Gemcitabine Plus Nab-paclitaxel as Switch Maintenance Versus Continuation of Modified FOLFIRINOX as 1st Line Chemotherapy in Patients With Advanced Pancreatic Cancer.

Inclusion Criteria:

• Patient able and willing to provide written informed consent and to comply with thestudy protocol.

• Subjects must be ≥18 years.

• Histologically or cytologically confirmed unresectable locally advanced ormetastatic pancreatic adenocarcinoma eligible for treatment in the first-linesetting.

• Presence of measurable or non-measurable disease assessed by CT scan and/or MRIaccording to RECIST 1.1. Note: any lesion which has been subjected to percutaneoustherapies or radiotherapy should not be considered measurable, unless the lesion hasclearly progressed since the procedure.

• Availability of archival tumor sample (primary tumor or metastatic site) forbiomarker analysis.

• ECOG performance status of 0-1 (if age < 70 years). If age ≥70 years, ECOG PS mustbe 0.

• Estimated life expectancy > 3 months.

• Adequate baseline hematologic function characterized by the following at screening:

• Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L.

• Platelets count ≥ 100 × 109/L.

• Hemoglobin ≥ 9 g/dl. Note: prior transfusions for patients with low hemoglobinare allowed.

• Adequate liver function characterized by the following at screening:

• Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note: Subjects with Serumtotal bilirubin ≥ 1.5 × ULN and conjugated bilirubin ≤ ULN or < 40% of totalbilirubin are allowed.

• Serum transaminases (AST and/or ALT) < 3 x ULN (< 5 x ULN in presence of livermetastasis). In participants with elevated AST or ALT, the values must bestable for at least 2 week and with no evidence of biliary obstruction byimaging.

• Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN andcalculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50mL/min.

• Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unlessreceiving anticoagulation therapy).

• No presence of complete dihydropyrimidine dehydrogenase (DPYD) enzyme deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT) withDPYD gene testing mandatory at screening as per national guidelines.UDP-glucuronosyltransferase 1A1 (UGT1A1) testing is not mandatory. However, if UGTtest is routinely performed in the participating centers, enrolment of patientscarriers of variants of DPYD and homozygous variant UGT1A1 [7/7] has to be discussedwith the Sponsor.

• Women of childbearing potential must agree to remain abstinent (refrain from sexualintercourse) or use highly effective contraceptive methods, as defined in APPENDIX Vof the full protocol, during the treatment period and for at least 7 months afterthe last administration of study treatments.

• Negative serum pregnancy test within 7 days of starting study treatment inpre-menopausal women and women <1 year after the onset of menopause.

• Men must agree to remain abstinent (refrain from sexual intercourse) or use highlyeffective contraceptive methods during the treatment period and for at least 7months after the last administration of study treatments.

• Participants must agree not to donate eggs/sperm for future use for the purposes ofassisted reproduction during the study and for a period of 7 months after receivingthe last dose of study treatment. Female and male participants should considerpreservation of eggs/sperm prior to study treatment as anti-cancer treatments mayimpair fertility.

Exclusion Criteria:

• Pancreatic neuroendocrine, acinar, squamous/adenosquamous, or islet tumors.

• Previous or concurrent systemic (e.g. cytotoxic or targeted or other experimentaldrugs) therapy for advanced pancreatic adenocarcinoma.

Note: previous (neo)adjuvant or perioperative anti-cancer therapy for non-metastatic, resectable or borderline resectable PDAC, associated with surgery on the primary tumor, is allowed if > 9 months have elapsed from the last dose of therapy and documented disease progression or relapse.

• Major surgery or radiation therapy performed within <4 weeks before randomization.Palliative radiotherapy to bone lesions is allowed if performed > 2 weeks prior tostart of study treatment. Patients must have recovered from an effect from majorsurgery.

• Known allergy or hypersensitivity to study drugs and/or their excipients.

• Unresolved toxicity ≥ CTCAE grade 2 attributed to any prior therapies (e.g. grade ≥2peripheral neurotoxicity), excluding anemia or alopecia.

• Presence of symptomatic central nervous system (CNS) metastases, or CNS metastasesthat requires directed therapy (such as radiotherapy or surgery) or increasing dosesof corticosteroids 2 weeks prior to study entry. Participants with treatedsymptomatic brain metastases should be neurologically stable for 4 weekspost-treatment and prior to study entry.

• Any known additional malignancy that is progressing or requires active treatment, orhistory of other malignancy within 2 years prior to study entry except forcuratively treated basal cell carcinoma of the skin, in situ carcinoma of thecervix, and prostate cancer.

• Know active uncontrolled hepatitis B or hepatitis C. Patients with a past orresolved HBV infection are eligible. Patients with chronic disease controlled byantiviral therapy or requiring prophylactic treatment are eligible.

• Chronic or current active infectious disease requiring systemic antibiotics orantifungal treatment within 2 weeks prior to enrollment.

• Known uncontrolled HIV infection. HIV-positive patients are eligible if their CD4+cell count amounts to 300 cells per μL or more; HIV viral load must be undetectableper standard of care assay, and patients must be compliant with antiretroviraltreatment.

• Pregnant or breast-feeding patient, or patient planning to become pregnant within 7months after the end of treatment.

• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA > II,unstable angina pectoris, history of myocardial infarction within 3 months beforestudy entry, significant arrhythmia).

• Presence of psychiatric disorder precluding understanding of information of trialrelated topics and giving informed consent.

• Any serious underlying medical conditions (judged by the investigator), that couldimpair the ability of the patient to participate in the trial.