Two Combination Treatment Regimens of Nivolumab and Ipilimumab in Patients With dMMR and / or MSI mCRC.

Inclusion Criteria

• •1. Signed and dated patient informed consent form and willingness to comply with all study procedures and availability for the study duration,
• •2. Age ≥ 18 years,
• •3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2,
• •4. Histologically or cytologically confirmed colorectal adenocarcinoma,
• •5. Documented advanced or metastatic disease not suitable for complete surgical resection,
• •6. At least one measurable lesion as assessed by CT-scan or magnetic resonance imaging (MRI) according to RECIST v1.1 and feasibility of repeated radiological assessments. Participants 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,
• •7. Deficient mismatch repair (dMMR) and/or Microsatellite instability (MSI) tumor status defined by:
• •* Loss of MMR protein expression using immunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies Nota Bene (NB): if loss of only one protein, necessary to have Polymerase Chain Reaction (PCR)
• •* and/or ≥ two instable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27), NB: if two instable markers in the pentaplex panel, it is required to present confirmation of the dMMR status by immunohistochemistry or a comparison of the tumor PCR test with matched normal tissue.
• •NB: Agreement of the Sponsor (GERCOR) is mandatory to include the patient (the patient's file will be verified to confirm MSI/dMMR status before inclusion \[an anonymized fax\] and confirmation of a patient's allocation will be sent by mail to the Investigator within 24h),
• •8. No or one prior line of systemic treatment for metastatic disease:
• •* No prior systemic treatment; if patient received neoadjuvant/adjuvant therapy this therapy should be completed \> 6 months prior the diagnosis of metastatic or recurrent disease is made,
• •* Maximum one prior line of systemic treatment; if patient received one prior line of systemic therapy in the metastatic setting and experienced progression or patient received neoadjuvant/adjuvant therapy and experienced recurrence within ≤ 6 months after completion of therapy,
• •9. Availability of a representative tumor specimen for exploratory translational research; tumor tissue specimens, either formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections (minimum of 30 positively charged slides) from primary or metastatic site must be submitted to the central laboratory,
• •10. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
• •\- Hematological status: White blood cell \> 2000/µL; Neutrophils \> 1500/µL; Platelets \> 100.000/µL; Hemoglobin \> 9.0 g/dL;
• •\- Adequate renal function: Serum creatinine level \< 150 µM;
• •\- Adequate liver function: Serum bilirubin ≤ 1.5 x upper normal limit (ULN); Alkaline phosphatase (ALP) ≤ 3 x ULN; Alanine aminotransferase (ALT) ≤ 3.0 x ULN ; Aspartame aminotransferase (AST) ≤ 3.0 x ULN; Prothrombin time (PT)/International normalized ratio (INR) and partial PT (PTT) ≤ 1.5 x ULN unless participants are receiving anticoagulant therapy and their INR is stable and within the recommended range for the desired level of anticoagulation,
• •11. Females of childbearing potential must have negative serum pregnancy test within 7 days before starting study treatment,
• •12. Women of childbearing potential should use effective contraception during treatment and 5 months thereafter. Males should use condoms during treatment and 7 months thereafter,
• •13. Registration in a national health care system ( "Protection Universelle Maladie" (PUMa) included).