Dostarlimab for Locally Advanced or Metastatic Cancer (non-colorectal/non-endometrial) with Tumor DMMR/MSI

Inclusion Criteria:

1. Patient must have signed a written informed consent form prior any trial specificprocedures. -

2. 18 years or older patients.

3. Documented locally advanced or metastatic disease with no previous systemicanti-cancer treatment in these settings and not suitable for complete surgicalresection.

4. Histologically proven, dMMR/MSI-H solid tumors that are not colorectal orendometrial cancers and including one of the following: duodenum and small boweladenocarcinoma, gastric and oeso-gastric junction adenocarcinoma with CPS<5,pancreatic adenocarcinoma, ampulla of Vater adenocarcinoma, adrenocorticalcarcinoma, carcinoma of unknown primary site, neuroendocrine carcinoma (Grade 3) allprimary, and soft tissue sarcoma except Gastro-Intestinal Stromal Tumor (GIST).

5. If patient received adjuvant therapy for non-metastatic disease, this therapy shouldbe completed more than 6 months before the diagnosis of metastatic or recurrentdisease.

6. Availability of minimum 1 block of tumor tissue or 20 slides (archival (<2 years) orfresh biopsy specimen of primary and or metastasis) for centralized confirmation ofMMR/MSI status by IHC or NGS/PCR, and for Translational Research.

7. Patients with dMMR/MSI tumor analyzed by IHC, PCR (for Gastric and OGJadenocarcinoma, and duodenum and small bowel adenocarcinoma only), and/or NGS at therecruiting center should be confirmed by central review within 24h (every anonymizedpatient analysis reporting will be provided for central review). Patients should notbe included in the study until the dMMR/MSI status is confirmed by the reviewcommittee. NB: In case of ambiguous result of IHC (lack of positive internal control,heterogeneous loss of MMR protein expression, ambiguous loss of only one proteinincluding HMSH6 and PMS2), the MSI-H status will be assessed by PCR or NGS forgastric and OGJ adenocarcinoma, and duodenum and small bowel adenocarcinoma, and byNGS for other primary. Based on IHC and PCR or NGS results (NGS will be centrallyperformed in this case ), the sponsor will decide if inclusion is possible;

8. Presence of at least one measurable lesion within 28 days before the start oftreatment according to RECIST v1.1.

9. Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1.

10. Haematological status: absolute neutrophil count (ANC) ≥1.5 x 10⁹/L; platelets ≥100x 10⁹/L; haemoglobin ≥9 g/dL.

11. Adequate renal function: serum creatinine level <120 µM, or clearance >50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault).

12. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alanineaminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless livermetastases are present, in which case they must be ≤ 5× ULN.

13. For patients not taking warfarin: International normalised ratio (INR) <1.5 orprothrombin time (PT) <1.5 x ULN and either partial thromboplastin time (PTT) oractivated PTT (aPTT) <1.5 x ULN. Participants taking warfarin may be included on astable dose with a therapeutic INR <3.5.

14. Women of childbearing potential must have a negative serum pregnancy test performedwithin 72 hours before the date of randomization.

15. Men, and women of childbearing potential must agree to use adequate contraceptionfor the duration of trial participation and for 4 months after the last dose ofdostarlimab (used in first line or at crossover) or for at least 6 months after thelast administration of the chemotherapy agent(s) used in the control arm if nocrossover with dostarlimab (according to the current version of the summary ofproduct characteristics (SmPC) of each chemotherapy agent). Men must also agree tonot donate sperm and women must agree to not donate oocytes during the specifiedperiod.

16. Registration in a National Health Care System.

17. Patient is willing and able to comply with scheduled visits, treatment schedule,laboratory tests, tumor biopsies, and other requirements of the study.

Exclusion Criteria:

1. Colorectal and endometrial cancer and all primary tumor not listed in inclusioncriterion #4.

2. Previous exposure to anti-PD-1 or PD-L1 or anti-CTL-4 antibodies or treatment withimmunotherapy.

3. Previous exposure to any investigational drug within 4 weeks (6 weeks for monoclonalantibodies) before the first dose in the study.

4. Previous exposure to any systemic anti-cancer therapy or radiation therapy for thecancer for which the patient is being enrolled.

5. Active autoimmune disease: Active autoimmune disease requiring systemic treatment inthe past 2 years (excluding replacement therapy) or any history of interstitial lungdisease (patients with ancient auto-immune disease with stable endocrine oralsubstitution are eligible).

6. Uncontrolled central nervous system metastases or carcinomatous meningitis or otherconcurrent illness or ongoing or active infections.

7. Patients with HER2-positive gastric carcinoma.

8. Other serious and uncontrolled non-malignant disease or is considered a poor medicalrisk due to a serious, uncontrolled medical disorder, non-malignant systemic diseaseor active infection requiring systemic therapy. Specific examples include, but arenot limited to, active, non-infectious pneumonitis; uncontrolled ventriculararrhythmia; recent (within 90 days) myocardial infarction; uncontrolled majorseizure disorder; unstable spinal cord compression; superior vena cava syndrome; orany psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the study.

9. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

10. Has received treatment with systemic corticosteroids or other systemicimmunosuppressive medications (including but not limited to prednisone,dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor agents) within 2 weeks prior to the first dose ofadjuvant treatment or is required to receive systemic immunosuppressive medicationsduring the study. Inhaled or topical steroids and adrenal replacement doses >10 mgdaily prednisone equivalents are permitted in the absence of active autoimmunedisease. Note 1: Patients who have received acute, low-dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled intothe study after approval of the Medical Contact. Note 2: patients are permitted the use of topical, ocular, intra-articular,intranasal, and inhalational corticosteroids (with minimal systemic absorption).Adrenal replacement steroid doses including doses >10 mg daily prednisone arepermitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.

11. Other concomitant or previous malignancy other than the disease under study, exceptas noted below: i. adequately treated in-situ carcinoma of the uterine cervix, ii. basal or squamouscell carcinoma of the skin, iii. cancer from which the patients was in completeremission for >2 years.

12. Known Human Immunodeficiency Virus (HIV) infection.

13. Received live vaccine within 14 days.

14. Patient has documented presence of HBsAg [or HBcAb] at pre-inclusion visit or within 3 months prior to first dose of study intervention. Participant has a positive hepatitis C virus (HCV) antibody test result atpre-inclusion visit or within 3 months prior to first dose of study intervention.Note: Participants with a positive HCV antibody test result due to prior resolveddisease can be enrolled, only if a confirmatory negative HCV RNA test is obtained. Participant has a positive HCV RNA test result at pre-inclusion visit or within 3months prior to first dose of study intervention. Note: The HCV RNA test is optionaland participants with negative HCV antibody test are not required to undergo HCV RNAtesting as well

15. Known prior severe hypersensitivity to investigational product or any component inits formulation.

16. Pregnant or breast feeding women.

17. Participation in another clinical trial within 30 days prior to the first studytreatment administration or concomitantly with the trial.

18. Presence of any psychological, familial, sociological, or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule.

19. Person deprived of their liberty or under protective custody or guardianship.

Patient randomized to receive SOC (Arm B) may crossover to receive dostarlimab (Arm A) in case of documented progressive disease according to RECIST v1.1.

Inclusion and exclusion are the same for the crossover except for the inclusion criteria #3 and #4.

The criterion #3 for crossover is: Patient included in the protocol and randomized in the arm "standard of care" with documented progressive disease by RECIST v1.1 on standard of care (defined in the protocol).

The criterion #4 for crossover is: Previous exposure to chemotherapy for locally advanced or metastatic disease.