CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative Chemotherapy Versus Immediate Resection in patIents With resecTable BiliarY Tract Cancers (BTC) at High Risk for Recurrence

Inclusion Criteria:

1. Patient able and willing to provide written informed consent and to comply with thestudy protocol and with the planned surgical procedures.

2. Female and male patients ≥18 years and <75 years.

3. Histologically or cytologically confirmed non metastatic resectable carcinoma ofbiliary tract (BTC), including gallbladder carcinoma (GBC), intrahepatic,periperihilar or distal Cholangiocarcinoma (CCA). Mixed tumor entities withhepatocellular carcinoma and ampullary cancers are excluded.

4. Availability of a tumoral sample

5. ECOG performance status of 0-1.

6. No prior tumor resection for BTC.

7. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax and PETscan.

8. Technically resectable BTC as per local Multidisciplinary Team (MDT) assessment,including a core team with at least one medical oncologist, one surgeon, oneradiologist, one endoscopist/gastroenterologist and one pathologist, all withexpertise > 3 years on biliary tract cancer and hepatobiliary oncology.

9. High risk for recurrence defined as the presence of at least one of the followingrisk features, as evaluated at baseline (pre-surgery):

10. For cholangiocarcinoma:

• Suspected or definite locoregional lymph node involvement (at least one ofthe following):
• positive FNA cytology (obtained by EUS).
• positive locoregional lymph nodes at PET-CT.
• suspected positive locoregional lymph nodes at imaging (CT or MRIscan) according to local MDT discussion (eg. short axis > 1.5 cm,contrast enhancement uptake, round shape, restriction at DWI).
• Macrovascular invasion at preoperative CT scan.
• Expected R1 resection due to proximity to major intrahepatic vascular andbiliary structures.
• For iCCA, presence of satellitosis or multifocal disease or radiologicalsuspicion of tumoral diaphragmatic adhesion.
• For iCCA, size of the liver lesion >5 cm.
• For eCCA, size of the primary lesion > 3cm.
• Ca19.9 >100 U/mL.

2. For GBC:

• Incidentally Detected Gallbladder Carcinoma (IGBC) after simplecholecystectomy with indication for radical second surgery (>pT2) or newlydiagnosed GBC.

10. Estimated life expectancy > 3 months.

11. Adequate baseline hematologic function characterized by the following at screening:

12. ANC ≥ 1.5 × 109/L

13. platelets ≥ 100 × 109/L

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

15. Adequate liver function characterized by the following at screening:

16. 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.

17. Serum transaminases (AST and/or ALT) < 3 x ULN.

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

19. 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).

20. No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency withDPYD gene testing mandatory at screening as per national guidelines

21. Females of childbearing potential must agree to remain abstinent (refrain fromsexual intercourse) or use highly effective contraceptive methods, as defined inAPPENDIX V of the full protocol, during the treatment period and for at least 7months after the last administration of study treatments.

22. Males must agree to remain abstinent (refrain from sexual intercourse) or use highlyeffective contraceptive methods, as defined in APPENDIX V of the full protocol.

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

24. A participant 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:

1. Known allergy or hypersensitivity to any of the study drugs.

2. Any known additional malignancy that is progressing or requires active treatment, orhistory of other malignancy within 2 years of study entry except for curativelytreated basal cell carcinoma of the skin, in situ carcinoma of the cervix, andprostate cancer.

3. Locally unresectable tumor according to local MDT (including radiological evidencesuggesting inability to resect with curative intent whilst maintaining adequatevascular inflow and outflow, and sufficient future liver remnant).

4. Evidence of distant metastases at any site.

5. Tumors requiring multi-step surgical procedures such as two-stage hepatectomy orAssociating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS)due to liver volumetry-based assessment of anticipated inadequate future liverremnant.

6. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and ahistory of hepatic decompensation in the year before enrolment.

7. 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.

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

9. 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 they must be compliant with antiretroviraltreatment.

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

11. Any other concurrent antineoplastic treatment including radiotherapy.

12. Previous or concurrent systemic (eg cytotoxic or targeted or other experimentaldrugs) therapy for BTC.

13. Prior surgery or locoregional therapy for BTC.

14. Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III orIV, unstable angina pectoris, history of myocardial infarction in the last threemonths, significant arrhythmia).

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

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

17. Presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency withDPYD gene testing mandatory at screening as per national guidelines.

18. Lack of physical integrity of the upper gastrointestinal tract, malabsorptionsyndrome, or inability to take oral medication.