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

PURITY is a multicentre, randomized adaptive phase II/III trial aimed at comparing the triplet combination of gemcitabine, cisplatin and nabpaclitaxel as neoadjuvant treatment (ARM A) versus standard upfront surgery (ARM B) in terms of 12-month PFS rate (phase II part) and PFS (phase III part) in patients with resectable BTC at high risk for recurrence.

Inclusion Criteria: 1. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures. 2. Female and male patients ≥18 years and \ 3 years on biliary tract cancer and hepatobiliary oncology. 9. High risk for recurrence defined as the presence of at least one of the following risk features, as evaluated at baseline (pre-surgery): 1. 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. 2. For GBC: * Incidentally Detected Gallbladder Carcinoma (IGBC) after simple cholecystectomy with indication for radical second surgery (\>pT2) or newly diagnosed GBC. 10. Estimated life expectancy \> 3 months. 11. Adequate baseline hematologic function characterized by the following at screening: 1. ANC ≥ 1.5 × 109/L 2. platelets ≥ 100 × 109/L 3. hemoglobin ≥ 9 g/dl. Note: prior transfusions for patients with low hemoglobin are allowed. 12. Adequate liver function characterized by the following at screening: 1. 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. 2. Serum transaminases (AST and/or ALT) \< 3 x ULN. 13. 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 14. 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). 15. No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines 16. 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. 17. 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. 18. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women \