Testing Ivonescimab Versus FOLFOX in Advanced Biliary Tract Cancer Patients

The object of this trial is to test whether ivonescimab is superior to standard chemotherapy (FOLFOX regimen) for the treatment of patients with advanced biliary tract cancer after failure of a first line of chemotherapy. It is only open to patients who participated in the SAFIR-ABC10 trial (NCT05615818) but did not receive experimental treatment. Eligible patients will be randomised (2:1) to receive either ivonescimab or FOLFOX. Treatment will be continued until disease progression, or a maximum of 34 cycles of ivonescimab (experimental arm), whichever occurs first.

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 \10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy. 15. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: 1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study, 2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study, 3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: * Rash must cover \< 10% of body surface area, * Disease is well controlled at baseline and requires only low-potency topical corticosteroids, * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months. 16. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 17. Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol. 18. Pregnant or breast-feeding females. 19. Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable. 20. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons. 21. Individuals deprived of liberty or placed under protective custody or guardianship.