The AGENT study (Phase III)

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.

Treatment arms

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.

Interim analysis

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.

Final analysis

In December 2020, the last of the AGENT study’s 440 patients was recruited, which is the basis in the statistical analysis plan. Recruitment has since continued in Japan to reach 56 Japanese patients. Isofol is now focusing on completing the ongoing AGENT study where the patients receive first-line standard treatment for metastatic colorectal cancer (mCRC). The company expects that the final results of the AGENT study will be available during H1 2022.

 

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.