Anti-PD-1 and mDCF Followed by Chemoradiotherapy in Patients With Stage III Squamous Cell Anal Carcinoma.

Inclusion Criteria:

• Signed and dated informed consent,

• Age ≥18 years,

• Ability to comply with the study protocol in the Investigator's judgment,

• Performance status ECOG-WHO ≤ 1,

• Histologically proved squamous cell anal carcinoma,

• Locally advanced disease defined as:

• Stage III (TxN1 or T4N0). Lymph node can be considered positive if one of thefollowing criteria is satisfied:

• Enlargement (largest short-axis diameter > 1 cm for mesorectal nodes, and > 1.5cm for other nodes) OR,

• Heterogeneity or necrosis OR,

• Irregular contours OR,

• Strong enhancement at magnetic resonance imaging (MRI) OR,

• Positivity on positron emission tomography (PET) scan,

• Patient eligible to the mDCF regimen,

• Computed tomography (CT) scan performed within 30 days prior inclusion,

• MRI of pelvis performed within 30 days prior inclusion,

• PET scan performed within 30 days prior inclusion,

• Adequate hematologic and end-organ function: defined by the following laboratorytest results obtained within 7 days prior to initiation of study treatment:

• Absolute neutrophil count (ANC) ≥ 1.5 X 109/L (1500/µL),

• Platelet count ≥ 100 X 109/L (100.000/µL) without transfusion,

• Hemoglobin ≥ 90 g/L (9g/dL); previous transfusion is allowed,

• Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 Xupper limit of normal (ULN), (≤ 5 X upper limit of normal (ULN) if known livermetastases)

• Serum bilirubin ≤ 2.5 X ULN (except patients with known Gilbert disease andserum bilirubin level ≤ 3 X ULN),

• Creatinine clearance (CrCl) > 60 ml/min (by the Modification of Diet in RenalDisease [MDRD], Cockroft formula, or chronic kidney disease [CKD] formula]),

• Serum albumin ≥ 25 g/L (2.5 g/dL),

• For patients not receiving therapeutic anticoagulation: International normalizedratio (INR) or activated partial thromboplastin time (PTT) ≤ 1.5 X ULN,

• Patient affiliated to or beneficiary of French social security health insurancesystem.

Exclusion Criteria:

• Previously received chemotherapy or pelvic radiotherapy,

• Previously received anti-tumor immunotherapy (HPV vaccination is allowed),

• Metastatic disease,

• Diagnosis of additional malignancy within 3 years prior to the inclusion date withthe exception of curatively treated basal cell carcinoma of the skin and/orcuratively resected in situ cervical or breast cancer,

• Patient with any medical or psychiatric condition or disease, which would make thepatient inappropriate for entry into this study,

• Current participation in a study of an investigational agent or in the period ofexclusion,

• Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertilepatients during the period of treatment and for 6 months from the last treatmentadministration; men must refrain from donating sperm during this same period. Inaddition, men who are sexually active with woman of childbearing potential will beinstructed to adhere to contraception for a period of 7 months after the lasttreatment administration,

• Female participants of childbearing potential and male participants with partners ofchildbearing potential must agree to use a highly effective method of birth control (i.e., pregnancy rate of less than 1% per year) during the study, A woman isconsidered to be of childbearing potential if she is postmenarcheal, has not reacheda postmenopausal state (≥ 12 continuous months of amenorrhea with no identifiedcause other than menopause), and has not undergone surgical sterilization (removalof ovaries and/or uterus),

• Contraceptive methods that result in a low failure rate when used consistently andcorrectly include methods such as combined hormonal contraception associated withinhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonalcontraception associated with inhibition of ovulation (oral, injectable,implantable), some intrauterine devices, intrauterine hormone-releasing stem, truesexual abstinence (when this is in line with the preferred and usual lifestyle ofthe participant), bilateral tubal occlusion, or a female partner who is not ofchildbearing potential or a male partner who has had a vasectomy. Women and femalepartners using hormonal contraceptive must also use a barrier method i.e. condom orocclusive cap (diaphragm or cervical/vault caps),

• Patient under guardianship, curatorship, or under the protection of justice

• Inadequate organ functions: uncontrolled cardiac condition, known cardiac failure,unstable coronaropathy, respiratory failure, and chronic obstructive pulmonarydisease,

• Diabetes with vascular or neurovascular complications,

• Preexistent peripheral neuropathy or impaired audition,

• HIV positive with CD4 count under 400/mm3 (HIV test is mandatory before inclusion),

• Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (chronicor acute), defined as having a positive hepatitis B surface antigen (HBsAg) test atscreening. Patients with a past or resolved HBV infection, defined as having anegative HBsAg test and a positive total HBV core antibody (HBcAb) test atscreening, are eligible for the study. Active hepatitis C virus (HCV) infection,defined as having a positive HCV antibody test followed by a positive HCV RNA testat screening. The HCV RNA test will be performed only for patients who have apositive HCV antibody test,

• Active tuberculosis,

• Concomitant treatment with CYP3A4 inhibitor like ritonavir, indinavir, ketoconazole,etc,

• Known hypersensitivity or contraindication to any of the study chemotherapy drugs (taxanes, cisplatin, 5-FU, mitomycin, capecitabine) and dihydro pyrimidinedehydrogenase (DPD) deficit,

• Uncontrolled infection or another life-risk condition,

• Known hearing impairment that contraindicates cisplatin administration,

• Administration of a (attenuated) live vaccine within 28 days of planned start ofstudy therapy of known need for this vaccine during treatment,

• Administration of prophylactic phenytoin,

• Inadequate laboratory values: MDRD CrCl < 60 ml/min, neutrophil count < 1500/mm3,platelets < 100.000/mm3, bilirubin 2.5 x ULN, AST/ALT 2.5 x ULN

• Previous major surgery (requiring general anesthesia) within 28 days of enrollment

• Any immunosuppressive therapy (i.e. corticosteroids > 10 mg of hydrocortisone orequivalent dose) within 14 days before the planned start of study therapy,

• Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.thyroxine, insulin) is allowed,

• Prior allogeneic bone marrow transplantation or prior solid organ transplantation,

• Known active central nervous system metastases and/or carcinomatous meningitis.Subject with previously treated brain metastases and with radiological and clinicalstability are allowed,

• Previously received an anti-PD-1, anti-PD-L1, or anti-CTLA4 (Cytotoxic T-LymphocyteAssociated Protein 4) agent,

• Known hypersensitivity or allergy to Chinese hamster ovary cell products or anycomponent of Ezabenlimab (BI 754091) formulation,

• History of colorectal inflammatory disease,

• History of idiopathic or secondary pulmonary fibrosis (History of radiationpneumonitis in the radiation field fibrosis is permitted), or evidence of activepneumonitis requiring a systemic treatment with 28 days before the planned start ofstudy therapy

• History of severe hypersensitivity reactions to others mAbs

• History of Chronic colorectal inflammatory disease (Ulcerative colitis, Crohn'sdisease),

• History of connective disease,

• History of autoimmune diseases.