NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer.

TPS4156 Background: Cisplatin and gemcitabine (CisGem) is the global standard of care for 1st-line treatment of patients (pts) with advanced biliary tract cancer (BTC). No agents have regulatory approval for this disease. CisGem achieves an objective response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (ABC-02). Key cancer resistance mechanisms limit gemcitabine efficacy. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome resistance mechanisms associated with poor gemcitabine response. Promising signs of efficacy have been observed with single agent in a phase I study in solid tumors (Blagden et al 2018) and in the phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg /m2 d1, d8 q 21 days for the 1st-line treatment of advanced BTC. 14 pts have been enrolled across 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2). In 11 pts evaluable for response ORR was 64% (1 CR, 6 PRs) and DCR was 73%. PFS/OS data is maturing. The combination was very well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D in combination with cisplatin is 725 mg/ m2. Safety, coupled with encouraging efficacy signal has led to initiation of a global Phase III development program. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus CisGem for the 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), that is not resectable and who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on Days 1 and 8 of a 21-day cycle, respectively. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT02351765.

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NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.tps602 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. TPS602-TPS602

Author(s):

Jennifer J. Knox ◽

Mairead Geraldine McNamara ◽

Lipika Goyal ◽

Mark Doherty ◽

Christoph Springfeld ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Single Agent ◽

Phase Iii ◽

Asia Pacific ◽

Tolerability Profile ◽

Line Treatment ◽

Cancer Resistance ◽

Tract Cancer ◽

Patient Reported

TPS602 Background: Biliary tract cancer (BTC) carries a poor prognosis and has no approved treatments. Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1st-line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome key cancer resistance mechanisms associated with gemcitabine. Promising signs of efficacy have been observed with single-agent NUC-1031 in a Phase I study in advanced solid tumors (Blagden et al 2018) and in the Phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for the 1st-line treatment of advanced BTC. Of 14 patients (pts) enrolled in 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2), 1 pt achieved a CR and 6 pts achieved PR, giving an unconfirmed ORR of 50% and representing an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D of NUC-1031 in combination with cisplatin is 725 mg/m2. The tolerability profile together with robust efficacy signals suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global Phase III study. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus GemCis for 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on days 1 and 8 of a 21-day cycle. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.

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Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps351 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS351-TPS351

Author(s):

Jennifer J. Knox ◽

Mairead Geraldine McNamara ◽

Lipika Goyal ◽

David Cosgrove ◽

Christoph Springfeld ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Phase Iii ◽

Asia Pacific ◽

Line Treatment ◽

Cancer Resistance ◽

First Line ◽

Tract Cancer ◽

Patient Reported ◽

First Line Treatment

TPS351 Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.

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Phase III study of NUC-1031 + cisplatin versus gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4164 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4164-TPS4164

Author(s):

Jennifer J. Knox ◽

Mairead Geraldine McNamara ◽

Lipika Goyal ◽

David Cosgrove ◽

Christoph Springfeld ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Resistance Mechanisms ◽

Phase Iii ◽

Asia Pacific ◽

Line Treatment ◽

Cancer Resistance ◽

First Line ◽

Tract Cancer ◽

First Line Treatment

TPS4164 Background: Biliary tract cancer (BTC) is an aggressive disease with a poor prognosis. Gemcitabine + cisplatin (GemCis) is the accepted global standard of care (SoC), however key cancer resistance mechanisms associated with the transport, activation and breakdown of gemcitabine are known to limit its clinical activity across a range of tumor types, including BTC. NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome these key resistance mechanisms and generate much higher levels of the active anti-cancer metabolite, dFdCTP, in cells. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 21 patients enrolled in 2 dose cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 16 were considered to be efficacy evaluable. In this population, 1 patient had a CR and 6 patients had PRs, resulting in an ORR of 44% (7/16). This compares favorably to the 26% ORR reported for the SoC regimen. In addition, 6 patients had SD, resulting in a DCR of 81% (13/16). The combination was well tolerated with no unexpected AEs or DLTs. The recommended dose of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy led to initiation of a global registrational study. Methods: NuTide:121 is a phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on Days 1 and 8 of 21-day cycles. Primary endpoints are OS and ORR. Secondary endpoints include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific. Clinical trial information: NCT04163900.

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NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121)

Future Oncology ◽

10.2217/fon-2020-0247 ◽

2020 ◽

Vol 16 (16) ◽

pp. 1069-1081 ◽

Cited By ~ 3

Author(s):

Mairéad Geraldine McNamara ◽

Lipika Goyal ◽

Mark Doherty ◽

Christoph Springfeld ◽

David Cosgrove ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Resistance Mechanisms ◽

Ampullary Cancer ◽

Cancer Resistance ◽

Tract Cancer ◽

Patient Reported

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

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