Chemotherapy treatment of Colorectal Cancer, often include 5-Fluorouracil (5- FU). 5-FU inhibits the enzyme thymidylate synthase (TS), stopping the supply of thymidine for DNA synthesis. 5-FU is always combined with a folate, which enhances the 5-FU effect. Marketed folates such as LV/L-LV are prodrugs needing enzymatic conversion. Arfolitixorin (formerly Modufolin®) is the natural, biologically active form of the folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability.
ISO-CC-005 is a multi-center, phase I/II study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. The study investigates safety and tolerability of arfolitixorin at 4 dose levels by analysing the number and severity of AEs, SAEs and DLTs. Efficacy is evaluated as ORR after 4 cycles of chemotherapy. Gene expression, deoxyuridine levels as an indirect marker of TS inhibition and time to death is also investigated. 3-6 patients per cohort are included. All receives arfolitixorin twice every two weeks during at least 4 cycles of chemotherapy.
Today, 67 patients have been enrolled and 59 have initiated treatment. 13 are 1st line patients, 16 are in 2nd line, 10 are in 3rd line and 1 is in 5th treatment line. 27 SAEs have been reported in 13 patients, 6 of these were judged as at least possibly related to arfolitixorin. No SAE were judged as solely related to arfolitixorin. 49 patients have today been evaluated for efficacy. ORR 1st line patients (n = 14) at 8 weeks All 43% (6 PR, 7 SD, 1PD) Patients with arfolitixorin dose ≥60 mg/m2 56% (5 PR, 3 SD, 1 PD) Patients with arfolitixorin dose ≥60 mg/m2 + oxaliplatin 60% (3 PR, 1 SD, 1 PD).
The lack of need for metabolic activation makes arfolitixorin a better candidate than LV/L-LV for improved outcome of 5-FU-based chemotherapy regimens in mCRC. The ISO-CC-005 study evaluates arfolitixorin in combination with 5-FU, irinotecan, oxaliplatin ± bevacizumab in mCRC patients in 4 countries in Europe. The results, so far, for both safety and efficacy seems promising.
Clinical trial identification
EudraCT: 2014-001862-84; NCT02244632.
Legal entity responsible for the study
Isofol Medical AB.
Isofol Medical AB.
P. Pfeiffer: Advisory board member: Isofol Medical AB. H. Taflin: Family member is the founder of, have a leadership role, owns shares, have an advisory role, have conducted funded research, hold patents and have received travel expenses: Isofol Medical AB. L. Skintemo, K.M.E. Ganlöv: Employee, stock ownership: Isofol Medical AB. B. Gustavsson: Founder of, have a leadership role, owns shares, advisory role, conducted funded research, hold patents, received travel expenses: Isofol Medical AB. All other authors have declared no conflicts of interest.