FDA Grants Fast Track Status to NUC-1031 for Biliary Tract Cancer

FDA

The FDA has granted a fast track designation to the first-in-class nucleotide analogue NUC-1031 (Acelarin) for use as a potential therapeutic option in the frontline treatment of patients with advanced biliary tract cancer, according to an announcement from NuCana plc.¹

NUC-1031 represents a new class of anticancer agents that was designed to overcome gemcitabine resistance mechanisms.² The agent is comprised of gemcitabine and a phosphoramidate moiety; the addition of this moiety alters the chemical properties of the agent which allows for the molecule to enter the cancer cell independently of nucleoside transporters.³ The molecule is protected from breakdown of deaminases and delivers the preactivated form of gemcitabine.

NUC-1031 has been found to have greater plasma stability than gemcitabine, at 8.3 hours vs 1.5 hours, respectively; increased intracellular levels of dFdCTP, an active anticancer metabolite; and less toxic metabolites.

The agent is now being examined in combination with cisplatin vs gemcitabine and cisplatin in the frontline treatment of patients with advanced biliary tract cancer as part of the phase 3 NuTide:121 trial (NCT04163900).⁴

“We are very pleased that the FDA recognizes the potential of [NUC-1031] to address the significant unmet need of patients with biliary tract cancer,” Hugh S. Griffith, founder and chief executive officer of NuCana, plc, stated in a press release. “We recently announced enrollment of 418 evaluable patients in our phase 3 study, which is expected to enable the first interim analysis in the first half of 2022. This has the potential to allow for an accelerated approval of a new drug application for [NUC-1031] in the United States. With both fast track and orphan drug designations in place, we look forward to working closely with the FDA in our efforts to gain approval for [NUC-1031] as the first approved frontline treatment option for patients with biliary tract cancer.”

To be eligible for enrollment to the phase 3 trial, patients need to have previously untreated histologically- or cytologically-confirmed adenocarcinoma of the biliary tract that is locally advanced, unresectable, or metastatic. Patients also needed to be 18 years of age or older, have a life expectancy of 16 weeks or longer, an ECOG performance status of 0 or 1, and acceptable biliary drainage without evidence of ongoing infection.

Randomization strata include measurable disease, metastatic disease, anatomic site of disease, and geography.

Study participants are receiving either NUC-1031 at 725 mg/m² and cisplatin at 25 mg/m² on days 1 and 8 of a 21-day cycle or gemcitabine at 1000 mg/m² and cisplatin at 25 mg/m² on days 1 and 8 of a 21-day cycle.

The primary end points of the trial are overall survival and objective response rate (ORR), and key secondary end points include progression-free survival, duration of response, safety, pharmacokinetics, and quality of life.

Previously, NUC-1031 was found to have early clinical activity in heavily pretreated patients with platinum-resistant ovarian cancer, according to preliminary findings from the phase 2 PRO-105 trial (NCT03146663).⁵

The randomized, open-label, 2-part PRO-105 trial was designed to determine the optimal dose of NUC-1031 in patients with platinum-resistant ovarian cancer who received 3 or more lines of chemotherapy.⁶ The trial enrolled heavily pretreated patients who received a median of 5 prior lines of therapy, and 72% of them had at least 1 comorbidity at the time of study entry.

In part 1 of the trial, patients were randomized to 1 of the 2 exploratory doses of NUC-1031: 500 mg/m2 or 750 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle. Randomization was stratified for both BRCA1/2 mutational status as well as the number of prior lines of chemotherapy that had been received.⁷

The primary end point was ORR at the selected dose level of either 500 mg/m2 or 750 mg/m2, as assessed by blinded independent central review. DOR, progression-free survival, overall survival, pharmacokinetics, and patient-reported outcomes are among the trial’s secondary end points.

Of 45 evaluable patients, NUC-1031 monotherapy elicited a complete response in 1 patient, partial responses in 2 patients, based on an assessment by blinded independent central review. Stable disease was achieved in 16 patients who received the agent.

In the 23 patients who were given 2 or more cycles of NUC-1031, the confirmed objective response rate was 13% and the disease control rate was 83%. However, these findings are preliminary and thus, are subject to change, according to NuCana plc.

Moreover, 45% of patients were unable to complete the first cycle of treatment with NUC-1031, despite the fact that they did not have progressive disease or any serious grade 3/4 adverse events.

For part 2 of the trial, investigators had planned to examine the safety more closely, along with the pharmacokinetics, dosing intensity, and clinical activity of the agent in an expansion cohort. However, NuCana has decided against proceeding with part 2 of the PRO-105 trial. Instead, the company will be focusing its resources on exploring the agent’s use in biliary tract cancer and examining NUC-3373, a ProTide transformation of fluorouracil, in colorectal cancer.

References

1. NuCana receives fast track designation from the US Food and Drug Administration for Acelarin (NUC-1031) for the treatment of biliary tract cancer. News release. NuCana plc. September 29, 2021. Accessed September 29, 2021. https://bit.ly/3mdUKZG
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. Acelarin NUC-1031: a transformation of gemcitabine. NuCana plc. Accessed September 29, 2021. https://bit.ly/2ZD0Yux
4. Comparing NUC-1031 plus cisplatin to gemcitabine plus cisplatin in patients with advanced biliary tract cancer. ClinicalTrials.gov. Updated September 13, 2021. Accessed September 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04163900
5. NuCana reports preliminary data from phase II study of single-agent Acelarin (NUC-1031) in patients with platinum-resistant ovarian cancer. News release. NuCana plc. March 10, 2020. Accessed September 29, 2021. https://bit.ly/33fcs52
6. NUC-1031 in patients with platinum-resistant ovarian cancer. ClinicalTrials.gov. Updated January 14, 2020. Accessed September 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03146663
7. Gourley C, Dalton HJ, Banerjee SN, et al. PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2018;36(suppl 15):TPS5612. doi:10.1200/JCO.2018.36.15_suppl.TPS5612