Short-course Versus Long-course Pre-operative Chemotherapy With mFOLFIRINOX or PAXG (CASSANDRA TRIAL)

Inclusion Criteria:

1. Cyto/histological diagnosis of pancreatic ductal adenocarcinoma*;

2. Clinical stage I-III disease according to TNM 8th Ed. 2017 [appendix 1];

3. Resectable or borderline resectable disease, as anatomically defined according toNCCN Guidelines Version 1.2020 - Pancreatic Adenocarcinoma [appendix 2] andbiologically defined according to the International consensus on definition andcriteria of borderline resectable pancreatic ductal adenocarcinoma 2017 (CA 19.9 > 500 IU/ml) (Isaji et al., 2018);

4. Karnofsky Performance Status > 60% [appendix 3];

5. Age > 18 and ≤ 75 years;

6. Adequate bone marrow function (GB ≥ 3500/mm3, neutrophils ≥1500/mm3, platelets ≥ 100000/mm3, Hb ≥10 g/dl);

7. Adequate kidney function (serum creatinine < 1.5 mg/dL);

8. Adequate liver function:

• ALT and AST < 3 ULN

• Serum total bilirubin ≤ 1.5 ULN or in subjects with biliary stenting ≤ 2 ULN;

9. No prior treatment (chemotherapy, radiotherapy and/or surgery) for pancreaticcancer;

10. Women must not be on pregnancy or lactation;

11. Patient of child-bearing potential must agree to use two medically acceptablemethods of contraception (one for the patient and one for the partner) during thestudy and for a minimum of the following 6 months; this applies to patients of bothsexes. [appendix 4];

12. Patient information and signed written informed consent.

Exclusion Criteria:

1. Other types of non-ductal tumor of the pancreas, including endocrine tumors oracinar cell adenocarcinoma, cystadenocarcinoma and other periampullary malignancies.

2. Prior (within 1 year) or concurrent malignancies at other sites with the exceptionof surgically cured carcinoma in-situ of the cervix and basal or squamous cellcarcinoma of the skin

3. Symptomatic duodenal stenosis;

4. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemictherapy, defined as ongoing signs/symptoms related to the infection withoutimprovement despite appropriate antibiotics, antiviral therapy, and/or othertreatment

5. Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subject receiving immunosuppressive or myelosuppressivemedications that would in the opinion of the investigator, increase the risk ofserious neutropenic complications

6. Clinical stage IV (including ascites or malignant pleural effusion) diseaseaccording to TNM 8th Ed. 2017 [appendix 1];

7. Locally advanced disease according to NCCN Guidelines Version 1.2020 - PancreaticAdenocarcinoma [appendix 2];

8. Serious medical risk factors involving any of the major organ systems, or seriouspsychiatric disorders, which could compromise the subject's safety or the study dataintegrity. These include, but are not limited to:

9. History of connective tissue disorders (eg, lupus, scleroderma, arteritisnodosa)

10. History of interstitial lung disease, slowly progressive dyspnea andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,pulmonary hypersensitivity pneumonitis or multiple allergies

11. History of the following within 6 months prior to Cycle 1 Day 1: a myocardialinfarction, severe/unstable angina pectoris, coronary/peripheral artery bypassgraft, New York Heart Association (NYHA) Class III-IV heart failure,uncontrolled hypertension, clinically significant cardiac dysrhythmia or ECGabnormality, cerebrovascular accident, transient ischemic attack, or seizuredisorder

12. Any significant medical condition, laboratory abnormality, or psychiatric illnessthat would prevent the subject from participating in the study

13. Any condition including the presence of laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study

14. Any condition that confounds the ability to interpret data from the study

15. Any familiar, sociologic or geographic conditions that can potentially interferewith the adhesion to the protocol or to the follow-up;

16. Pre-existing neuropathy

17. c.1679GG, c.1905+1AA, c.2846TT mutations in homozygous in DPYD gene. Dosemodification according to DPYD and UGT1A1 mutations are reported in Table 1 (https://www.aiom.it/wp-content/uploads/2019/10/2019_Racc-analisi-farmacogenetiche.pdf.)

18. Inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of theintestine.

19. Concurrent treatment with other experimental drugs;

20. Fructose intolerance.