This is a multicenter, randomized, parallel-group, Phase III study in at least 440 patients with advanced colorectal cancer to compare the efficacy of treatment with arfolitixorin versus Leucovorin in combination with 5-fluorouracil, oxaliplatin, and bevacizumab according to modified FOLFOX-6 until PD according to RECIST 1.1 criteria.

Inclusion Criteria:

1. Colorectal adenocarcinoma verified by biopsy.
2. Availability of biopsy material, from the primary tumor or metastasis, allowing for analysis of tumor gene expression.
3. Non-resectable metastatic CRC planned for first line therapy with 5-FU, Leucovorin, oxaliplatin, and bevacizumab.
4. Evaluable disease with at least one measurable lesion of metastatic disease (≥10 mm in longest diameter on axial image on CT-scan or alternatively MRI with <5 mm reconstruction interval) or lymph node (≥ 15 mm in shortest axis when assessed by CT) obtained within 28 days of randomization.
5. Life expectancy of more than 4 months.
6. ECOG performance status 0 or 1.
7. Hemoglobin (Hb) > 80 g/L, Absolute neutrophil count (ANC) > 1.5x10E9/L. Thrombocytes > 100x10E9/L.
8. Creatinine clearance > 50 mL/min, Total bilirubin < 1.5 x ULN, AST and ALT < 3 x ULN (and < 5 x ULN in case of liver metastases).
9. Male or female ≥18 years of age.
10. Female patients of childbearing potential must have a negative urine pregnancy test and use adequate contraceptive measures . Male patients must use adequate contraceptive measures .
11. Voluntarily signed informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Malignant tumors other than colorectal adenocarcinomas (current or within the previous five years), with the exception for curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix.
2. Less than 6 months between randomization and completion of the last anti-cancer treatment (chemotherapy/radiotherapy/immunotherapy, etc.). (NB: Rectal cancer treatment shorter than 8 weeks of chemo/radiation therapy is allowed.)
3. Confirmation of progressive disease within 6 months after completion of prior adjuvant anti-cancer treatment.
4. Indication for any metastatic Colo-rectal Cancer (mCRC) surgery or anti-cancer treatment other than study treatment.
5. Prior treatment with arfolitixorin.
6. Indication for treatment with a 5-FU analogue, or 5-FU for a condition other than mCRC.
7. Known Dihydropyrimidine Dehydrogenase Deficiency (DPD) deficiency.
8. Known or suspected central nervous system (CNS) metastases.
9. Unresolved bowel obstruction, uncontrolled Crohn's disease, or ulcerative colitis.
10. History of cardiac disease with a New York Heart Association Class II or greater, congestive heart failure, myocardial infarction, or unstable angina at any time during the 6 months prior to randomization, or serious arrhythmias requiring medication for treatment.
11. Current CTCAE ≥ grade 3 diarrhea.
12. Current chronic infection or uncontrolled serious illness causing immunodeficiency.
13. Known or suspected hypersensitivity or intolerance to arfolitixorin, LV, 5-FU, oxaliplatin, or bevacizumab.
14. Breastfeeding patients.
15. Patient who received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug, prior to randomization.
16. Patient with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
17. Ongoing drug or alcohol abuse, as deemed by the Investigator.
18. Any condition that, in the opinion of the Investigator, could compromise the patient's safety or adherence to the study protocol.
19. Involvement, or related to people involved in the planning or conduct of the study (applies to both Isofol Medical AB (publ) staff and staff at the study site)
20. Surgery (excluding previous diagnostic biopsy) in the 28-day period before randomization