III期扁平上皮肛門癌患者における抗PD-1およびmDCFとその後の化学放射線療法。 (INTERACT-ION)

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 the following criteria is satisfied:
  • Enlargement (largest short-axis diameter > 1 cm for mesorectal nodes, and > 1.5 cm 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 laboratory test 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 X upper limit of normal (ULN), (≤ 5 X upper limit of normal (ULN) if known liver metastases)
  • Serum bilirubin ≤ 2.5 X ULN (except patients with known Gilbert disease and serum bilirubin level ≤ 3 X ULN),
  • Creatinine clearance (CrCl) > 60 ml/min (by the Modification of Diet in Renal Disease [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 normalized ratio (INR) or activated partial thromboplastin time (PTT) ≤ 1.5 X ULN,

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

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 with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer,
• Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study,
• Current participation in a study of an investigational agent or in the period of exclusion,
• Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertile patients during the period of treatment and for 6 months from the last treatment administration; men must refrain from donating sperm during this same period. In addition, men who are sexually active with woman of childbearing potential will be instructed to adhere to contraception for a period of 7 months after the last treatment administration,
• Female participants of childbearing potential and male participants with partners of childbearing 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 is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus),
• Contraceptive methods that result in a low failure rate when used consistently and correctly include methods such as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), some intrauterine devices, intrauterine hormone-releasing stem, true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant), bilateral tubal occlusion, or a female partner who is not of childbearing potential or a male partner who has had a vasectomy. Women and female partners using hormonal contraceptive must also use a barrier method i.e. condom or occlusive 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 pulmonary disease,
• 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 (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBV core antibody (HBcAb) test at screening, 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 test at screening. The HCV RNA test will be performed only for patients who have a positive 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 pyrimidine dehydrogenase (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 of study 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 or equivalent 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 clinical stability are allowed,
• Previously received an anti-PD-1, anti-PD-L1, or anti-CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) agent,
• Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of Ezabenlimab (BI 754091) formulation,
• History of colorectal inflammatory disease,
• History of idiopathic or secondary pulmonary fibrosis (History of radiation pneumonitis in the radiation field fibrosis is permitted), or evidence of active pneumonitis requiring a systemic treatment with 28 days before the planned start of study therapy
• History of severe hypersensitivity reactions to others mAbs
• History of Chronic colorectal inflammatory disease (Ulcerative colitis, Crohn's disease),
• History of connective disease,
• History of autoimmune diseases.