Nuc-7738, A Novel Protide Transformation Of 3'-Deoxyadenosine, In Patients With Advanced Solid Tumors.

Abstract Background: The novel ProTide NUC-7738 is a phosphoramidate transformation of 3'-deoxyadenosine (3'-dA or 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, which inhibits DNA and RNA synthesis. Although 3'-dA has potent in vitro anti-tumor activity, it has not been successful in clinical studies due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 was designed to overcome the key cancer resistance mechanisms associated with 3'-dA. NUC-7738 is resistant to breakdown by ADA, enters cancer cells independently of the human equilibrative nucleoside transporter (hENT1) and it does not require adenosine kinase for phosphorylation. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors or lymphoma who have exhausted all standard treatment options. The primary objective is to determine the recommended phase 2 dose (RP2D) and schedule of NUC-7738. Secondary objectives include safety, pharmacokinetics and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and schedule of NUC-7738. Part 2 will further evaluate NUC-7738 in expansion cohorts of patients with advanced solid tumors or lymphomas. Results: As of 25 Sept 2020, 15 patients had received escalating doses of 14-600 mg/m2 (IV infusion from 30-120 mins) NUC-7738 q1w in Part 1. Patients had received a mean of 3 prior lines of therapy (range: 1 to 5), with melanoma (n=5) and lung (n=3) the most common primary tumor types enrolled. NUC-7738 was well tolerated, with no Grade 3 or 4 treatment-related AEs. No dose-limiting toxicities have been reported. Encouraging signals of anti-cancer activity were observed in three patients who continued to receive clinical benefit for over 6 months (1 patient remained on treatment for over 17 months). NUC-7738 has a predictable plasma PK profile, with a dose proportional increase in Cmax and AUC. High intracellular levels of the anti-cancer metabolite 3'-dATP in PBMCs were detected 2 hours after the start of infusion and maintained for at least 24 hours. Conclusion: NUC-7738 has shown promising anti-cancer activity and a favorable tolerability profile in patients with advanced, treatment-refractory tumors. Patients had high and durable intracellular levels of the anti-cancer metabolite 3'-dATP, supporting non-clinical data that NUC-7738 overcomes the key cancer resistance mechanisms associated with 3'-dA. Citation Format: Ruth Plummer, Farasat Kazmi, Noor Md Haris, Tze-en Ding, Francesca Aroldi, Michelle Myers, Stefan Symeonides, Sarah Blagden. NUC-7738, a novel ProTide transformation of 3′-deoxyadenosine, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT136.