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

Mairead Mcnamara; John Bridgewater; Dan Palmer; Harpreet Wasan; WD Ryder; C Gnanaranjan; E Ghazaly; TRJ Evans; Juan W Valle

Abstract

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: 758P

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.

Original language	English
Pages	viii205-viii270
Publication status	Published - 21 Oct 2018
Event	ESMO 2018 - Munich, Germany Duration: 19 Oct 2018 → 23 Oct 2018

Conference

Conference	ESMO 2018
Country/Territory	Germany
City	Munich
Period	19/10/18 → 23/10/18

Keywords

Biliary tract cancer
Acelarin
Cisplatin
Advanced disease

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

https://oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/A-new-ProTide-NUC-1031-combined-with-cisplatin-for-the-first-line-treatment-of-advanced-biliary-tract-cancer-ABC-08

Cite this

Mcnamara, M., Bridgewater, J., Palmer, D., Wasan, H., Ryder, WD., Gnanaranjan, C., Ghazaly, E., Evans, TRJ., & Valle, J. W. (2018). A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08). viii205-viii270. Abstract from ESMO 2018, Munich, Germany. https://oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/A-new-ProTide-NUC-1031-combined-with-cisplatin-for-the-first-line-treatment-of-advanced-biliary-tract-cancer-ABC-08

@conference{6183d495a00345a4a90cc844b2f19907,

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

abstract = "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: 758PConclusions: 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.",

keywords = "Biliary tract cancer, Acelarin, Cisplatin, Advanced disease",

author = "Mairead Mcnamara and John Bridgewater and Dan Palmer and Harpreet Wasan and WD Ryder and C Gnanaranjan and E Ghazaly and TRJ Evans and Valle, {Juan W}",

year = "2018",

month = oct,

day = "21",

language = "English",

pages = "viii205--viii270",

note = "ESMO 2018 ; Conference date: 19-10-2018 Through 23-10-2018",

}

Mcnamara, M, Bridgewater, J, Palmer, D, Wasan, H, Ryder, WD, Gnanaranjan, C, Ghazaly, E, Evans, TRJ & Valle, JW 2018, 'A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08)', ESMO 2018, Munich, Germany, 19/10/18 - 23/10/18 pp. viii205-viii270. <https://oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/A-new-ProTide-NUC-1031-combined-with-cisplatin-for-the-first-line-treatment-of-advanced-biliary-tract-cancer-ABC-08>

TY - CONF

T1 - A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08)

AU - Mcnamara, Mairead

AU - Bridgewater, John

AU - Palmer, Dan

AU - Wasan, Harpreet

AU - Ryder, WD

AU - Gnanaranjan, C

AU - Ghazaly, E

AU - Evans, TRJ

AU - Valle, Juan W

PY - 2018/10/21

Y1 - 2018/10/21

N2 - 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: 758PConclusions: 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.

AB - 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: 758PConclusions: 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.

KW - Biliary tract cancer

KW - Acelarin

KW - Cisplatin

KW - Advanced disease

M3 - Abstract

SP - viii205-viii270

T2 - ESMO 2018

Y2 - 19 October 2018 through 23 October 2018

ER -