A Phase Ib/II multi-arm, dose finding and expansion study of a novel thymidylate synthase inhibitor with immune modulating properties, NUC-3373, in combination with pembrolizumab or docetaxel in patients with advanced solid tumors (NuTide:303)

BackgroundNUC-3373 is a novel thymidylate synthase (TS) inhibitor designed to directly deliver the active anti-cancer metabolite fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP) intracellularly. In addition to being a potent TS inhibitor, NUC-3373 has also been shown to cause DNA damage and promote the release of damage-associated molecular patterns. These diverse mechanisms position NUC-3373 as a potentially effective combination partner for several other anti-cancer agents. MethodsNuTide:303 was a Phase Ib/II open label, multi-arm, parallel cohort dose-finding and expansion study designed to evaluate optimal combination partners for NUC-3373. Module 1 planned to enroll up to 12 evaluable patients with advanced/metastatic solid tumors to determine the recommended dose for NUC-3373 in combination with leucovorin (LV) and pembrolizumab. Module 2 planned to enroll approximately 6-12 evaluable patients with advanced/metastatic non-small cell lung cancer (of any histology) or pleural mesothelioma to determine the recommended dose for NUC-3373 in combination with LV and docetaxel. A 3+3 dose escalation design was used in both modules, with safety parameters continually assessed and tumor assessments conducted at screening and every 8 weeks from C1D1 until progression. The study was terminated early and the Phase II part was not initiated; therefore, only results of the Phase Ib part of the study are presented. ResultsFifteen patients were enrolled in Module 1, of whom 13 received study treatment and were included in the safety population. Nine patients were evaluable for anti-tumor activity. No DLTs were observed in these heavily pre-treated PD-(L)1 experienced patients with a variety of different tumor types. An objective response rate of 22% and a disease control rate of 67% were reported. NUC-3373 + LV + pembrolizumab was well tolerated, the most common treatment-related adverse events (AEs) were nausea, vomiting, diarrhea, and fatigue and the majority of events were Grade 1 or 2. Four patients were enrolled in Module 2, all of whom received study treatment. Three evaluable for anti-tumor activity. Two patients treated at the first dose level achieved stable disease and completed >6 months of treatment. The most common treatment-related AE was fatigue (n=4) and the majority of events were Grade 1 or 2. ConclusionsThe results from the Phase Ib part of NuTide:303 suggest that NUC-3373 may be an effective combination partner for pembrolizumab in a variety of advanced solid tumors. The probability of being able to escalate to typical efficacious doses of docetaxel used in combination is low due to overlapping toxicity. The use of a different taxane in this combination is currently being considered.