Immunotherapy with dostarlimab for locally advanced or metastatic cancer (non-colorectal/non-endometrial) with tumor dMMR/MSI

Prior treatment

• Has received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within 2 weeks prior to the first dose of adjuvant treatment or is required to receive systemic immunosuppressive medications during the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Received live vaccine within 14 days.
• Known active hepatitis, including the following: Participant has an acute hepatitis and untreated chronic hepatitis B at the pre-inclusion visit. i. Chronic HBV carriers (HBsAg positive, HBcAb positive) can be included provided that they receive effective antiviral therapy (i.e., with nucleos(t)ide analogs) for at least 14 days prior to first dose and are willing to continue for at least 6 months after treatment discontinuation or longer at the discretion of the treating hepatologist. HBV DNA must be adequately suppressed, per institutional or local guidelines, prior to initiation of study intervention. ii. Participants with past HBV infection (HBcAb positive, HBsAg negative) can be enrolled if HBV DNA is undetectable at screening.
• Known prior severe hypersensitivity to investigational product or any component in its formulation
• Participation in another clinical trial within 30 days prior to the first study treatment administration or concomitantly with the trial.
• Previous exposure to anti-PD-1 or PD-L1 or anti-CTL-4 antibodies or treatment with immunotherapy.
• Previous exposure to any investigational drug within 4 weeks (6 weeks for monoclonal antibodies) before the first dose in the study.
• Previous exposure to any systemic anti-cancer therapy or radiation therapy for the cancer for which the patient is being enrolled.
• Uncontrolled central nervous system metastases or carcinomatous meningitis or other concurrent illness or ongoing or active infections.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation,

Other illness

• Colorectal and endometrial cancer and all primary tumor not listed in inclusion criterion #4.
• Known Human Immunodeficiency Virus (HIV) infection.
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Active autoimmune disease: Active autoimmune disease requiring systemic treatment in the past 2 years (excluding replacement therapy) or any history of interstitial lung disease (patients with ancient auto-immune disease with stable endocrine oral substitution are eligible).
• Other serious and uncontrolled non-malignant disease or is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,

Age

• Other concomitant or previous malignancy other than the disease under study, except : i. adequately treated in-situ carcinoma of the uterine cervix, ii. basal or squamous cell carcinoma of the skin, iii. cancer from which the patients was in complete remission for >2 years.

Other

• Pregnant or breast feeding women.
• Person deprived of their liberty or under protective custody or guardianship.
• Patients with HER2-positive gastric carcinoma.

• Patient must have signed a written informed consent form prior any trial specific procedures.
• 18 years or older patients.
• Documented locally advanced or metastatic disease with no previous systemic anticancer treatment in these settings and not suitable for complete surgical resection.
• Histologically proven, dMMR/MSI-H solid tumors that are not colorectal or endometrial cancers and including one of the following: duodenum and small bowel adenocarcinoma, gastric and oeso-gastric junction adenocarcinoma with CPS<5, pancreatic adenocarcinoma, biliary tract carcinoma including ampulla of Vater adenocarcinoma, adrenocortical carcinoma, carcinoma of unknown primary site, neuroendocrine carcinoma (Grade 3) all primary, and soft tissue sarcoma except Gastro-Intestinal stromal tumor (GIST).
• If patient received adjuvant therapy for non-metastatic disease, this therapy should be completed more than 6 months before the diagnosis of metastatic or recurrent disease.
• Patients with dMMR/MSI tumor analyzed by IHC, PCR (for Gastric and OGJ adenocarcinoma, and duodenum and small bowel adenocarcinoma only), and/or NGS at the recruiting center should be confirmed by central review within 24h (every anonymized patient analysis reporting will be provided for central review). Patients should not be included in the study until the dMMR/MSI status is confirmed by the review committee.
• Presence of at least one measurable lesion within 28 days before the start of treatment according to RECIST v1.1.
• Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1.
• Haematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; haemoglobin ≥9 g/dL.
• 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).
• Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless liver metastases are present, in which case they must be ≤ 5× ULN
• For patients not taking warfarin: INR <1.5 or PT <1.5 x ULN and either PTT or aPTT <1.5 x ULN. Participants taking warfarin may be included on a stable dose with a therapeutic INR <3.5
• Women of childbearing potential must have a negative serum pregnancy test performed within 72 hours before the date of randomization.
• Men, and women of childbearing potential (WOCBP) must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of dostarlimab (used in first line or at crossover) or for at least 6 months after the last administration of the chemotherapy agent(s) used in the control arm if no crossover with dostarlimab (according to the current version of the SmPC of each chemotherapy agent). Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period.
• Registration in a National Health Care System.
• Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.