Sequential Treatment With GEMBRAX and Then FOLFIRINOX Followed by Stereotactic MRI-guided Radiotherapy in Patients With Locally Advanced Pancreatic Cancer

Inclusion Criteria:

1. Patient aged from 18 to 75 years at the date of signature of the consent form
2. Histologically or cytologically proven pancreatic adenocarcinoma
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
4. Non-resectable tumour according to the National Comprehensive Cancer Network (NCCN) 1.2015 recommendations after external review of imaging data by multidisciplinary experts.
5. Non-metastatic cancer confirmed by thorax-abdomen-pelvis computerized tomography (CT) scan and liver MRI
6. SMART feasibility confirmed by centralized review
7. Uracilemia \< 16 ng/ml
8. Hematological assessment within 14 days before inclusion, defined by:

   * Neutrophils ≥ 2 000/mm3 (2 × 109/L);
   * Platelets ≥ 100 000/mm3 (100 × 109/L);
   * Hemoglobin ≥ 9 g/dl
9. Liver function (within 14 days before inclusion) defined by:

   * ASpartate Transaminase (AST) and ALanine Transaminase (ALT) ≤ 2.5 x Upper Limit of Normal (ULN);
   * Total bilirubin ≤ 1.5 x ULN. Patients with a metallic biliary prosthesis due to biliary obstruction caused by the cancer may be included, if: a CT scan with injection of contrast medium and thin pancreas sections was performed before placing the biliary prosthesis, the bilirubin level after prosthesis fitting decreased to ≤20 mg/L (≤34 μmol/L), and in the absence of cholangitis.
10. Creatininaemia within the reference limits, or calculated clearance ≥50 ml/min for patients with a serum creatinine value above or below the reference values (clearance calculated using the Chronic Kidney Disease EPIdemiology collaboration (CKDEPI formula).
11. Serum calcium AND magnesium AND potassium ≥ Lower Limit Normal (LLN and ≤ 1.2 x Upper Limit Normal (ULN)
12. Cancer Antigen (CA 19.9) \<500 IU/mL (without cholestasis). Patients with CA 19.9 between 500 IU/mL and 1000 IU/mL can be included if the Positron Emission Tomography (PET) scan and peritoneal MRI (optional) do not detect any distant fixation, indicative of metastasis. Patients with CA 19.9 ≥ 1000 IU/mL cannot be included.
13. Sexually active patients must use a contraceptive method considered adequate and suitable by the investigator during the entire period of administration of the study treatment and up to 6 months after the treatment end, for female and male patients.
14. Signature of the consent form before any study-specific procedure.
15. Covered by the French health insurance.

Exclusion Criteria:

1. Any previous treatment for pancreatic cancer (e.g. chemotherapy, radiotherapy, surgery, targeted therapy, experimental therapy)
2. Gilbert's syndrome or homozygous Uridine DiPhosphate Glucuronosyl Transferase 1 A1 (UGT1A1 \* 28)
3. Other concomitant cancer or history of cancer, except for treated in situ cancer of the cervix , basal cell or squamous cell carcinoma, superficial bladder tumour (Ta, Tis, and T1), or good-prognosis tumour cured without chemotherapy and without signs of disease in the 3 years before inclusion
4. Prior radiotherapy likely to overlap with the planned study radiotherapy area (e.g. previous abdominal irradiation).
5. Patients with high cardiovascular risk, including, but not limited to, coronary stent or myocardial infarction in the past 6 months.
6. Peripheral neuropathy ≥ grade 2
7. ECG with QTcorrected (QTc) interval longer than 450 ms for men and longer than 470 ms for women
8. Contraindication to MRI and MRI-guided radiotherapy
9. History of chronic inflammatory disease of the colon or rectum
10. Any other concomitant and not controlled serious illness or disturbance that may interfere with the patient's participation in the study and safety during the study (e.g. severe liver, kidney, lung, metabolic, or psychiatric disorder)
11. Intolerance or allergy to one of the study drugs (gemcitabine, Nab-paclitaxel, oxaliplatin, irinotecan, 5-FU) or to one of their excipients (e.g. fructose) listed in the Contraindications or Warnings sections and Special precautions of the Summary of Product Characteristics (SmPC) or prescription information
12. Legal incapacity (patient under guardianship or wardship)
13. Pregnant or breastfeeding woman. Fertile women must have a negative pregnancy test (serum β-hCG) performed 72 hours before inclusion
14. Patient using vitamin K antagonists (Coumadin…) (possible modification of the treatment before inclusion)
15. Active and uncontrolled bacterial or fungal infection that requires systemic treatment.
16. Know active HIV infection
17. History of peripheral arterial disease (e.g. lameness, Buerger's disease).
18. Patient who received a attenuated live vaccine in the 10 days before inclusion
19. Patient with history of pulmonary fibrosis or interstitial pneumonia.
20. Inability to attend the follow-up visits due to geographic, social or mental reasons.
21. Participation in another clinical study with a research product during the last 30 days before inclusion.