The AGENT study
The AGENT study is a randomized, controlled, multi-centre study assessing the efficacy and safety of arfolitixorin, [6R]-5,10-methylene-THF acid (MTHF), compared to leucovorin, both used in combination with 5- FU, oxaliplatin, and bevacizumab, in first line metastatic colorectal cancer patients. Patients are randomized in a 1:1 ratio.
The primary focus of the study will be to measure the percentage of patients who experience tumour size reduction, (Objective Response Rate, ORR). The secondary endpoint will be the measurement of Progression Free Survival (PFS), i.e. the time until the tumour begins to grow again or the patient dies.
The statistically significant is to show an improvement in tumor shrinkage in the patients treated with arfolitixorin compared to those treated with leukovorin by at least 10 percentage points. At the same time, we at least want to see a positive trend in progression-free survival.
The study is designed to show superiority for arfolitixorin over leucovorin. The study is ongoing at approximately 90 sites in the U.S., Canada, Europe, Australia and Japan. Further information about the study, including patient eligibility requirements, is available at www.clinicaltrials.gov id: NCT03750786.
The study will have two treatment arms: the first group will be treated with arfolitixorin, and the second, with leucovorin (today’s folate-based treatment), both in combination with the 5-FU and oxaliplatin chemotherapeutic agents and the biological therapy, bevacizumab (Avastin), see illustration below.
The interim analysis is based on 330 patients and was initiated when the 330th patient had been treated for 16 weeks and had two tumor evaluations. The independent Data Safety and Monitoring Board (iDSMB) has evaluated safety and efficacy (ORR and PFS). iDSMB has recommended Isofol to continuation the AGENT study with 440 patients, in accordance with the study design. Isofol remains blinded to the interim analysis results.
Recruitment of Japanese patients completed
The Japanese medical products agency, the PMDA set a specific requirement for the number of participating Japanese patients to a total of 56 Japanese patients in the AGENT-study. The rationale for the specific requirement from PMDA is e.g. that the metabolism of Japanese patients tends to differ from patients in other countries, which is why the effect and potential side effects must be investigated separately. We have had 15 sites in Japan that have recruited patients and in May 2021 we announced that 56 patients had been recruited and that inclusion in the study was closing.
Of the 56 patients, 14 was already included in the primary recruitment of 440 patients in the AGENT-study. The full patient population, including the entire Japanese cohort, will be included in PMDA’s assessment for a potential market approval in Japan.
Fast Track Designation Granted
The Food and Drug Administration (FDA) in USA has granted a Fast Track Designation (FTD) for the development of arfolitixorin. The FDA’s decision is based on the potential for arfolitixorin to address a large unmet medical need for new and more effective treatments of mCRC, the second deadliest and third most common form of cancer. A Fast Track Designation facilitates frequent communication with the FDA and can result in expedited review timelines and a potential earlier market authorization, all with the aim to make new treatments available more quickly to patients with serious diseases. Read more in the press release >>
In December 2020, the last of the AGENT study’s 440 patients was recruited, which is the basis in the statistical analysis plan. Recruitment then continued in Japan to reach 56 Japanese patients, who have now been included in the study. This means that Isofol’s application to the FDA will be based on the analysis of 490 patients enrolled in the study.
In April 2022, the analysis process of study data in the AGENT study began, which means work on compiling, quality assurance and conducting statistical analyses. Top-line results from studies were presented at the beginning of August 2022 (read more in the press release) and analysis of the final data is now underway. After that, Isofol will communicate with regulatory authorities and present the data.
The AGENT study is stopped
Isofol assesses that it is not justified to continue the AGENT study (read the press release). Based on that the company have received access to additional study data and performing further data analysis, Isofol’s assessment that the conclusions related to the endpoints objective response rate (ORR) and progression-free survival (PFS) that were presented in connection with top line results on August 3 will not change. However, the analysis indicates that both arms of the AGENT study performed well for all-comer patients with non-operable metastatic colorectal cancer (mCRC), irrespective of mutational status, in relation to today’s standard of care. Isofol will continue to further analyze the study data as it becomes available in order to compile a final study report. This report will consist of, among other things, analysis of subgroups and gene expression as well as additional safety data. Patients who are still being treated in the experimental arm of the study will therefore be offered the opportunity to switch to standard of care and follow-up of patients will thereby be terminated. Review of study data will continue until the company can compile the final study report which is estimated to take place during the fourth quarter of 2022.
Last updated 09-06-2022