novartis Pharmaceuticals UK Ltd.; Honoraria (self), Research grant/Funding (institution): AstraZeneca/MedImmune. S. Blagden: Honoraria (self), Travel/Accommodation/Expenses: NuCana; Advisory/Consultancy: Ellipses Pharma; Research grant/Funding (self): NuCana; Research grant/Funding (self): Sierra Oncology; Research grant/Funding (self): Astex Pharmaceuticals; Research grant/Funding (self): Incyte; Research grant/Funding (self): Octimet; Research grant/Funding (self), Travel/Accommodation/Expenses: Tesaro; Research grant/Funding (self): Redx Pharma; Research grant/Funding (self): UCB; Research grant/Funding (self): MSD Brasil; Research grant/Funding (self): Roche; Licensing/Royalties: RNA Guardian. All other authors have declared no conflicts of interest.