First Patient Enrolled in Phase III Study of Novel Agent Arfolitixorin in mCRC

The first patient has been enrolled in the pivotal phase III AGENT trial, which is investigating arfolitixorin in combination with 5-fluorouracil (5-FU), oxaliplatin, and bevacizumab (Avastin) compared with FOLFOX plus bevacizumab in patients with metastatic colorectal cancer (mCRC), according to Isofol Medical AB, the company developing arfolitixorin.

Arfolitixorin, [6R]-5,10-methylene-tetrahydrofolic acid, is being developed to increase the efficacy of 5-FU, which has been shown to be a cytotoxic agent, as well as a rescue drug after methotrexate treatment. Arfolitixorin is the key active metabolite in leucovorin and levoleucovorin and does not require metabolic activation to exert effect.

The multicenter, randomized, controlled study (NCT03750786) will enroll approximately 440 patients aged 18 years and over who have mCRC. Patients will be randomized 1:1 to receive either arfolitixorin or leucovorin in combination with 5-FU, oxaliplatin, and bevacizumab.

"I am very pleased to announce the enrollment of the first patient in the AGENT study, which to date is the most important achievement in accelerating the development of arfolitixorin towards a market registration," said Anders Rabbe, the CEO of Isofol.

The AGENT trial aims to assess the efficacy and safety of arfolitixorin compared with leucovorin in the first-line treatment of patients with mC-RC. The primary endpoint of the trial is overall response rate, and key secondary endpoints are progression-free survival and duration of response. Additional secondary endpoints include overall survival, number of curative metastasis resections, safety, and patient-reported outcomes, such as quality of life. Investigators will also look at pharmacokinetic measurements and level of gene expression of folate-relevant genes in tumor cells as exploratory endpoints.

To be included in the study, patients must have an ECOG performance status of 0 or 1, hemoglobin >100 g/L, absolute neutrophil count >1.5 x 10⁹L, and thrombocytes >100 x 10⁹L. A creatinine clearance of >50 mL/min, total bilirubin <1.5 times the upper limit of normal, and alanine and aspartate aminotransferase levels <3 times the upper limit of normal are also required. Patients are not eligible to be included in the study if they have previously been treated with arfolitixorin, if it has been less than 6 months between randomization and completion of the last anti-cancer treatment, or if they have known or suspected central nervous system metastases.

Patients will be enrolled at approximately 80 sites in the United States, Canada, and Western Europe. The first patient was enrolled at Pinellas Hematology Oncology Clinic in Saint Petersburg, Florida. Topline data from the study is expected to be available in 2021.

"We are now looking forward to quickly ramping up enrollment to meet the interest from participating hospitals and physicians. Arfolitixorin, which has shown promising efficacy and good safety, is an important new treatment option for patients since few new therapeutic agents have been introduced in first-line treatment of mCRC the last decade," said Karin Ganl&ouml;v, MD, the chief medical officer of Isofol.

Arfolitixorin has previously shown promise as a superior option over leucovorin for improving outcomes with 5-FU—based regimens. In findings presented at the 2018 European Society of Medical Oncology Annual Congress in October from a phase I/II study of arfolitixorin in combination with 5-FU, irinotecan, oxaliplatin, and bevacizumab, investigators reported promising efficacy and safety with the regimen.

Among 49 patients evaluated for efficacy, 56% of patients who received a dose of arfolitixorin &ge;60&thinsp;mg/m²had a response, including 5 patients with a partial response and an additional 3 who achieved stable disease, and 60% who received a dose of arfolitixorin &ge;60&thinsp;mg/m²plus oxaliplatin had a response, with 3 partial responses and 1 patient who had stable disease.

Reference:

Carlsson G U, Guren T K, Haux J, et al. ISO-CC-005; A Phase I/II study of arfolitixorin (MTHF) in combination with 5-FU, irinotecan, and oxaliplatin&plusmn; bevacizumabin patients with metastasizing colorectal cancer.Ann Oncol.2018;29(suppl 8; abstr 569P). doi: 10.1093/annonc/mdy281.115.