Inclusion Criteria:
1. Patient must have signed a written informed consent form prior any trial specific
procedures.
18 years or older patients.
3. Documented locally advanced or metastatic disease with no previous systemic
anti-cancer treatment in these settings and not suitable for complete surgical
resection.
4. 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, 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).
5. 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.
6. Availability of minimum 1 block of tumor tissue or 20 slides (archival (<2 years) or
fresh biopsy specimen of primary and or metastasis) for centralized confirmation of
MMR/MSI status by IHC or NGS/PCR, and for Translational Research.
7. 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.
NB: In case of ambiguous result of IHC (lack of positive internal control,
heterogeneous loss of MMR protein expression, ambiguous loss of only one protein
including HMSH6 and PMS2), the MSI-H status will be assessed by PCR or NGS for gastric
and OGJ adenocarcinoma, and duodenum and small bowel adenocarcinoma, and by NGS for
other primary. Based on IHC and PCR or NGS results (NGS will be centrally performed 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 of
treatment 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 ≥100 x
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), alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless liver
metastases are present, in which case they must be ≤ 5× ULN.
13. For patients not taking warfarin: International normalised ratio (INR) <1.5 or
prothrombin time (PT) <1.5 x ULN and either partial thromboplastin time (PTT) or
activated PTT (aPTT) <1.5 x ULN. Participants taking warfarin may be included on a
stable dose with a therapeutic INR <3.5.
14. Women of childbearing potential must have a negative serum pregnancy test performed
within 72 hours before the date of randomization.
15. Men, and women of childbearing potential 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 summary of product
characteristics (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.
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 inclusion
criterion #4.
2. Previous exposure to anti-PD-1 or PD-L1 or anti-CTL-4 antibodies or treatment with
immunotherapy.
3. Previous exposure to any investigational drug within 4 weeks (6 weeks for monoclonal
antibodies) before the first dose in the study.
4. Previous exposure to any systemic anti-cancer therapy or radiation therapy for the
cancer for which the patient is being enrolled.
5. 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).
6. Uncontrolled central nervous system metastases or carcinomatous meningitis or other
concurrent 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 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.
9. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
10. Has received treatment with systemic corticosteroids or other systemic
immunosuppressive medications (including but not limited to prednisone, dexamethasone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 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.
Note 1: Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled into
the 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 are
permitted. 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, except as
noted below:
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.
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 at
pre-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 resolved
disease 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 3
months prior to first dose of study intervention. Note: The HCV RNA test is optional
and participants with negative HCV antibody test are not required to undergo HCV RNA
testing as well. 15. Known prior severe hypersensitivity to investigational product or any component in its
formulation.
16. Pregnant or breast feeding women.
17. Participation in another clinical trial within 30 days prior to the first study
treatment administration or concomitantly with the trial.
18. Presence of any psychological, familial, sociological, or geographical condition
potentially 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.
