A Single-arm, Multicenter Clinical Study of Iparomlimab and Toripalimab in Combination With Bevacizumab and Chemotherapy as First-line Treatment for Advanced Biliary Tract Cancer

Inclusion Criteria:

• Informed Consent: Patients voluntarily join this study and sign the informed consent form.
• Age: 18 to 75 years old, male or female.
• Histologically or cytologically confirmed, unresectable locally advanced or metastatic biliary tract cancer (BTC), including cholangiocarcinoma (intrahepatic and extrahepatic) and gallbladder carcinoma.
• No prior systemic anti-tumor therapy for locally advanced or metastatic BTC.
• At least one measurable lesion according to RECIST v1.1 that is suitable for accurate repeated measurement. Lesions previously irradiated or brain metastases are not eligible as target lesions.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• Adequate organ function
• For HBsAg positive subjects: HBV DNA must be < 2000 IU/mL (or < 10⁴ copies/mL), and effective antiviral therapy (e.g., Entecavir, Tenofovir, TAF, or Tenofovir Amibufenamide) must be administered throughout the study.

Subjects with a history of HCV infection but negative HCV RNA PCR results may be considered uninfected.

• Female subjects of childbearing potential must have a negative urine or serum pregnancy test (if urine test is not definitively negative, a serum test is required).
• Willingness to use highly effective contraceptive measures during the study and for 3 months after the last dose.
• Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other requirements of the study.

Exclusion Criteria:

• Histologically or cytologically confirmed small cell carcinoma, neuroendocrine tumors, lymphoma, sarcoma, colloid carcinoma, adenosquamous carcinoma, squamous cell carcinoma, mucinous intraductal papillary neoplasm, mucinous cystic neoplasms, or other rare pathological types of biliary tract tumors.
• Brain Metastases: History of brain metastases or presence of active brain metastases.
• Vascular Invasion & Bleeding Risk: Imaging at screening shows tumor invasion or encasement (>180 degrees) of major blood vessels; or the tumor presents with significant necrosis or cavitation, and the investigator judges that enrollment poses a high risk of bleeding.

• Cardiac Disease: Uncontrolled cardiac clinical symptoms or diseases, including but not limited to:

  1. Cardiac insufficiency classified as Class II or higher according to the New York Heart Association (NYHA) criteria, or Left Ventricular Ejection Fraction (LVEF) < 50% on echocardiography;
  2. Unstable angina pectoris;
  3. Myocardial infarction within 1 year prior to study entry;
  4. Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;
  5. QTc interval > 450 ms (male) or > 470 ms (female) (QTc calculated using the Fridericia formula; if abnormal, repeat ECG three times at 2-minute intervals and use the average value).
• Autoimmune Disease: Active autoimmune disease or a history of autoimmune disease likely to recur (including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism [patients controlled solely by hormone replacement therapy are not excluded]).
• Esophageal/Gastric Varices: History of esophageal or gastric variceal bleeding due to portal hypertension within 6 months prior to the first dose; known severe varices on endoscopy within 3 months prior to the first dose; or evidence of portal hypertension (including splenomegaly on imaging) with high bleeding risk assessed by the investigator (including moderate-to-severe esophageal/gastric varices with bleeding risk, local active gastrointestinal ulcers, and persistent positive fecal occult blood tests). Endoscopy is required to exclude patients with "red color signs." Patients with a history of "red color signs" are excluded.
• Hemorrhage: Any life-threatening bleeding event within 3 months prior to the first dose, including events requiring blood transfusion, surgery, local therapy, or continuous medication.
• Systemic Immunosuppression: Use of systemic corticosteroids or other immunosuppressive therapies for active autoimmune diseases within the past 2 years. Note: Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic treatment.
• Inflammatory Bowel Disease: Active or prior history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or chronic diarrhea.
• Transplantation: History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Pneumonitis/ILD: Previous or current history of non-infectious pneumonitis/interstitial lung disease requiring systemic glucocorticoid therapy.

Surgery: Major surgical procedure or severe trauma within 30 days prior to the first dose, or planned major surgery within 30 days after the first dose (as determined by the investigator); minor local surgery within 3 days prior to the first dose (excluding peripherally inserted central catheter [PICC] line placement and implantable venous port insertion).

• Infection: Severe active infection judged by the investigator.
• Pregnancy: Pregnant women or those planning to become pregnant during the study period.
• Prior Trials: Participation in another drug clinical trial within 12 months prior to enrollment.
• Other: Other conditions deemed unsuitable for enrollment by the investigator.