Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer

Inclusion Criteria: Inclusion Criteria : 1. Signed and dated patient informed consent form (ICF) and willingness to comply with all study procedures and availability for the study duration, 2. Age ≥ 18 years, 3. Body weight \> 35 kg, 4. Eastern Cooperative Oncology Group performance status of 0 or 1, 5. Life expectancy ≥ 12 weeks, 6. Histologically confirmed carcinoma, 7. dMMR and/or MSI tumor status defined by: * Loss of MMR protein expression using immunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies, * and/or ≥ two instable markers by polymerase chain reaction using standard panels; 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 to normal tissue. 8. Documented advanced or metastatic disease not suitable for complete surgical resection, 9. Patients with unresectable or metastatic MSI cancer, intolerant to or progressive under or after at least one line of therapy, with no satisfactory alternative option 10. 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, 11. 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, 12. Baseline-corrected QT interval \< 470 ms 13. 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 and calculated creatinine clearance (Cockcroft-Gault) ≥ 45 mL/minute, \- Adequate liver function: * Serum bilirubin ≤ 1.5 x upper normal limit (ULN) or direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × 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, 14. Females of childbearing potential: \- Must have negative pregnancy test at screening , prior to each administration of investigational product and at each follow-up visit until 140 days after last treatment; * If sexually active with a nonsterilized male partner, must use at least one highly effective method of birth control from screening to 140 days after the last dose of MEDI5752 and monalizumab; * IT IS STRONGLY RECOMMENDED THAT nonsterilized male partners of female subjects of childbearing potential use a male condom plus spermicide from screening to 140 days after the last dose of MEDI5752 (Note: Male condoms are not reliable as a sole contraception method) * Refer to APPENDIX 18.1 : Definition of Women of Childbearing Potential for definitions of females of childbearing potential 15. Female subjects must not breastfeed and must not donate, or retrieve for their own use, ova from screening to 140 days after the last dose of MEDI5752 and monalizumab 16. Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 140 days after the last dose of MEDI5752 and monalizumab (Note: Male condoms are not reliable as a sole contraception method). IT IS STRONGLY RECOMMENDED THAT female partners of a male subject also use at least one highly effective method of contraception throughout this period. In addition, male subjects must refrain from fathering a child or donating sperm during the study and for 140 days after the last dose of MEDI5752 and monalizumab. 17. Registration in a national health care system (AME are not allowed). Exclusion Criteria: 1. Active brain metastases or known leptomeningeal metastases. 2. Other anti-cancer drugs and treatments: -Chemotherapy, targeted therapies, and immunotherapies \- Radiofrequency, radiotherapy 3. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy), 4. Major surgical procedure within 4 weeks prior to initiation of study treatment, 5. More than 3 prior lines of chemotherapy, 6. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents, 7. Patients receiving any investigational drug within the previous 21 days before study treatment, 8. Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons, 9. Patients with an active, known or suspected autoimmune disease. Can be enrolled: Patients with type I diabetes mellitus, hypothyroidism requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger, 10. History of interstitial lung disease or pneumonitis, 11. Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to treatment initiation. Treatment permitted in the absence of active autoimmune disease: Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent., 12. History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤ T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention 13. Evidence of the following infections: * Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination, and radiographic findings and TB testing in line with local practice), * or human immunodeficiency virus (HIV) (positive for HIV-1 or HIV-2 antibodies), * or active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV). Participants are eligible if they: * Have controlled hepatitis C viral load defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy, * Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis, * Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii below: * Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: HBV DNA viral load \<100 IU/mL Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT \<3 × ULN, which are not attributable to HBV infection Start or maintain antiviral treatment if clinically indicated as per the investigator. \- or active hepatitis A (refer to Section 5.7 for screening tests) 14. Prior allogeneic bone marrow transplantation or prior solid organ transplantation, 15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiomyopathy of any etiology, symptomatic congestive heart failure (as defined by New York Heart Association class \> 2), uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within the past 12 months, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent, 16. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of the subject's safety or study results 17. Known allergy/hypersensitivity to any component or excipients of study agents, 18. Administration of a (attenuated) live vaccine within 30 days of planned start of study therapy of known need for this vaccine during treatment, 19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 140 days after the last dose of Monalizumab and MEDI5752 20. Patient on tutelage or guardianship. 21. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 500 ms calculated from 3 ECG