A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08)

Background: Cisplatin + gemcitabine (cis/gem) is the global standard of care for 1st-line treatment of patients (pts) with locally advanced/metastatic biliary tract cancer (BTC). No agents have regulatory approval for this disease. Cis/gem achieves an objective response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (ABC-02). Inherent/acquired resistance mechanisms limit gemcitabine efficacy. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome resistance mechanisms associated with poor gemcitabine response. Methods: Pts with locally advanced/metastatic BTC, ECOG PS of 0-1 and no prior systemic therapy received NUC-1031 (625 or 725 mg/m2) combined with cisplatin (25 mg/m2) on days 1 + 8 every 21 days. Primary endpoints: safety and determination of RP2D. Secondary endpoints: ORR, pharmacokinetics, progression-free and OS. Results: 14 pts (median age 61 yrs, 8 male; 5 hilar, 4 distal bile duct, 2 intrahepatic, 2 ampullary and 1 gallbladder) were enrolled across cohorts 1 (625 mg/m2, n = 8) and 2 (725 mg/m2, n = 6). 11 pts completed >1 cycle and were efficacy evaluable, receiving a median of 6.5 cycles (range 3.5-12). ORR was 64% (1 CR, 6 PRs) and DCR: 73%. PFS/OS data collection is ongoing. High, durable intracellular levels of the active anti-cancer metabolite dFdCTP were generated in PBMCs (t1/2=22 h). Treatment was well tolerated with no unexpected AEs/DLTs. Grade 3 TEAEs included neutropenia (14%), fatigue (14%), pyrexia (14%), ALT (7%), AST (7%), GGT (7%) and nausea (7%). Based on high response rate and favourable safety profile, 625 mg/m2 was deemed RP2D. An expansion cohort is ongoing (n = 6).Table: 758PITTEfficacy evaluable625 mg/m2 (n = 8) n (%)725 mg/m2 (n = 6) n (%)Total (n = 14) n (%)625 mg/m2 (n = 6) n (%)725 mg/m2 (n = 5) n (%)Total (n = 11) n (%)CR1 (13)0 (0)1 (7)1 (17)0 (0)1 (9)PR3 (38)3 (50)6 (43)3 (50)3 (60)6 (55)ORR4 (50)3 (50)7 (50)4 (67)3 (60)7 (64)SD0 (0)1 (17)1 (7)0 (0)1 (20)1 (9)DCR4 (50)4 (67)8 (57)4 (67)4 (80)8 (73) Open table in a new tab Conclusions: NUC-1031 + cisplatin demonstrated a very high ORR, with a favourable safety profile, and may provide an improved treatment option over cis/gem for advanced BTC. Further development of NUC-1031 in BTC is planned. Clinical trial identification: NCT02351765. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: NuCana. Disclosure: All authors have declared no conflicts of interest.