PRODIGE 90 - FFCD 22024 - PREDIR-NEOREC - Neoadjuvant dostarlimab with short course radiotherapy in a watch-and-wait strategy for microsatellite unstable or mismatch repair-deficient locally advanced rectal cancer patients: a randomized phase II trial

Prior treatment

• Patients who have already received immunotherapy, chemotherapy or radiotherapy for rectal cancer
• Participant has an active infection requiring systemic therapy within 1 week prior to the anticipated first dose of study treatment.
• Contraindication to pelvic radiotherapy

Other illness

• 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.
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or followup schedule
• 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
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Interstitial lung disease
• Reccurent rectal cancer

Lab values

• 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
  • Tumor is causing symptomatic bowel obstruction (diverting stoma (ileostomy or colostomy) is allowed in case of obstructive rectal cancer. Bowel obstruction should not be an exclusion criteria as the obstruction has been relieved by a diverting stoma. It should be reminded that a stent is not recommended but not excluded in mid and low rectal cancer)
  • 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 within the past 2 years or documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents at non-physiologic doses
  • History of organ transplantation
  • Pregnant or breastfeeding women

Other

• Upper third rectal adenocarcinoma (above 10 cm from the anal verge or sus-peritoneal on standard clinical and MRI criteria)
• Persons deprived of liberty or under guardianship or incapable of giving consent
• Uncontrolled central nervous system metastases or carcinomatous meningitis

• Age ≥18 years
• Middle and lower third rectal adenocarcinoma (diagnosed on the basis of standard clinical and MRI criteria)
• Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
  • 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).
  • T2-T4 Nany and Tany N+ disease
  • 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)
  • Negative pregnancy test done 72 hours prior to registration, for women of childbearing potential only. 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