Zanidatamab Combined With Liposomal Irinotecan and Capecitabine for Second-line Treatment of HER2-positive Unresectable Biliary Tract Tumors

Inclusion Criteria

1. Informed consent: Voluntary provision of written informed consent; age ≥18 years.
2. Pathologic diagnosis: Histologically or cytologically confirmed unresectable locally advanced or metastatic biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer.
3. HER2 status: HER2 positivity confirmed by immunohistochemistry and/or fluorescence in situ hybridization, defined as IHC 3+ or IHC 2+ with FISH-confirmed amplification. Local test results from each participating center will be used for eligibility screening.
4. Prior treatment:

   1. Disease progression after or intolerance to a standard first-line regimen containing a programmed cell death protein 1 or programmed death-ligand 1 inhibitor.
   2. No prior treatment with irinotecan, capecitabine, or any HER2-targeted therapy.
5. Measurable disease: At least one measurable target lesion according to RECIST version 1.1.
6. Performance status: Eastern Cooperative Oncology Group performance status of 0 or 1.
7. Life expectancy: ≥12 weeks.
8. Adequate organ function, based on test results obtained within 14 days before the first dose:

   1. Hematologic function: Absolute neutrophil count ≥1.5 × 10⁹/L; hemoglobin ≥90 g/L; platelet count ≥100 × 10⁹/L.
   2. Hepatic function: Total bilirubin ≤1.5 × the upper limit of normal; alanine aminotransferase and aspartate aminotransferase ≤2.5 × the upper limit of normal, or ≤5 × the upper limit of normal in patients with liver metastases.
   3. Renal function: Serum creatinine ≤1.5 × the upper limit of normal or creatinine clearance ≥30 mL/min.
   4. Cardiac function: Left ventricular ejection fraction ≥50%.
   5. Coagulation function: International normalized ratio ≤1.5 × the upper limit of normal.
9. Contraception: Patients of childbearing potential must agree to use effective contraception during the study and for 6 months after the last dose.

Exclusion Criteria

1. History of malignancy: Another active malignancy within the previous 5 years, except for cured cervical carcinoma in situ or basal cell carcinoma of the skin.
2. Tumor type: Ampullary carcinoma.
3. Uncontrolled conditions:

   1. Uncontrolled pleural effusion, ascites, or pericardial effusion. Patients requiring drainage only may be enrolled if there is no clinically significant reaccumulation within 3 days after drainage is discontinued.
   2. Known active central nervous system metastases and/or carcinomatous meningitis.
4. Recent treatment:

   1. Major surgery or radiotherapy within 4 weeks before the first dose.
   2. Traditional Chinese medicines with an approved antitumor indication within 2 weeks before the first dose.
   3. Participation in another interventional clinical study within 4 weeks before the first dose.
5. Comorbidities:

   1. A history of myocardial infarction or unstable angina within 6 months before enrollment; troponin levels meeting diagnostic criteria for myocardial infarction; or clinically significant cardiac disease, including ventricular arrhythmias requiring treatment, uncontrolled hypertension, or any history of symptomatic heart failure.
   2. Active infection, including hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection.

   Patients positive for hepatitis B surface antigen must have an HBV DNA level \<1,000 IU/mL and agree to receive antiviral therapy throughout the study.

   Hepatitis C virus infection, except that the following patients are eligible: (i) patients with no history of curative antiviral therapy who have a confirmed negative viral load; or (ii) patients who completed curative antiviral therapy ≥12 weeks before enrollment and have a negative viral load.
6. Gastrointestinal conditions: Factors that may affect absorption of oral medication, such as chronic diarrhea or intestinal obstruction; or Grade ≥2 diarrhea.
7. Drug interactions: Use of strong CYP3A4 or UGT1A1 inhibitors or inducers within 3 weeks before the first dose.
8. Adverse reactions: Toxicities from prior therapy that have not recovered to Grade ≤1, except alopecia and peripheral neuropathy of Grade ≤2.
9. History of a life-threatening hypersensitivity reaction to monoclonal antibodies, recombinant proteins, or any excipient in the zanidatamab formulation.
10. Women who are pregnant or breastfeeding, and women or men planning to conceive a child.