A Phase II Study of Ivonescimab in Combination With GEMOX as Neoadjuvant and Conversion Therapy for Biliary Tract Cancer

Inclusion Criteria:

• 1. Subjects voluntarily participate in the study, agree to sign a written informed consent form, demonstrate good compliance, and are willing to cooperate with follow-up.

• 2. Male or female aged >= 18 and <= 80 years at the time of signing the ICF.

• 3. Histologically or cytologically confirmed biliary tract cancer (BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), and radiologically assessed as locally advanced or with oligometastases (defined as Stage IIIA or higher lesions according to the 8th edition of the AJCC staging system). Subjects must agree to provide archived or fresh tumor biopsy specimens and peripheral blood samples for biomarker testing.

• 4. Lesion assessment meets one of the following conditions:

• Neoadjuvant Therapy Cohort: The tumor is graded as locally advanced with no distant metastasis, and theoretically can achieve radical resection through complex resection combined with vascular reconstruction, but both the surgical risk and postoperative recurrence risk are high (single tumor diameter > 5 cm; imaging suggests vascular invasion or hilar lymph node metastasis; tumor number > 3 or any single tumor > 3 cm; preoperative CA19-9 > 37 U/mL or exceeding the upper limit of normal [applicable to centers where the normal range is not < 37 U/mL]).

• Conversion Therapy Cohort: The tumor is graded as locally advanced, unresectable, or combined with oligometastatic status (oligometastasis is defined as: metastatic lesions confined to a single organ or specific regional lymph nodes, and the number of metastatic lesions is <= 5), with the possibility of achieving radical resection of the primary lesion and no evidence of disease (NED) status for metastatic lesions after comprehensive treatment.

• 5. At least one measurable lesion (according to RECIST v1.1 criteria, the longest diameter of the measurable lesion on spiral CT scan >= 10 mm or the shortest diameter of enlarged lymph nodes >= 15 mm).

• 6. No prior systemic therapy for biliary tract cancer.

• 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.

• 8. Child-Pugh class A liver function.

• 9. Normal bone marrow, liver, and kidney function, meeting the following clinical laboratory evaluation criteria within 7 days prior to treatment (the conditions cannot be met by administering any blood components, cell growth factors, albumin, or other corrective medications within 14 days prior to obtaining the laboratory tests; patients developing obstructive jaundice after percutaneous transhepatic cholangial drainage [PTCD] or endoscopic retrograde cholangiopancreatography [ERCP] treatment may be considered for enrollment if liver function indicators meet the inclusion criteria):

  1. Absolute neutrophil count (ANC) >= 1.5 x 10^9/L, platelet count >= 90 x 10^9/L, hemoglobin >= 90 g/L; AST and ALT <= 3 x ULN (upper limit of normal); TBil <= 1.5 x ULN;
  2. Hemoglobin > 9 g/dL without blood transfusion or use of erythropoietin within the past 14 days;
  3. Serum creatinine <= 1.5 x ULN and creatinine clearance rate (calculated using Cockcroft-Gault formula) >= 60 ml/min;
  4. Good coagulation function, International Normalized Ratio (INR) <= 1.2 or Prothrombin Time (PT) <= 1.2 x ULN;
  5. Normal thyroid function, defined as Thyroid Stimulating Hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with total T3 (or FT3) and FT4 within the normal range are also eligible;
  6. Myocardial enzyme spectrum within the normal range (isolated laboratory abnormalities judged by the investigator to have no clinical significance are also permitted).

• 10. Subjects with previous or current Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection must have received standard antiviral therapy, and the investigator must confirm that the current liver disease status is stable and suitable for receiving the study treatment.

• 11. Women of childbearing potential: agree to use effective contraceptive methods during the study period and for 120 days after the last dose, and have a negative urine or serum pregnancy test within 7 days prior to the first dose.

• 12. Men: agree to use effective contraceptive methods during the study period and for 120 days after the last dose.

