Personalized First-line Chemotherapy Choice in Advanced Pancreatic Adenocarcinoma Using Transcriptomic Signatures

Inclusion Criteria:

1. Written informed consent obtained from the patient prior to performing anyprotocol-related procedures, including screening evaluations.

2. Willing and able to comply with the protocol for the duration of the study includingundergoing treatment and scheduled visits and examinations including follow up.

3. Histologically or cytologically proven Pancreatic Ductal Adenocarcinoma (PDAC).

4. Metastatic disease.

5. Measurable or evaluable lesions according to RECIST v1.1 criteria.

6. First-line therapy (previous neoadjuvant/adjuvant chemotherapy not allowed).

7. Age ≥ 18 years (no upper limit, patients ≥ 75 years old must have a G8 score ≥ 14).

9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.

10. Availability of tumor tissue sample from the primary pancreatic tumor or livermetastasis (chemo-naïve) before inclusion in step 1.

11. Adequate organ function, as defined by the following (blood test ≤ 7 days prior toinclusion):

12. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (≤ 5 ULN in case of liver metastases)

13. Total serum bilirubin ≤ 1.5 ULN

14. Serum albumin ≥ 28 g/L

15. Hemoglobin ≥ 9.0 g/dl

16. Absolute neutrophil count (ANC) ≥ 1,500/μL

17. Platelets ≥ 100,000/μL

18. Creatinine clearance ≥ 50 mL/min (MDRD).

19. No Dihydropyrimidine dehydrogenase (DPD) deficiency (normal uracil level).

20. Life expectancy ≥ 3 months.

21. a. Evidence of post-menopausal status b. (or) negative urinary or serum pregnancytest for female pre-menopausal patients.

22. Registration in a National Health Care System.

Exclusion Criteria:

1. Concurrent enrolment in another interventional clinical study.

2. Previous treatment with chemotherapy for pancreatic cancer.

3. Uncontrolled massive pleural effusion or massive ascites.

4. Known deficiency in UGT1A1 (homozygous UGT1A1*28 allele).

5. Active bacterial, viral, or fungal infection requiring systemic therapy, includingtuberculosis, hepatitis B (known positive Hepatitis B Virus surface antigen (HBsAg)result), hepatitis C (with positive RNA), Sars-Cov-2 or human immunodeficiency virus (positive HIV 1/2 antibodies).

6. Diagnosis of any second malignancy within the last 3 years, except for adequatelytreated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervixuteri.

7. Known active central nervous system metastases and/or carcinomatous meningitis;patients with previously treated brain metastases may participate provided they arestable (without evidence of progression by imaging for at least 4 weeks prior to thefirst dose of trial treatment and any neurologic symptoms have returned tobaseline).

8. Uncontrolled intercurrent illness, including but not limited to, symptomaticcongestive heart failure or coronary disease, peripheral artery disease, severechronic obstructive pulmonary disease, decompensated cirrhosis, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent.

9. Live vaccine administration within 30 days prior to the first dose of studytreatment.

10. Known or suspected allergy or hypersensitivity to any of the study drugs or any ofthe study drug excipients.

11. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with participation for thefull duration of the trial, or is not in the best interest of the participant, inthe opinion of the treating investigator.

12. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug.

13. Major surgical procedure (as defined by the Investigator) within 4 weeks prior tothe first dose of trial treatment.

14. Pregnancy/lactation.

15. Person under legal protection or tutelage or guardianship.