Acelarin ascends to Phase 3

NuCana announces first patients dosed in Phase 3 Acelarin (NUC-1031) study for biliary tract cancer 

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SAN FRANCISCO—NuCana plc announced today that the first patients have been dosed in the company’s Phase 3 study of Acelarin (NUC-1031) plus cisplatin for first line treatment of patients with biliary tract cancer.
NuCana also recently presented a poster, entitled “NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121),” at the ASCO-GI Conference in San Francisco. The poster detailed the study design of NuTide:121 and reviewed the encouraging results previously reported in the Phase 1b ABC-08 study. 
“We are pleased to have commenced dosing the first patients in our Phase 3 NuTide:121 study,” said Hugh Griffith, NuCana’s chief executive officer. “Acelarin in combination with cisplatin has been shown in early clinical studies to achieve higher response rates compared to the current standard of care in patients with advanced biliary tract cancer, a devastating disease for which there is a significant need for more effective medicines.”
NuTide:121 is a global, multi-center, randomized Phase 3 study enrolling up to 828 patients in approximately 120 sites across North America, Europe, Asia and Australia. Patients are being randomized 1:1 and treated with either a combination of Acelarin (725 mg/m2) plus cisplatin (25 mg/m2) or the current standard of care regimen, gemcitabine (1,000 mg/m2) plus cisplatin (25 mg/m2). The primary objectives of NuTide:121 are overall survival (OS) and objective response rate (ORR). Three interim analyses — including two designed to support accelerated approval — are planned as part of the Phase 3 study protocol, in addition to the final analysis.
Biliary tract cancer, including cholangiocarcinoma, gallbladder and ampullary carcinoma, is cancer which originates in the bile duct. Approximately 178,000 new cases of biliary tract cancer are diagnosed each year. There are currently no agents approved for the treatment of biliary tract cancer; the worldwide standard of care in biliary tract cancer patients with locally advanced or metastatic disease is the combination of gemcitabine and cisplatin. Patients receiving this regimen have a median overall survival of 11.7 months.
Acelarin “is comprised of a ‘pre-activated’ nucleotide analog (gemcitabine monophosphate) and a protective phosphoramidate moiety, which is a specific combination of an aryl, ester and amino acid grouping,” according to NuCana’s website. “This chemical structure profoundly changes the dynamic properties of the molecule, enabling Acelarin to enter the cancer cell independent of membrane transporters and protecting it from both extracellular and intracellular degradation.”
“Once Acelarin has entered the cancer cell, the moiety is optimally cleaved off, resulting in ‘deprotection’ and the release of an activated, phosphorylated form of gemcitabine, dFdCMP. Accordingly, the activating enzyme, dCK, which drives the rate-limiting phosphorylation of gemcitabine, is no longer required and the cancer cells’ deficiency of dCK does not result in resistance to Acelarin, as it does with gemcitabine,” continues the website. “The activated nucleotide analog, dFdCMP, is then rapidly converted to the diphosphate, dFdCDP, and then to the key anti-cancer triphosphate metabolite, dFdCTP. As a result, Acelarin achieves much higher intracellular levels of dFdCTP inside the patients’ cells than gemcitabine.”
Acelarin is currently being evaluated in four clinical studies, including a Phase 3 study for patients with biliary tract cancer, a Phase 1b study for patients with biliary tract cancer, a Phase 2 study for patients with platinum-resistant ovarian cancer and a Phase 3 study for patients with metastatic pancreatic cancer, for which enrollment has been suspended.
The enrollment of patients in NuTide:121 follows the U.S. Food and Drug Administration (FDA) clearance of NuCana’s investigational new drug application for Acelarin. Based on discussions with the FDA, NuCana believes that a statistically significant improvement in ORR at either of the first two interim analyses, supported by positive trends in other endpoints, could potentially allow for an accelerated approval of a new drug application (NDA) for Acelarin. Accelerated approval requires a confirmatory clinical study to verify the drug’s clinical benefit. If accelerated approval were to occur, NuCana anticipates that data from subsequent analyses could provide the confirmatory data to support full, regular approval.

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