Exclusion Criteria:

• 1. Diagnosed with mixed periampullary cancer, or mixed hepatocellular-cholangiocarcinoma.
• 2. Prior systemic anti-tumor therapy for BTC.
• 3. Prior treatment with gemcitabine-based chemotherapy, platinum-based chemotherapy, or any tumor immunotherapy/targeted therapy (e.g., PD-1/PD-L1 inhibitors, VEGF inhibitors, etc.).
• 4. History of severe allergy to other monoclonal antibodies. Known severe allergy or intolerance to gemcitabine, platinum drugs, or any of their components/excipients.
• 5. Known allergy or intolerance to recombinant humanized PD-1 monoclonal antibody drugs, VEGF monoclonal antibody drugs, and their components (or any excipients), or a history of severe allergy to other monoclonal antibodies.
• 6. Pericardial effusion, uncontrollable pleural effusion, or clinically significant ascites within 7 days prior to treatment, defined as meeting the following criteria: (a) ascites detectable by physical examination during the screening period, or (b) ascites requiring therapeutic paracentesis during the screening period.
• 7. Clinical evidence of portal hypertension with esophageal or gastric varices within 6 months prior to the start of treatment.
• 8. Any bleeding or thrombotic disorders within 6 months prior to the start of treatment, or currently taking any anticoagulants (e.g., warfarin or similar drugs) requiring monitoring of the International Normalized Ratio (INR) during treatment.
• 9. History of any malignant tumor, except for the BTC studied in this clinical trial and cured locally recurrent cancers (e.g., resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical cancer or breast cancer in situ, occult thyroid cancer).
• 10. Known central nervous system metastasis and/or leptomeningeal disease prior to treatment.
• 11. History of any active immunodeficiency or autoimmune disease, and/or any immunodeficiency or autoimmune disease that may relapse at the time of screening.
• 12. Any severe chronic or active infection (except viral hepatitis) requiring systemic antibacterial, antifungal, or antiviral therapy (e.g., tuberculosis) prior to the start of treatment.
• 13. Electrocardiogram (ECG) during screening shows a heart rate-corrected QT interval (QTc) (corrected using Fridericia's formula) exceeding 450 milliseconds. Note: If the QTc interval exceeds 450 milliseconds on the first ECG, a repeat ECG will be performed to confirm the result.
• 14. Presence of any of the following cardiovascular risk factors: cardiogenic chest pain within 28 days prior to treatment, defined as moderate pain limiting activities of daily living (ADL); symptomatic pulmonary embolism within 28 days prior to treatment; acute myocardial infarction within 6 months prior to treatment; history of New York Heart Association (NYHA) Class III or IV heart failure within 6 months prior to treatment; Grade >= 2 ventricular arrhythmia within 6 months prior to treatment; cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months prior to treatment.
• 15. Organ transplantation or hematopoietic stem cell transplantation (HSCT) or any major surgery within 28 days prior to treatment.
• 16. Known psychiatric or substance abuse disorders that may interfere with cooperation in the trial.
• 17. Receipt of live vaccine within 28 days prior to treatment. Note: Seasonal influenza vaccines are generally inactivated influenza vaccines and are permitted.
• 18. Known history of Human Immunodeficiency Virus (HIV) infection or syphilis infection.
• 19. Any history of disease, treatment, or laboratory abnormalities that, in the opinion of the principal investigator, may confound the test results, interfere with the subject's participation throughout the trial, or are not in the best interest of the subject.
• 20. Currently participating in and receiving treatment in another drug or device study, or having participated in such studies within 4 weeks prior to the first dose of the study drug.
• 21. Pregnant or breastfeeding from the screening visit to 120 days after the last dose, or expecting to conceive or give birth within the planned duration of the trial.
• 22. Poor compliance as judged by the investigator, or presence of other conditions making the patient unsuitable to participate in this trial.
• 23. Presence of multiple medical contraindications making it unsuitable to undergo contrast-enhanced imaging (CT or MRI) examinations.
• 24. Presence of surgical contraindications; patients deemed unsuitable for surgery by the investigators.