Acelarin Study in Biliary Tract Cancer Terminated With No Survival Benefit

Acelarin (NUC-1031) plus cisplatin did not show overall survival (OS) benefit in patients with biliary tract cancer, leading to the discontinuation of the NuTide:121 study (NCT04163900), according to a press release from NuCana.¹

Despite showing a higher objective response rate (ORR) than cisplatin plus gemcitabine, acelarin plus cisplatin did not improve OS by at least 2.2 months in patients with advanced biliary tract cancer. Both ORR and OS were primary end points of the phase 3 trial.

“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, said in a statement. “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.”

Acelarin, or fosgemcitabine palabenamide, is a derivative of gemcitabine intended to improve efficacy by maximizing intratumoral active metabolites. Data from the phase 1b ABC-08 study (NCT02351765) of patients with advanced biliary cancer indicated that it was well-tolerated and had an ORR of 33%.²

In the phase 3 global, open-label NuTide:121 study, 828 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder, or ampullary cancer who had not received prior systemic chemotherapy were randomized 1:1 to receive either 725 mg/m² acelarin and 25 mg/m² cisplatin or 1000 mg/m² gemcitabine with the same dose of cisplatin on days 1 and 8 of 21-day cycles.³

Secondary end points of the study included progression-free survival, duration of response, and safety. Acelarin plus cisplatin was generally well tolerated by patients.¹

Following a preplanned futility assessment by the independent data monitoring committee at the first of 3 planned interim data cutoffs,³ the investigators determined that the OS benefit goal would not be met and NuCana announced that the study would be discontinued.

“Biliary tract cancer comprises a very difficult group of tumors to treat and developing effective therapies in this setting is extremely challenging,” said Jennifer J. Knox, MSc, MD, professor of medicine at the University of Toronto, clinician investigator at the Princess Margaret Cancer Centre, and chief investigator of the NuTide:121 study.¹ “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.”

Two other agents produced with NuCana’s ProTide transformation process are being evaluated in clinical trials for other disease types, according to Griffith. “NuCana remains committed to improving the survival outcomes for patients with cancer. Our other ProTides in clinical development, NUC-3373 and NUC-7738, are based on unique chemical entities with distinct modes of action and we expect numerous data readouts and development milestones throughout 2022.”

NUC-3373, a transformation of fluorodeoxyuridine-monophosphate, is being investigated in the phase 1b/2 NuTide:302 study (NCT03428958) of patients with colorectal cancer, as well as a phase 1/2 study (NCT02723240) of patients with advanced solid tumors. “In addition, we anticipate dosing the first patients in the phase 3 study of NUC-3373 combined with other agents for the treatment of patients with colorectal cancer in the second half of 2022,” Griffith stated.

The other agent, NUC-7738, is progressing in a phase 1/2 dose-escalation study (NCT03829254). “NUC-7738 is entering phase 2 development in patients with solid tumors and lymphoma and we expect to announce additional data in 2022,” Griffith concluded.

_References:

_{1. NuCana announces update for phase 3 biliary tract cancer study. NuCana. Published March 2, 2022. Accessed March 7, 2022. https://bit.ly/3IQuCy8}

_{2. McNamara MG, Bridgewater J, Palmer DH, et al. A phase Ib study of NUC-1031 in combination with cisplatin for the first-line treatment of patients with advanced biliary tract cancer (ABC-08). Oncologist. 2021;26(4):e669-e678. doi:10.1002/onco.13598}

_{3. Knox J, McNamara MG, Goyal L, Cosgrove D, et al. 59TiP - Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121). Ann Oncol. (2021) 32 (suppl_5): S376-S381. 10.1016/annonc/annonc685}