Testing Ivonescimab Versus FOLFOX in Advanced Biliary Tract Cancer Patients

Inclusion Criteria: 1. Signed a written informed consent form prior to any trial specific procedures. 2. Histologically-proven intrahepatic cholangiocarcinoma, perihilar / distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded). 3. Locally advanced (non-resectable) or metastatic disease. 4. Participated in the Screening phase of the SAFIR-ABC10 trial. 5. Progression after first line standard of care (1L-SoC) regimen (CISGEM ± immunotherapy) as assessed by the investigator. 6. Eligible for second-line treatment with FOLFOX. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. Presence of at least one evaluable lesion according to RECIST v1.1. 9. Age ≥18 years. 10. Adequate bone marrow function: absolute neutrophil count (ANC) ≥2 × 10⁹/L, platelet count ≥100 × 10⁹/L, and haemoglobin ≥9 g/dL. Note: Blood transfusion or growth factor therapy should not be performed within 7 days prior to the screening haematology analysis. 11. Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (≤3 x ULN for patients with liver metastases or confirmed/suspected Gilbert syndrome, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 x ULN when documented liver metastasis). 12. Adequate renal function: estimated creatinine clearance ≥50 mL/min according to the Cockcroft-Gault formula, or estimated glomerular filtration rate value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and urine protein \< 2+ or 24 hour urine protein quantification \< 1.0 g. 13. Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN, and partial prothrombin time (PTT) or activated PTT ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy,or prophylactic coagulation). 14. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥50% at baseline as determined by either echocardiogram or multigated acquisition (MUGA) scan. 15. Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) tests: For patients with active HBV: HBV DNA \<500 IU/ml during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir). For patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidence by detectable HCV RNA), are eligible. 16. Performance of an esophagogastroduodenoscopy within 6 months of inclusion and assessment and treatment of varices of all sizes per local standard of care prior to randomisation. 17. Biliary tract obstruction has been relieved. 18. Adequate biliary drainage, with no evidence of ongoing infection. 19. Women of childbearing potential (WOCBP) having sex with an unsterilized male partner and unsterilized males having sex with a female partner of childbearing potential, must agree to use an effective method of contraception for the duration of trial participation and as required after completing study treatment. Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period. 20. WOCBP must have a negative serum pregnancy test performed within 3 days before randomisation and a negative urine pregnancy test on the day of first dose, prior to treatment administration. 21. Willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests, and other study procedures. 22. Affiliated to a social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials). Exclusion Criteria: 1. Toxicities from 1L-SoC not resolved to Grade ≤ 1 (according to version 5.0 of the National Cancer Institute - Common terminology criteria for adverse events \[NCI-CTCAE v5.0\]) before randomisation with the exception of alopecia. 2. Received first-line maintenance therapy with a matched target therapy proposed in SAFIR ABC10, or any second-line treatment. 3. Contraindication to ivonescimab. 4. Proven complete deficiency of dihydropyrimidine dehydrogenase (DPD). 5. Treatment with brivudine, sorivudine or their chemical analogues in the 4 weeks prior to randomisation. 6. Major surgical procedures or serious trauma within 4 weeks prior to randomisation, or plans for major surgery within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterisation and port implantation) within 3 days prior to randomisation. 7. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomisation, including but not limited to: 1. Gastrointestinal bleeding. 2. Haemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: transient haemoptysis associated with diagnostic bronchoscopy is allowed. 3. Nasal bleeding /epistaxis (bloody nasal discharge is allowed). 4. Need for therapeutic anticoagulant therapy within 14 days prior to randomization. Note: Prophylactic anticoagulation for deep vein thrombosis or pulmonary embolism or to maintain venous patency is allowed. 8. Current hypertension with systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy. 9. History of major diseases before randomization, specifically: 1. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association classification ≥ grade 2) or vascular disease (eg, aortic aneurysm at risk of rupture) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poo