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

• Female and male patients ≥18 years and \<75 years.

• Histologically or cytologically confirmed non metastatic resectable carcinoma of biliary tract (BTC), including gallbladder carcinoma (GBC), intrahepatic, periperihilar or distal Cholangiocarcinoma (CCA). Mixed tumor entities with hepatocellular carcinoma and ampullary cancers are excluded.

• Availability of a tumoral sample

• ECOG performance status of 0-1.

• No prior tumor resection for BTC.

• Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax and PET scan.

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

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

∙ For cholangiocarcinoma:

⁃ Suspected or definite locoregional lymph node involvement (at least one of the following):

∙ positive FNA cytology (obtained by EUS).

‣ positive locoregional lymph nodes at PET-CT.

‣ suspected positive locoregional lymph nodes at imaging (CT or MRI scan) 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 and biliary structures.

• For iCCA, presence of satellitosis or multifocal disease or radiological suspicion 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.

‣ For GBC:

⁃ Incidentally Detected Gallbladder Carcinoma (IGBC) after simple cholecystectomy with indication for radical second surgery (\>pT2) or newly diagnosed GBC.

⁃ Estimated life expectancy \> 3 months.

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

• ANC ≥ 1.5 × 109/L

∙ platelets ≥ 100 × 109/L

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

⁃ Adequate liver function characterized by the following at screening:

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

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

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

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

⁃ No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines

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

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

⁃ Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women \<1 year after the onset of menopause.

⁃ A participant must agree not to donate eggs/sperm for future use for the purposes of assisted reproduction during the study and for a period of 7 months after receiving the last dose of study treatment. Female and male participants should consider preservation of eggs/sperm prior to study treatment as anti-cancer treatments may impair fertility.