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 be determined 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 the basis 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 MDRD formula)
• Women of childbearing potential must agree to use contraception during the trial treatment and for at least 4 months after discontinuation of the experimental treatments. Men who have sex with women of childbearing potential must agree to use contraception during treatment and for at least 4 months after discontinuation of the experimental treatments
• Ability of patient to understand, sign and date the informed consent form before any study 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 or sus-peritoneal on standard clinical and MRI criteria)
• Patients who have already received immunotherapy, chemotherapy or radiotherapy for rectal cancer
• Persistent toxicities related to prior treatment of grade greater than 1
• Participant has an active infection requiring systemic therapy within 1 week prior to 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 months prior to first dose of study intervention
• Patient has a positive HCV antibody test result at screening 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
• Patient has a positive HCV RNA test result at Screening 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
• Known HIV infection
• Vaccinations (live vaccine) within 14 days prior to start of treatment
• Immunosuppression, including subjects with conditions requiring systemic corticosteroid treatment (>10 mg/day prednisone equivalent)
• Active autoimmune disease requiring systemic treatment (vitiligo excluded) in the past 2 years or recent receipt within the previous 7 days of immunosuppressive therapy
• History of organ transplantation
• Pregnant or breastfeeding women
• Patient has experienced any of the following with prior immunotherapy: any immune-related AE (irAE) of Grade 3 or higher, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia 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: hepatic insufficiency, renal insufficiency, respiratory insufficiency, etc
• Other cancer treated within the last 5 years except in situ cervical carcinoma or basocellular/ spinocellular carcinoma or a cancer of the lynch syndrome spectrum considered 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 potentially hampering compliance with the study protocol or follow-up schedule