Background: 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. 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 Methods: 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 Modufolin at 4 dose levels by analysing the number and severity of AEs, SAEs and DLTs. Efficacy is evaluated as ORR after four cycles of chemotherapy. Gene expression, deoxyuridine levels as an indirect marker of TS inhibition and time to death is also investigated. Three to six patients per cohort are included. All receives Modufolin twice every two weeks during at least four cycles of chemotherapy. Results: Today, 42 patients have been enrolled and 40 have initiated treatment. 13 are 1^st line patients, 16 are in 2^nd line, 10 are in 3^rd line and 1 is in 5^th treatment line. 19 SAEs have been reported in 12 patients, 3 of these were judged as at least possibly related to Modufolin. No SAE were judged as solely related to Modufolin. 31 patients have today been evaluated for efficacy. ORR 1^st line patients (n=12) All 50% (6 PR, 6 SD) Patients with Modufolin dose ≥60 mg/m2 71% (5 PR, 2 SD) Patients with Modufolin dose ≥60 mg/m2 + oxaliplatin 100% (3 PR) Conclusions: The lack of need for metabolic activation makes Modufolin a better candidate than LV/L-LV for improved outcome of 5-FU-based chemotherapy regimens in mCRC. The ISO-CC-005 study evaluates Modufolin 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 information: NCT02244632