San Francisco, CA—Cholangiocarcinoma (CCA), a type of biliary tract cancer, is a rare malignancy, with no FDA-approved medications specifically for this type of cancer. The current standard first-line treatment for patients with locally advanced or metastatic CCA is a chemotherapy combination of gemcitabine and cisplatin.
Of the approximately 18,000 individuals who are diagnosed annually in the United States with biliary cancer, an estimated 8000 are diagnosed with CCA, and the 5-year survival rate is less than 20%. CCA is often diagnosed at advanced stages, when treatment is only minimally effective, according to data from the Cholangiocarcinoma Foundation.
Given the poor prognosis of patients with CCA and the need for more effective therapies, several systemic treatments are being investigated for CCA. At the 2020 Gastrointestinal Cancers Symposium, researchers presented a poster that discussed the ongoing study called NuTide:121, which investigates the benefits of NUC-1031, a new treatment for CCA.
Study lead investigator Jennifer J. Knox, MD, MSc, FRCPC, Medical Oncologist, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada, discussed the study in an interview. NUC-1031 is different from other cancer therapies, Dr Knox said. This therapy uses ProTide technology to modify nucleoside analogs, in this case gemcitabine, to render them more effective chemotherapy drugs.
“It [NUC-1031] allows the active form of gemcitabine to get into cancer cells much more effectively and at higher levels. It does not rely on human equilibrative nucleoside cell transporter 1 (hENT-1) or other biochemical steps to activate,” Dr Knox explained.
“Studies show that as high as 30% of patients with biliary cancer are hENT-1-deficient and would have no benefit from receiving gemcitabine, one of the few active drugs used in biliary cancer,” she added.
Dr Knox noted that early studies with NUC-1031 alone or in combination with cisplatin showed higher-than-expected responses in patients, supporting that this mechanism is working, with no new or worsening side effects compared with gemcitabine. Results from phase 1/1b studies of NUC-1031 have shown promise: of 14 patients with advanced biliary tract cancer, 1 patient achieved complete response and 6 patients achieved partial responses.
The NuTide:121 Study
This multicenter, open-label, randomized, phase 3 clinical trial is comparing the investigational therapy NUC-1031 plus cisplatin versus gemcitabine plus cisplatin in patients with treatment-naïve, locally advanced or metastatic biliary tract cancer. The NuTide:121 study began to enroll and treat patients in December 2019.
The study will enroll a total of 828 patients aged 18 years or older with histologically or cytologically proved biliary tract cancer—including CCA, gallbladder, or ampullary cancer—who have not received systemic chemotherapy for locally advanced or metastatic disease.
Patients will be randomized in a 1:1 ratio to NUC-1031 725 mg/m2 plus cisplatin 25 mg/m2 or to gemcitabine 1000 mg/m2 plus cisplatin 25 mg/m2, to be administered on days 1 and 8 of a 21-day cycle. The study primary objectives are overall survival (OS) and objective response rate (ORR). The secondary objectives include further evaluation of overall efficacy, safety, pharmacokinetics, and patient-reported quality-of-life outcomes.
Interim and Final Analyses
Three interim analyses, including 2 designed to support accelerated FDA approval of NUC-1031, are planned as part of the study protocol in addition to the final analysis of the NuTide:121 study. The FDA approved the study launch in late 2019.
“The purpose of the early analysis is to see if there is a strong enough signal of efficacy (ie, response) to have accelerated approval by regulatory agencies while the overall survival data are still maturing,” said Dr Knox. “This is possible, in fact encouraged, as biliary cancer is considered an area of unmet need for drug development with the FDA and other regulatory agencies.”
The first interim analysis will evaluate the ORR at 22 weeks after 418 patients with measurable disease at baseline have been randomized. A significant difference in ORR would require the NUC-1031 arm to have at least 14% ORR higher than the gemcitabine arm.
The second interim analysis will evaluate the ORR and OS at 28 weeks after the randomization of 644 patients with measurable disease at baseline. A significant difference in ORR would require the NUC-1031 arm to have an approximately 9% higher ORR than the gemcitabine arm. If a significant difference in ORR is found, the OS will also be analyzed. A difference in median OS of approximately 3.4 months in the NUC-1031 arm would be deemed a statistically significant improvement in OS.
The third interim analysis will evaluate the OS after 541 events have been observed. A significant difference in OS in support of the NUC-1031 arm would be achieved with an improvement in median OS of approximately 2.6 months.
In the final analysis, researchers will evaluate the OS after 637 events have been observed. A significant improvement in OS in the NUC-1031 arm would be achieved with a median OS of approximately 2.2 months.
If the study is successful and NUC-1031 is granted FDA approval, Dr Knox said that the FDA would recommend that NUC-1031 plus cisplatin become a new standard of care for the first-line treatment of patients with advanced biliary tract cancer.
“The advantage for patients, doctors, and payers would be a more active and well-tolerated doublet combination that is easy to deliver and tolerate, with no unexpected toxicities,” said Dr Knox. “Other areas of research in biliary tract cancer are evaluating triplets and even 4 drugs in combination,” she said.
“These may also be more effective than the gemcitabine plus cisplatin standard but harder to deliver, more complex toxicity, and potentially more patient care costs.” Therefore, NUC-1031 “may achieve the same or more benefit with the simple doublet. It may also provide a better chemotherapy platform to add on biologics and immunotherapy in new studies than other tougher regimens,” she added.
The researchers are planning an innovative tumor and blood correlate component to this study that may shed better light on how best to optimize treatment for the subtypes of biliary tract cancer.
“This is a large international trial, and there is real potential to learn quite a lot to advance the field for these patients,” Dr Knox concluded.