5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

(applies to phase 2 part) Inclusion criteria 1. Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum. 2. Confirmed MGMT promoter methylation by PSQ (\> 5%) and absent MGMT expression by immunohistochemistry. 3. Locally assessed pMMR or MSS status. 4. Written informed consent obtained prior to any study procedures. 5. Availability of archival tumor tissue (primary tumor and metastases or at least one of the two) for confirmation of MGMT, MMR/MSI status and biomarker analyses. 6. Availability of blood sample for biomarker analysis. 7. Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease. 8. At least one measurable lesion according to RECIST 1.1. 9. Age ≥ 18 and less or equal than 75 years. 10. ECOG PS ≤ 1 if patient \< 70 years old; ECOG PS 0 if patient 70-75 years old. 11. Life expectancy of at least 12 weeks. 12. Previous (neo)adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed only if more than 6 months elapsed between the end of (neo)adjuvant therapy and first evidence of disease relapse. 13. Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥ 9 g/dl. 14. Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or \<5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases). 15. Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL. 16. Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of amenorrhea, a single FSH measurement is insufficient. 17. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must be willing to use adequate contraception as approved be the Investigator (barrier contraceptive measure or oral contraception) as outlined in Section 7.6, starting with the screening visit and through 6 months after the last treatment dose. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 18. Will and ability to comply with the protocol. 19. Is willing and able to provide an adequate archival tumor sample (FFPE) available for molecular screening and exploratory analyses. If the tumor block is not available, a minimum of 25 3-micron unstained sections on charged slides of tumor will be required. Exclusion criteria 1. Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications. 2. Metastatic disease deemed R0 resectable upfront or after induction therapy by means of multidisciplinary team assessment. 3. Radiotherapy to any site within 4 weeks before the study. 4. Presence of one of the following: DPYD2a (c.1905+1G\>A); DPYD13 (c.1679 T\>G); DPYD D949V (c.2846 A\>T); DPYD IVS10 (c.1129-5923 C\>G). 5. Presence of one of the following UGT1A1 1(TA)6/UGT1A1 36(TA)5; UGT1A1 28(TA)7/UGT1A1 37(TA)8 (homozygous genotype). 6. In the dose escalation phase, untreated brain metastases or spinal cord compression or primary brain tumors; in the dose expansion phase, known history of brain metastases. 7. History or evidence upon physical examination of central nervous system disease unless adequately treated.8. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration. 9\. Evidence of bleeding diathesis or coagulopathy. 10. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy. 11\. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication. 12\. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment. 13\. Any previous venous thromboembolism ≥ NCI CTCAE Grade 4. 14. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment. 15\. Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer). 16\. Other co-existing malignancies or malignancies diagnosed within the last 3 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ. 17\. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication. 18\. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs. 19\. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies. 20\. Pregnant or lactating women.