Phase 3 NuTide:121 Study Examining NUC-1031 in Biliary Tract Cancer to be Discontinued

Hugh S. Griffith

The phase 3 NuTide:121 trial (NCT04163900) examining the first-in-class nucleotide analogue NUC-1031 (Acelarin) in combination with cisplatin vs gemcitabine plus cisplatin in patients with advanced biliary tract cancer is being discontinued, according to an announcement from NuCana plc, the drug developer.¹

The decision follows a preplanned futility analysis conducted at the first interim analysis by the study’s independent data monitoring committee (IDMC). Although the NUC-1031/cisplatin combination produced a higher objective response rate than the control regimen per blinded independent central review, this was not found to translate into an overall survival (OS) benefit.

The IDMC concluded that the combination was not likely to achieve the trial’s primary objective of improving OS by at least 2.2 months vs standard-of-care chemotherapy.

“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 of NuCana plc, stated in a press release. “NuCana will carefully review these data to determine future potential development pathways for [NUC-1031]. 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 ProTide transformation of gemcitabine that is believed to overcome key gemcitabine resistance mechanisms.² The agent has cellular uptake that is independent of nucleoside transporters, activation that is independent of deoxycytidine kinase, and it is protected from breakdown by cytidine deaminase. The agent also has greater plasma stability vs gemcitabine, at 8.3 hours vs 1.5 hours, respectively, increased intracellular levels of dFdCTP, and fewer toxic metabolites.

Data from the phase 1b ABC-08 trial (NCT02351765), showed that NUC-1031 elicited an objective response rate (ORR) of 44% across all subtypes of biliary tract cancer, and that the agent had an acceptable toxicity profile in that it was tolerated over multiple treatment cycles.

NuTide:121 enrolled patients with previously untreated histologically- or cytologically-confirmed adenocarcinoma of the biliary tract that was locally advanced, unresectable, or metastatic. To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, a life expectancy of at least 16 weeks, and acceptable biliary drainage without evidence of infection.

Study participants received NUC-1031 at a dose of 725 mg/m² in combination with cisplatin at 25 mg/m² on days 1 and 8 of a 21-day treatment cycle or gemcitabine at 1000 mg/m² plus cisplatin at 25 mg/m² given on days 1 and 8 of each 21-day cycle.

Stratification factors included measurable disease, metastatic disease, anatomic site of disease, and geography.

The primary end points of the research included OS and ORR, and key secondary end points comprised progression-free survival, duration of response, safety, pharmacokinetics, and quality of life.

“Biliary tract cancer comprises a very difficult group of tumors to treat and developing effective therapies in this setting is extremely challenging,” Jennifer J. Knox, MSc, MD, FRCPC, professor of medicine at the University of Toronto, clinician investigator at the Princess Margaret Cancer Centre, and chief investigator of NuTide:121, added in the press release. “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 NuTude:121 is disappointing, it will not diminish our determination to address the unmet needs of these patients.”

Other Protides beyond NUC-1031 are under clinical development. NUX-3373, a ProTide transformation of 5-fluorouracil (5-FU), was designed to overcome key resistance mechanisms and pharmacologic challenges that limit the utility of 5-FU.³ The agent has been shown to produce much higher concentrations of FUDR-MP in patients’ cells, as well as to have a more convenient administration schedule that does not result in toxic metabolite levels.

The agent is under development for exploration in a wide range of cancers. Specifically, a phase 3 trial is evaluating the use of NUC-3373 in combination with other drugs in the treatment of patients with colorectal cancer. Investigators expect to anticipate the first study participants in the second half of 2022.

Additionally, NUC-7738, a ProTide transformation of 3’-deoxyadenosine or cordycepin, has been shown to have strong antitumor activity in non-clinical studies.4 This agent is entering phase 2 development for exploration in patients with solid tumors and lymphoma, and data are expected in 2022.

References

1. NuCana announces update for phase 3 biliary tract cancer study. News release. NuCana plc; March 2, 2022. Accessed March 8, 2022. https://bit.ly/3vQfRYn
2. 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):TPS4164. doi:10.1200/JCO.2021.39.15_suppl.TPS4164
3. NUC-3373: a transformation of fluorouracil (5-FU). Nucana, plc. Accessed March 8, 2022. https://bit.ly/3sQztdd
4. NUC-7738: a transformation of 3’-deoxyadenosine (3’-dA). Nucana, plc. Accessed March 8, 2022. https://bit.ly/3Kjg3nc