455MO - NUC-7738 in patients with advanced solid tumours: Phase I results from the NuTide:701 phase I/II study

Background

NUC-7738 is an anti-cancer ProTide designed to overcome the key limitations of 3’-deoxyadenosine (3’-dA; cordycepin). The cytotoxicity of 3’-dA is largely attributed to intracellular generation of 3’-dATP, which interferes with RNA polyadenylation. NUC-7738, a phosphorylated and protected version of 3’-dA that is resistant to breakdown by adenosine deaminase, enters cancer cells independently of the hENT1 transporter and bypasses the need for initial, rate-limiting phosphorylation. In vitro, NUC-7738 generated higher intracellular levels of 3’-dATP and had greater anti-cancer activity compared to 3’-dA. Unlike 3’-dA, NUC-7738 retains cytotoxicity under cancer resistance conditions.

Methods

NuTide:701 is a phase I/II study of NUC-7738 in patients with advanced solid tumours. NUC-7738 is administered Q1W by IVI. In phase I, primary objectives were safety, tolerability and determination of the MTD. In phase II, the primary objective is efficacy. Secondary objectives include PK, efficacy and safety. Translational work will establish the pharmacodynamics of NUC-7738 and metabolites in blood and tumour.

Results

Phase I is complete and recruitment for phase II is ongoing. As of April 2022, 38 patients (58% female, median 2 prior lines; range: 0-7) with 17 advanced cancers in phase I and 1 patient (3 prior lines) in phase II received NUC-7738. NUC-7738 was well-tolerated, with no grade 4 treatment related AEs (TRAEs) and 4 patients with Grade 3 TRAEs (2 at doses above the MTD) of anaemia, fatigue and vomiting. The most frequent (≥15%) TRAEs were nausea (42%), fatigue (37%), anaemia (21%), diarrhoea and vomiting (both 18%). MTD was defined as 1350 mg/m2 Q1W based on two DLTs (G3 fatigue; 2000 mg/m2 cohort). RP2D is currently being defined and will be reported. NUC-7738 generated high levels of intracellular 3’-dATP that were detectable up to 50 hours after dosing. Encouraging anti-cancer signals were observed in several tumour types, particularly melanoma, with prolonged stable disease and symptom benefit. Additional data from phase I and phase II will be presented.

Conclusions

NUC-7738 has a favourable toxicity profile. Single-agent MTD is 1350 mg/m². Encouraging efficacy signals were observed in several tumour types including melanoma.

Clinical trial identification

NCT03428958.

Editorial acknowledgement

Legal entity responsible for the study

NuCana plc.

Funding

NuCana plc.

Disclosure

S.N. Symeonides: Financial Interests, Institutional, Advisory Board: Ellipses, Vaccitech, Medannex, EUSA, Eisai, MSD, BMS, Pfizer, Merck Serono; Financial Interests, Institutional, Research Grant: MSD, Verastem, Roche; Financial Interests, Institutional, Invited Speaker: MSD, BioNTech, Nouscom, Roche, Nucana, Sapience Therapeutics, BioLineRx, Boston Pharmaceuticals, Sierra Oncology; Other, Conference attendance (no personal gain): Ipsen, BMS, EUSA. A. Skolariki: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche. M. Myers: Financial Interests, Personal, Full or part-time Employment: NuCana plc. E.M. Oelmann: Financial Interests, Personal, Full or part-time Employment: NuCana plc. J.D. Bloss: Financial Interests, Personal, Full or part-time Employment: NuCana. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. S.P. Blagden: Financial Interests, Personal, Advisory Role: UCB, Oxford Investment Consultants; Financial Interests, Personal, Royalties: WO 2016075455 A1 circulating LARP1; Financial Interests, Personal, Stocks/Shares: RNA Guardian; Financial Interests, Personal, Other, honoraria: Amphista Therapeutics, Theolytics, UCB, RApport Global; Financial Interests, Institutional, Research Grant: NuCana, Redx Pharma, UCB, MINA THERAPEUTICS, Nurix, BerGenBio, MSD Oncology. All other authors have declared no conflicts of interest.