PRODIGE 90 - (FFCD 2204) Neoadjuvant Dostarlimab with Short Course Radiotherapy in a Watch-and-wait Strategy for Microsatellite Unstable or Mismatch Repair-deficient Locally Advanced Rectal Cancer Patients

Inclusion Criteria:

• Age ≥18 years

• Histologically proven rectal adenocarcinoma with Mismatch-repair Deficient (dMMR)/microsatellite instability-high (MSI-H). Tumour status (dMMR/MSI-H) should bedetermined using both IHC (Immunohistochemistry) and PCR (polymerase chain reaction)or NGS (Next-Generation sequencing)

• Stage II or III and middle and lower third rectal adenocarcinoma (diagnosed on thebasis of standard clinical and MRI criteria)

• WHO performance status 0 or 1

• Adequate liver function: AST and ALT ≤ 5 x ULN (upper normal limit), total bilirubin ≤ 35 μM/L, albumin ≥ 28 g/L and Child-Pugh A score (if cirrhosis associated)

• Adequate hematological and renal function (hemoglobin > 9 g/dl, platelets > 100 G/L,ANC ≥ 1.5 G/L) and renal function (creatinine clearance ≥ 40ml/min according to MDRDformula)

• Women of childbearing potential must agree to use contraception during the trialtreatment and for at least 4 months after discontinuation of the experimentaltreatments. Men who have sex with women of childbearing potential must agree to usecontraception during treatment and for at least 4 months after discontinuation ofthe experimental treatments

• Ability of patient to understand, sign and date the informed consent form before anystudy specific screening procedures

• Patient affiliated to a social security scheme

Exclusion Criteria:

• Stage IV and upper third rectal adenocarcinoma (above 10 cm from the anal verge orsus-peritoneal on standard clinical and MRI criteria)

• Patients who have already received immunotherapy, chemotherapy or radiotherapy forrectal cancer

• Persistent toxicities related to prior treatment of grade greater than 1

• Participant has an active infection requiring systemic therapy within 1 week priorto the anticipated first dose of study treatment

• Contraindication to pelvic radiotherapy

• Hypersensitivity to dostarlimab or any of its excipients

• Allergy to any component of Chinese hamster ovary cells

• History of severe active life-threatening autoimmune disease

• History of uncontrolled or symptomatic cardiac disease.

• Interstitial lung disease

• Uncontrolled central nervous system metastases or carcinomatous meningitis

• Patient has documented presence of HBsAg [or HBcAb] at screening or within 3 monthsprior to first dose of study intervention

• Patient has a positive HCV antibody test result at screening or within 3 monthsprior to first dose of study intervention. NOTE: Participants with a positive HCVantibody test result due to prior resolved disease can be enrolled, only if aconfirmatory negative HCV RNA test is obtained

• Patient has a positive HCV RNA test result at Screening or within 3 months prior tofirst dose of study intervention. NOTE: The HCV RNA test is optional andparticipants with negative HCV antibody test are not required to undergo HCV RNAtesting as well

• Known HIV infection

• Vaccinations (live vaccine) within 14 days prior to start of treatment

• Immunosuppression, including subjects with conditions requiring systemiccorticosteroid treatment (>10 mg/day prednisone equivalent)

• Active autoimmune disease requiring systemic treatment (vitiligo excluded) in thepast 2 years or recent receipt within the previous 7 days of immunosuppressivetherapy

• History of organ transplantation

• Pregnant or breastfeeding women

• Patient has experienced any of the following with prior immunotherapy: anyimmune-related AE (irAE) of Grade 3 or higher, immune-related severe neurologicevents of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis,Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of anygrade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or drug reaction witheosinophilia and systemic symptoms [DRESS] syndrome), or myocarditis of any grade.Non-clinically significant laboratory abnormalities are not exclusionary

• Any progressive disease that has not been balanced over the last 6 months: hepaticinsufficiency, renal insufficiency, respiratory insufficiency, etc

• Other cancer treated within the last 5 years except in situ cervical carcinoma orbasocellular/ spinocellular carcinoma or a cancer of the lynch syndrome spectrumconsidered cured at the time of inclusion

• Major surgery within 4 weeks before inclusion

• Persons deprived of liberty or under guardianship or incapable of giving consent

• Any psychological, familial, sociological, or geographical condition potentiallyhampering compliance with the study protocol or follow-up schedule