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

A Prospective, Open-Label, Multicenter Phase II Clinical Study of Trastuzumab Rezetecan Combined With Pertuzumab and Iparomlimab and Tuvonralimab as First-Line Therapy for HER2-Expressing Locally Advanced or Metastatic Biliary Tract Cancer

Based on unmet clinical needs, relevant research backgrounds, and scientific evidence, it is planned to conduct a prospective, dual-cohort exploratory study. The aim of this study is to explore the efficacy and safety of ricartuzumab combined with pertuzumab and epalrestat-vorolizumab in the first-line treatment of HER2-expressing locally advanced or metastatic biliary tract cancer. It is expected to provide more treatment options for biliary tract cancer patients, optimize treatment strategies, and improve patients' long-term survival rates.

The aim of this study is to explore the efficacy and safety of ricartuzumab combined with pertuzumab and epalrestat-vorolizumab in the first-line treatment of HER2-expressing locally advanced or metastatic biliary tract cancer. It is expected to provide more treatment options for biliary tract cancer patients, optimize treatment strategies, and improve patients' long-term survival rates.

Inclusion Criteria:

1. Patients must voluntarily participate in the trial, provide fully informed consent with signed written documentation, and demonstrate good compliance.
2. 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.
3. Patients must have histologically or cytologically confirmed locally advanced or metastatic biliary tract cancer, including: Cholangiocarcinoma (intrahepatic or extrahepatic) and Gallbladder carcinoma
4. 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)
5. 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.
6. Patients must have at least one measurable lesion meeting RECIST v1.1 criteria, and the lesion must be suitable for repeated accurate measurements.
7. ECOG performance status of 0 or 1;
8. estimated life expectancy ≥12 weeks;
9. 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 × 10⁹/L Platelets (PLT) ≥75 × 10⁹/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);
10. 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.
11. 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.
12. 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.
13. Subjects must comply with visits, treatment, lab tests, and study requirements.

Exclusion Criteria:

1. Histologically or cytologically confirmed ampullary carcinoma, small cell carcinoma, neuroendocrine tumors, sarcoma, mucinous cystic neoplasms, or other rare biliary tract malignancies.
2. Active other malignancies within 5 years or concurrently.
3. History of leptomeningeal disease, brain metastases, or current brain metastases.
4. 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).
5. 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.
6. 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.
7. 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)
8. Previous treatment with HER2-targeted agents, HER2-ADCs, or immunotherapy (e.g., checkpoint inhibitors/agonists, cell therapy). Therapeutic cancer vaccines excluded.
9. Prior anti-tumor therapy toxicities not recovered to CTCAE v5.0 Grade ≤1 (alopecia/lab abnormalities meeting inclusion criteria allowed per investigator).
10. Unexplained intra-abdominal gas unrelated to recent surgery/paracentesis.
11. 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.
12. Immunodeficiency (e.g., HIV infection) or history of organ transplantation.
13. Active tuberculosis (TB): Active TB within 1 year prior to enrollment；Untreated active TB history >1 year prior.
14. Bleeding/thrombotic risks: Gastrointestinal bleeding within 6 months or high bleeding tendency；Known hereditary/acquired bleeding disorders or thrombophilia.
15. 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；
16. Severe/unhealed wounds, active ulcers, or untreated fractures.
17. CNS metastases (past or present).
18. 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.
19. Other exclusionary factors per investigator judgment (e.g., substance abuse, severe comorbidities, abnormal lab values, psychosocial circumstances).