Phase 3 Trial of NUC-1031/Cisplatin Discontinued for Advanced Biliary Tract Cancer

The phase 3 NuTide:121 study (NCT04163900), assessing the use of NUC-1031 (Acelarin) and cisplatin in advanced biliary tract cancer, has been discontinued after a pre-planned futility analysis via independent data monitoring committee (IDMC), according to a press release by developer NuCana plc.¹

Despite NUC-1031 and cisplatin having a higher objective response rate (ORR) than the study’s comparator arm, experts concluded that this did not translate to an overall survival (OS) benefit. Due to this, the IDMC concluded the combination was not likely to meet the study’s primary end point of improved OS of 2.2 months vs gemcitabine and cisplatin.

“This disappointing news highlights the challenges associated with developing new medicines for patients with biliary tract cancer,” Hugh S. Griffith, founder and chief executive officer at NuCana, said in the press release. “NuCana will carefully review these data to determine future potential development pathways for Acelarin. We are extremely grateful to all the patients, their families, the investigators and other health care professionals involved in the NuTide:121 study.”

NUC-1031 is a phosphoramidate transformation of gemcitabine that was designed to overcome certain key mechanisms of resistance and result in a higher level of active anti-cancer metabolite, dFdCTP, in cells.

NUC-1031 and cisplatin previously received a fast track designation from the FDA for advanced biliary tract cancer in September 2021 based on findings from the NuTide:121 trial.² The study accrued a total of 21 patients who received either 625 mg/m² or 725 mg/m² of NUC-1031 plus 25 mg/m² of cisplatin on days 1 and 8 of every 21-day cycle.³ Sixteen patients were evaluable in the efficacy analysis.

The ORR was 44%, which included 6 partial responses and 1 complete response—a favorable outcome vs the standard of care regimen that yielded an ORR of 26%. Treatment with NUC-10301 also achieved stable disease in 6 patients, translating to a disease control rate of 81%.

Additionally, the combination was well tolerated with no unexpected adverse effects or dose-limiting toxicities. The recommended phase 2 dose of NUC-1031 plus cisplatin was 725 mg/m².

At the time of publication, 828 patients were being randomized 1:1 to receive either 725 mg/m² of NUC-1031 or 1000 mg/m² of gemcitabine plus a 25 mg/m² cisplatin backbone in both arms. Investigators planned 3 interim analyses plus the final analysis.

“Biliary tract cancer comprises a very difficult group of tumors to treat and developing effective therapies in this setting is extremely challenging. I, along with the other NuTide:121 investigators, am dedicated to developing better treatment options for patients with biliary tract cancer. While the outcome of NuTide:121 is disappointing, it will not diminish our determination to address the unmet needs of these patients,” chief investigator Jennifer J. Knox, MSc, MD, FRCPC, professor of medicine at the University of Toronto and clinician investigator at the Princess Margaret Cancer Centre, concluded.

References

1. NuCana announces update for phase 3 biliary tract cancer study. News release. NuCana plc. March 2, 2022. Accessed March 3, 2022. https://bit.ly/3C9aAwr
2. NuCana receives fast track designation from the U.S. Food and Drug Administration for Acelarin® (NUC-1031) for the treatment of biliary tract cancer. News release. NuCana plc. September 29, 2021. Accessed March 3, 2022. https://bit.ly/3trkSnx
3. Knox JJ, McNamara MG, Goyal L, et al. Phase III study of NUC-1031 + cisplatin versus gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). J Clin Oncol. 2021;39(suppl 15). doi:10.1200/JCO.2021.39.15_suppl.TPS4164