Association of Radiochemotherapy and Immunotherapy for the Treatment of Unresectable Oesophageal caNcer

Inclusion Criteria: 1. Histologically proven squamous cell carcinoma or adenocarcinoma of the oesophagus, 2. Unresectable disease due to anatomical consideration or medical condition (patient unfit for surgical procedure), 3. Presence of at least one measurable lesion \>10 mm with spiral CT scan, 4. No prior therapy for pathology investigated including chemotherapy or radiotherapy prior to the study, except anterior out of field radiotherapy, received for treatment of another primary tumor considered in remission, in the past 5 years, 5. Age ≥18 years old, 6. WHO performance status \<2 (i.e., 0 or 1), 7. Body weight \>35 kg, 8. Life expectancy of at least 12 weeks , 9. Adequate haematology laboratory data within the 7 days before randomization 1. Absolute neutrophils \>1.5 x 109/L 2. Platelets \>100 x 109/L 3. Haemoglobin ≥9 g/dL, 10. Adequate Biochemistry laboratory data within the 7 days before randomization 1. Total bilirubin ≤1.5 x upper limit of normal (ULN) 2. Transaminases ≤2.5 x ULN 3. Alkaline phosphatases ≤5 x ULN, 4. Measured creatinine clearance (CL) \>40 mL/min by the Cockcroft-Gault formula, 5. Glycaemia ≤1.5 x ULN 6. Cholesterolaemia ≤7.30 mmol/L, 7. Albumin \>28 g/L 11. Adequate haemostasis laboratory data within 7 days prior to randomization: prothrombin time (PT) within the normal range, 12. Adequate values for calcium, potassium and magnesium levels measured within 7 days prior to randomization, 13. Women should be post-menopaused or willing to accept the use an effective contraceptive regimen during the treatment period and for at least 6 months after the end of the study. All non-menopausal women should have a negative pregnancy test within 72 h prior to randomization. Men should accept to use an effective contraception during treatment period and at least 6 months after the end of the study especially after the last dose of oxaliplatin treatment. 14. Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses, 15. Patient affiliated to a social security regimen. 16. Uracilemia \< 16ng/ml 17. Forced expiratory volume (FEV) \>1 liter or \> 50% of the theoretical value Exclusion Criteria: 1. Previous treatment with another PD-1, PD-L1 including durvalumab or CTLA-4 inhibitor 2. Metastatic disease, 3. Patients should not receive live vaccine 30 days prior to study drug 4. Female patients who are pregnant or breastfeeding 5. Uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, pulmonary failure, chronic renal or hepatic diseases, active peptic ulcer disease or gastritis, active bleeding, diatheses... (non-exhaustive list), 6. Clinically significant cardiac disease or impaired cardiac function, such as: 1. Congestive heart failure requiring treatment (New York Heart Association \[NYHA\] grade ≥2), left ventricular ejection fraction (LVEF) \<50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO), or uncontrolled arterial hypertension defined by blood pressure \>140/100 mmHg at rest (average of 3 consecutive readings), 2. History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high- grade/complete AV-blockage, 3. Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), \<3 months prior to screening, 4. MeanQT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction. 7. Current or prior use of immunosuppressive medication within 28 days before the first administration of durvalumab (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) - Topical, inhaled, nasal, and ophthalmic steroids are allowed, 8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: 1. Patients with vitiligo or alopecia 2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stabilised with hormone replacement therapy 3. Any chronic skin condition that does not require systemic therapy 4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician 5. Patients with coeliac disease controlled by diet alone 9. Known primary immunodeficiency or active HIV, 10. Patient with a dihydropyrimidine dehydrogenase (DPD) deficiency (Uracilemia ≥ 16 ng/ml, the test should be done for all patients before 5-FU administration)\* , 11. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive HBS antibody test for hepatitis B or hepatitis C virus ribonucleic acid (HCV antibody), 12. History of organ transplantation requiring the use of immunosuppressive medication, including allogenic stem cell transplant 13. History of active tuberculosis or latent disease capable of reactivation, 14. Current pneumonitis or interstitial lung disease, 15. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only, 16. History of severe allergic reactions or hypersensitivity to any unknown allergens or any components of the study drug (refer to IB of durvalumab section 5.5.1.11). 17. Any prior corticosteroid-refractory immune-related adverse event (irAE), 18. Oeso-tracheal or oeso-bronchial fistulae, 19. Major surgery within 28 days prior to the first dose of study treatment 20. Toxicities of grade ≥1 from any previous therapy, 21. Peripheral sensory neuropathy with functional impairment 22. Severe infection requiring parenteral antibiotic treatment 23. Patients treated with sorivudine or analogues as brivudine 24. Patients treated with phenytoin for prophylaxis 25. Participation in another therapeutic trial within the 30 days prior to study inclusion, 26. Patients deprived of liberty or under guardianship, 27. Patients unable to adhere to the protocol for geographical, social, or psychological reasons.