Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC

Inclusion Criteria: 1. Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 2. Male or female age more than 18 years 3. Performance status of 0 or 1 according to the ECOG and WHO 4. Histologically confirmed diagnoses of colorectal cancer with positive mutated KRas. 5. Patients with metastatic disease 6. First line therapy 7. Life expectancy of more than 12 weeks 8. Adequate normal organ and marrow function as defined below: * Haemoglobin \> 9.0 g/dL * Absolute neutrophil count (ANC) \> 1.5 x 109/L (\>1500 per mm3) * Platelet count \> 100 x 109/L (\>100,000 per mm3) * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN * Albumin \> 30g/L * Creatinine \< 1.5 X institutional upper limit of normal (ULN) * Serum creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance 9. Tumour evaluation in the previous 4 weeks with presence of at least one measurable lesion according to RECIST 1.1 criteria 10. At least 4 weeks since the last chemotherapy, immunotherapy or other drug therapy and / or radiotherapy 11. Recovery to grade ≤ 1 from any AE derived from previous treatment according to the criteria of the NCI-CTCAE version 4.0 12. Biopsable disease (for ancillary studies) or willingness to provide consent for use of archieved tissue for research purposes 13. Female subjects must either be of non-reproductive potential or must have a negative serum pregnancy test upon study entry 14. Patients must be affiliated to a social security system 15. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up Exclusion Criteria: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrolment in the present study 2. Participation in another clinical study with an investigational product during the last 4 weeks 3. Any previous treatment with a PD-1 or PD-L1 /CTLA-4 inhibitor, including durvalumab or tremelimumab 4. History of another malignancy within the 5 previous years with low potential risk for recurrence other than : * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ 5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 28 days prior to the first dose of study drug (14 days prior to the first dose of study drug for subjects who have received prior TKIs (e.g., erlotinib, gefitinib and crizotinib) and within 6 weeks for nitrosourea or mitomycin C). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.) 6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction 7. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid 8. Any history of hypersensitivity to durvalumab or tremelimumab, FOLFOX or their excipients 9. Any unresolved toxicity (CTCAE grade \>1) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy) 10. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1 11. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded 12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) 13. History of primary immunodeficiency 14. History of organ transplant that requires use of immunosuppressive 15. History of allogeneic organ transplant 16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; Clinically significant cardiovascular disease including: myocardial infarction within 6 months,, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia; history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, hypotension; rest limb claudication or ischemia within 6 months; active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent 17. Sever concurrent disease, or co-morbidity that in the judgment of the investigator, would make the patient inappropriate for enrolment 18. Ongoing treatment with CYP3A4 substrates or regularly taking of grapefruit juice 19. Known history of active tuberculosis 20. History of leptomeningeal carcinomatosis 21. Brain metastases or spinal cord compression 22. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab 23. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control 24. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results 25. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids 26. Subjects with uncontrolled seizures, 27. Subjects under guardianship, curatorship or judicial protection 28. Known allergy or hypersensitivity to IP or any excipient