NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer

Inclusion Criteria: 1. Have provided written informed consent prior to any study specific procedures 2. Willing and able to comply with the protocol 3. ≥18 years of age 4. ECOG status 0 - 1 5. At least 12 weeks of life expectancy at time of entry into the study 6. Histologically confirmed metastatic or inoperable adenocarcinoma of the colon and/or rectum, with centrally confirmed mismatch repair proficiency (microsatellite stable \[MSS\]) by multiplex polymerase chain reaction (PCR), MGMT promoter methylation by methylation-specific PCR (MSP) and MGMT low expression by IHC 7. Patients with progressive disease or that are not candidate for oxaliplatin irinotecan fluoropirimidin based chemotherapy and anti EGFR mAbs (in RAS/BRAF wild type tumors) in the metastatic setting 8. Patients with documented disease relapsed within 6 months from the completion of adjuvant oxaliplatin-based chemotherapy are considered eligible 9. Measureable, unresectable disease according to RECIST 1.1. Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately. 10. Is willing and able to provide an adequate archival tumor sample (FFPE) available for tissue screening for central tissue screening. If the tumour block is not available, a minimum of twenty 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. Inability to swallow pills 3. Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption 4. Inadequate haematological function indicated by all of the following: * White Blood Cell (WBC) count \< 2 x 109/L * Absolute neutrophil count (ANC) \< 1.5 x 109/L * Platelet count \< 100 x 109/L * Haemoglobin \< 9 g/dL (patients may have transfusions and/or growth factors to attain adequate Hb) 5. Inadequate liver function indicated by all of the following: * Total bilirubin ≥ 1.5 x upper limit of normal (ULN) * Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≥ 3 x ULN (≥ 5 x ULN in patients with known liver metastases) * Alkaline phosphatase (ALP) ≥ 2 x ULN (≥ 5 x ULN in patients with known liver metastases) 6. Inadequate renal function indicated by all of the following: \- Serum creatinine \> 1.5 x ULN or calculated creatinine clearance \< 40 ml/min 7. INR \> 1.5 and aPTT \> 1.5 x ULN within 7 days prior to the start of study treatment for patients not receiving anti-coagulation a. NOTE: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the start of study treatment 8. Active infection requiring intravenous antibiotics at the start of study treatment 9. Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast, or other cancer for which the patient has been disease-free for three years prior to study entry 10. Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results 11. Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to start of study treatment, myocardial infarction ≤ 6 months prior to study enrolment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment 12. History or evidence upon physical or neurological examination of central nervous system (CNS) disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy 13. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Cases should be discussed with the medical monitor. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\>10mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. 14. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to start of study treatment, or anticipation of need for major surgical procedure during the course of the study. 15. Treatment with any chemotherapy, curative intent radiation therapy, biologics for cancer, or investigational therapy within 28 days of first administration of study treatment (subjects with prior cytotoxic or investigational products \< 4 weeks prior to treatment might be eligible after discussion between investigator and sponsor, if toxicities from the prior treatment have been resolved to Grade 1 (NCI CTCAE version 4). Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration. 16. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll. 17. Known hypersensitivity to any of the study medications or Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of the NIVO formulation 18. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 19. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix IV for a more comprehensive list of autoimmune diseases) a. Note: history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Subjects with controlled type I diabetes mellitus on a stable insulin regimen, vitiligo or psoriasis not requiring systemic treatment may be eligible. 20. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 21. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on Screening chest CT scan 22. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to start of study treatment 23. Treatment with systemic corticosteroids (\>10 mg daily prednisone equivalents) or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor \[TNF\] agents) within 2 weeks prior to start of study treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed. a. Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Sponsor. 24. Positive test for human immunodeficiency virus (HIV) 25. Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test prior to randomization) or hepatitis C 1. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients with detectable HBV-DNA are not eligible. 2. Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA). 26. Active tuberculosis 27. Administration of a live, attenuated vaccine within 4 weeks prior to start of study treatment or anticipation that such a live attenuated vaccine will be required during the study 28. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines. 29. Pregnancy or lactation. A serum pregnancy test is required within 7 days prior to start of study treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior start of study treatment 30. For women who are not post-menopausal (\< 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): refusal to use a highly effective contraceptive method (i.e. with a failure rate of \< 1% per year such as sexual abstinence, hormonal implants, combined oral contraceptives, vasectomised partner), during the study drug administration and for at least 6 months after the last dose of study medication. Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception. A combination of male condom with cap, diaphragm or sponge with spermicide (double barrier methods) is not considered highly effective, birth control methods. Acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. A Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success. 31. For men: refusal to use a highly effective contraceptive method (i.e. with a failure rate of \< 1 % per year such as vasectomy, sexual abstinence or female partner use of hormonal implants or combined oral contraceptives) during the study drug administration and for a period of at least 6 months after the last dose of study medication. Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post ovulation methods\] and withdrawal are not acceptable methods of contraception. A combination of male condom with either, cap, diaphragm or sponge with spermicide (double barrier methods) is not considered highly effective, birth control methods. Acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. A vasectomised trial participant is a highly effective birth control method provided that the trial participant has received medical assessment of the surgical success.