Trastuzumab Rezetecan Combined With Pertuzumab and Iparomlimab and Tuvonralimab for Biliary Tract Cancer

Prior treatment

• Participation in other investigational drug trials within the past 3 months, or concurrent enrollment in another interventional clinical trial (observational/non-interventional studies or follow-up phases allowed).
• Previous treatment with HER2-targeted agents, HER2-ADCs, or immunotherapy (e.g., checkpoint inhibitors/agonists, cell therapy). Therapeutic cancer vaccines excluded.
• Prior anti-tumor therapy toxicities not recovered to CTCAE v5.0 Grade ≤1 (alopecia/lab abnormalities meeting inclusion criteria allowed per investigator).
• Unexplained intra-abdominal gas unrelated to recent surgery/paracentesis.
• Active tuberculosis (TB): Active TB within 1 year prior to enrollment；Untreated active TB history \>1 year prior.
• Surgical history: Major surgery within 4 weeks prior (excluding biopsies) or unhealed surgical wounds ；Planned major surgery during the study；Minor traumatic surgery within 7 days prior；
• Live attenuated vaccines: Administered within 28 days before the first study dose; Planned use during the study or within 60 days after the last dose.

Other illness

• Histologically or cytologically confirmed ampullary carcinoma, small cell carcinoma, neuroendocrine tumors, sarcoma, mucinous cystic neoplasms, or other rare biliary tract malignancies.
• Active other malignancies within 5 years or concurrently.
• History of leptomeningeal disease, brain metastases, or current brain metastases.
• Any condition deemed by the investigator to compromise safety or compliance, including: Uncontrolled systemic diseases (e.g., severe hypertension, moderate/severe symptomatic ascites) Uncontrolled/moderate-or-greater pleural/pericardial effusion Acute/chronic uncontrolled pancreatitis Active bleeding disorders, infections, or ILD/interstitial lung disease Severe chronic GI disorders with diarrhea Psychiatric illness/social circumstances affecting compliance History of allogeneic organ or bone marrow transplantation.
• Active autoimmune disease within 2 years or history of recurrent autoimmune disease (e.g., autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyper/hypothyroidism). (Except hypothyroidism controlled by hormone replacement)
• Abdominal complications within 6 months: Abdominal fistula, gastrointestinal perforation, or abscess；Tumor invasion of adjacent organs (e.g., aorta, trachea) with high bleeding/fistula risk.
• Immunodeficiency (e.g., HIV infection) or history of organ transplantation.
• Bleeding/thrombotic risks: Gastrointestinal bleeding within 6 months or high bleeding tendency；Known hereditary/acquired bleeding disorders or thrombophilia.

Lab values

• Within 12 months prior: NYHA Class ≥II congestive heart failure Unstable angina, myocardial infarction Poorly controlled arrhythmia or cerebrovascular accident LVEF \<50% by echocardiogram QTc \>480 ms (Fridericia method; average of 3 measurements if abnormal) Uncontrolled hypertension (SBP≥150 mmHg and/or DBP≥100 mmHg, average of ≥2 readings) History of hypertensive crisis or encephalopathy.
• Other exclusionary factors per investigator judgment (e.g., substance abuse, severe comorbidities, abnormal lab values, psychosocial circumstances).

Other

• Severe/unhealed wounds, active ulcers, or untreated fractures.
• CNS metastases (past or present).

• Patients must voluntarily participate in the trial, provide fully informed consent with signed written documentation, and demonstrate good compliance.
• Age between 18 and 75 years (inclusive), calculated as of the day of signing the informed consent form; both male and female patients are eligible.
• Patients must have histologically or cytologically confirmed locally advanced or metastatic biliary tract cancer, including: Cholangiocarcinoma (intrahepatic or extrahepatic) and Gallbladder carcinoma
• HER2 Expression Criteria: HER2 Overexpression: IHC 3+ OR IHC 2+ with FISH-positive (gene amplification); HER2 Moderate/Low Expression: Moderate: IHC 2+ with FISH-negative (no gene amplification) Low: IHC 1+ (any level of HER2 staining)
• Patients must not have received prior systemic anti-tumor therapy for advanced disease. Prior neoadjuvant/adjuvant chemotherapy and/or radiotherapy is permitted, provided ≥6 months have elapsed between the last dose and disease recurrence.
• Patients must have at least one measurable lesion meeting RECIST v1.1 criteria, and the lesion must be suitable for repeated accurate measurements.
• ECOG performance status of 0 or 1;
• estimated life expectancy ≥12 weeks;
• Adequate organ and bone marrow function meeting all criteria below (within 14 days prior to treatment initiation): 1. Hematological Tests \*(No transfusion, G-CSF use, or corrective medication within 14 days before screening)\* Hemoglobin (Hb) ≥90 g/L Absolute Neutrophil Count (ANC) ≥1.5 × 10\<sup\>9\</sup\>/L Platelets (PLT) ≥75 × 10\<sup\>9\</sup\>/L 2. Biochemical Tests (No albumin infusion within 14 days before screening) Total Bilirubin (TBIL) ≤2 × ULN Gilbert's syndrome: ≤3 × ULN ALT/AST ≤3.0 × ULN Liver metastasis: ≤5 × ULN Serum Creatinine (Cr) ≤1.5 × ULN OR Creatinine Clearance (CrCl) ≥50 mL/min (Cockcroft-Gault formula);
• Patients with detectable HBV DNA levels (≥10 IU/mL or above the lower limit of quantification per local laboratory assays) who are HBV-infected (HBsAg-positive and/or anti-HBc-positive) must receive antiviral therapy prior to treatment initiation according to institutional practice to achieve sufficient viral suppression. Antiviral therapy must be maintained throughout the study and for 6 months after the last dose of study treatment. Patients with positive anti-HBc but undetectable HBV DNA (\<10 IU/mL or below the lower limit of quantification per local laboratory assays) do not require antiviral prophylaxis unless HBV DNA exceeds 10 IU/mL or reaches detectable levels during treatment monitoring.
• Childbearing potential females: Negative pregnancy test (urine/serum) within 7 days pre-dose (serum result definitive if urine inconclusive). Sexually active with non-sterilized males: Use acceptable contraception from screening until 120 days post-last dose.
• Non-sterilized males sexually active with childbearing-potential partners: Use effective contraception from screening until 120 days post-last dose. Discontinuation post-120 days requires investigator discussion.
• Subjects must comply with visits, treatment, lab tests, and study requirements.