Abstract CT028: First-in-human phase I study of the nucleotide analogue NUC-3373 designed to overcome fluoropyrimidine drug resistance mechanisms
Authors: Sarah P. Blagden, Magdalena Slusarczyk, Michaela Serpi, Christopher McGuigan, Essam A. Ghazaly
Journal: Cancer Research (2016)

Abstract Background: NUC-3373 is the first nucleotide analogue to bypass the key cancer resistance mechanisms associated with 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine (FUDR) that significantly impede their clinical activity. In EC50 assays, NUC-3373 demonstrated up to 330x greater activity than 5-FU across multiple cancer cell lines and retained its activity in conditions mimicking drug resistance: thymidine kinase inhibition, thymidine phosphorylase over-expression and membrane transporter inhibition. In addition, whilst dihydropyrimidine dehydrogenase (DPD) significantly degraded 5-FU in cell lysates (p = 0.039), levels of NUC-3373 remained unaffected. Importantly, NUC-3373 generated 363x higher intracellular levels of the anti-cancer agent 5-fluorodeoxyuridine monophosphate, the active metabolite of 5-FU and FUDR. In colorectal cancer xenografts, NUC-3373 administered at 30 mg/kg 5-FU equimolar dose, demonstrated significantly greater tumour growth inhibition (47%) than 5-FU (25%). Finally, in formal toxicology studies NUC-3373 was significantly better tolerated than 5-FU, showing low conversion into the metabolite dihydrofluorouracil, dhFU (AUC plasma ratio dhFU:NUC-3373 = 0.03). NUC-3373 warrants clinical evaluation. Study Design: A two-part, Phase I open label, dose escalation and expansion study will be conducted to assess safety, pharmacokinetics and clinical activity of single agent NUC-3373 in participants with advanced solid tumours. A standard 3+3 dose escalation scheme will be used to identify the recommended Phase 2 dose (RP2D) of NUC-3373 comparing, in Part 1, a weekly schedule of administrationon days 1, 8, 15 and 22 of a 28-day cycle; and in Part 2 a fortnightly schedule of administration on days 1 and 15 of a 28-day cycle. Objectives: The primary objective is to establish the RP2D of NUC-3373 administered weekly and fortnightly. The secondary objectives are to assess the safety, pharmacokinetics, pharmacodynamics and anti-tumour activity of the agent. Tertiary objectives are to identify biomarkers that may help select those patients more likely to benefit from NUC-3373 than 5-FU. Major eligibility criteria: Histologically confirmed diagnosis of solid tumour, which is not amenable to, or refractory to standard chemotherapy, or for which no standard chemotherapy exists; measurable/evaluable disease; ECOG score 0-2; adequate bone marrow, liver and renal functions. Patients with a history of allergic reactions attributed to previous 5-FU or capecitabine treatment are excluded. Conclusions: NUC-3373 overcomes key cancer resistance mechanisms associated with 5-FU and a Phase I clinical study has been initiated. Citation Format: Sarah P. Blagden, Magdalena Slusarczyk, Michaela Serpi, Christopher McGuigan, Essam A. Ghazaly. First-in-human phase I study of the nucleotide analogue NUC-3373 designed to overcome fluoropyrimidine drug resistance mechanisms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT028.