NuTide:323 Study of NUC-3373 Regimen in Second-Line CRC is Discontinued

The phase 2 NuTide:323 trial (NCT05678257) evaluating NUC-3373, a novel chemical entity derived from 5-fluorouracil (5-FU; Tolak),in combination with leucovorin, irinotecan (Onivyde), and bevacizumab (Avastin) for the treatment of patients with colorectal cancer (CRC) in the second line has been discontinued.¹

This decision followed data from a preplanned initial analysis and a recommendation from the NuTide:323 Study Steering Committee, which contended that the combination was not likely to reach the study’s primary end point of progression-free survival (PFS) despite prognostic imbalances favoring the control arm. However, the regimen did display a favorable safety profile; across all 3 arms of the study (n = 175), only 12 patients discontinued treatment due to adverse effects (AEs).

“[Although] we are disappointed with this unexpected outcome, especially for [individuals] living with CRC, we gained valuable knowledge from the NuTide:323 study which will inform our ongoing development programs. We are extremely grateful to the study participants, their families, the investigators and study teams for their participation and efforts,” Hugh S. Griffith, MBA, founder and CEO of NuCana, stated in a news release.¹ “These results highlight the challenges associated with developing new medicines for patients with complex and heterogenous cancers such as metastatic CRC We will leverage insights from these data to identify future potential development options for NUC-3373 in CRC.”

“In the NuTide:323 study, we were aiming to develop NUC-3373 as a replacement for 5-FU, in combination with leucovorin, irinotecan and bevacizumab in patients with second-line colorectal cancer,” Josep Tabernero, MD, PhD, head of the Medical Oncology Department at the Vall d´Hebron University Hospital, Barcelona, and chair of the NuTide:323 Study Steering Committee, added in the news release. “The premise of this ambitious goal was based on robust non-clinical and clinical data and the NuTide:323 study team are very disappointed with this outcome.”

NuTide:323 was an open-label, dose/schedule optimization study that enrolled patients with unresectable metastatic CRC. To be eligible for the study, patients were required be at least 18 years of age, have a minimum life expectancy of 12 weeks, an ECOG performance status of 1 or less, and have known RAS, BRAF, and UGT1A1 mutation status.²

The study aimed to enroll approximately 182 patients. Upon enrollment, eligible patients were randomly assigned 1:1:1 to receive NUC-3373 plus leucovorin, irinotecan, and bevacizumab on a once-weekly NUC-3373 schedule, NUC-3373 plus leucovorin, irinotecan, and bevacizumab on a twice-weekly NUC-3373 schedule, or FOLFIRI plus bevacizumab on a twice-weekly dosing schedule. Beyond the primary end point of PFS, secondary end points included overall survival, safety, and objective response rate.

NUC-3373 is still being evaluated in the ongoing phase 1b/2 NuTide:302 (NCT03428958) and NuTide:303 (NCT05714553) studies. NuTide:302 is examining NUC-3373 in combination with leucovorin, irinotecan or oxaliplatin, and bevacizumab in patients with metastatic CRC. Meanwhile, NuTide:303 is investigating the agent in combination with pembrolizumab (Keytruda) for the treatment of patients with advanced solid tumors and with docetaxel in patients with lung cancer.¹

“NuCana remains committed to improving survival outcomes for patients with cancer,” Giffith added in the news release. “The results of the NuTide:323 study do not impact the ongoing NuTide:303 study, in which NUC-3373 is being combined with either pembrolizumab in solid tumors or docetaxel in patients with lung cancer. Furthermore, we are excited about the potential of NUC-7738, a novel agent that profoundly impacts gene expression in cancer cells and targets multiple aspects of the tumor microenvironment. We look forward to sharing the latest data from the phase 2 part of the [phase 1/2] NuTide:701 [NCT03829254] study of NUC-7738 in combination with pembrolizumab in patients with melanoma at the ESMO Annual Congress in September 2024.”

References

1. NuCana announces update for phase 2 randomized colorectal cancer study. News release. NuCana. August 29, 2024. Accessed August 30, 2024. https://ir.nucana.com/news-releases/news-release-details/nucana-announces-update-phase-2-randomized-colorectal-cancer
2. A study of NUC-3373 in combination with other agents in patients with colorectal cancer. ClinicalTrials.gov. Updated April 3, 2024. Accessed August 30, 2024. https://www.clinicaltrials.gov/study/NCT05678257