Hepatic Arterial Infusion Chemotherapy Plus Envafolimab and Lenvatinib for First-Line Unresectable Advanced Biliary Tract Cancer

Inclusion criteria

Patients must meet all of the following inclusion criteria:

• Age between 18 years and [missing value] years, inclusive.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically or cytologically confirmed biliary tract carcinoma, deemed unsuitable for radical surgical resection.
• At least one measurable lesion as determined by the investigator in accordance with mRECIST or RECIST version 1.1.
• Estimated life expectancy greater than 3 months.
• No prior systemic therapy or local anti-tumor treatment, except for surgery (biliary drainage is permitted).
• Patients who experience relapse more than 6 months after completion of postoperative adjuvant therapy may be enrolled.
• Child-Pugh score of [missing value] points.
• Adequate organ function to meet the criteria for chemotherapy:

• Bone marrow function: absolute neutrophil count ≥ [missing value]/L; platelet count ≥ [missing value]; hemoglobin ≥ [missing value];
• Hepatic function: total bilirubin ≤ [missing value] × upper limit of normal (ULN); for patients without liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ [missing value] × ULN; for patients with confirmed liver metastases, AST and ALT ≤ [missing value] × ULN;
• Renal function: serum creatinine ≤ [missing value] × ULN; routine urinalysis showing urinary protein < [missing value]; if baseline urinary protein is [missing value], a 24-hour urine collection must confirm total protein ≤ 1 g/24 h;
• Coagulation function: international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; for patients receiving anticoagulant therapy, PT must be within the therapeutic range intended for the anticoagulant used.
• Female patients must be postmenopausal or, if premenopausal, have a negative urine or serum pregnancy test; male patients must agree to use effective contraception or have undergone surgical sterilization during the trial and for 8 weeks following the final dose of the study drug.

Exclusion criteria

Patients meeting any of the following criteria will be excluded:

• Known hypersensitivity to the investigational drug(s).
• Current participation in another interventional clinical trial, or receipt of any investigational drug or use of investigational device within 4 weeks prior to first dosing.
• History of malignancy outside the biliary tract within 5 years prior to first dosing, except for adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ that has been completely resected.
• Previous treatment with immune checkpoint inhibitors including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or drugs targeting other stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137).
• History of solid organ or hematopoietic stem cell transplantation.
• Any condition requiring systemic corticosteroids (equivalent to prednisone or above) or other immunosuppressive therapy within 14 days prior to randomization.
• Active autoimmune disease or history of autoimmune disease with potential for recurrence.
• Radiographic evidence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or prior noninfectious pneumonitis identified on screening chest computed tomography (CT).
• Severe infection within 4 weeks prior to randomization, including but not limited to hospitalization due to infectious complications, bacteremia, or severe pneumonia.
• Severe chronic or active infection (including tuberculosis) requiring systemic (oral or intravenous) antibiotic therapy within 14 days prior to randomization.
• Known history of Human Immunodeficiency Virus (HIV) infection (i.e., HIV-1/2 antibody positive); untreated active Hepatitis B. *Note: Subjects with Hepatitis B meeting the following criteria are eligible: HBV viral load < 2000 copies/mL (200 IU/mL) prior to the first dose, with anti-HBV therapy administered throughout the chemotherapy period to prevent viral reactivation. For subjects who are anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is necessary.* Patients with active Hepatitis C infection (HCV antibody positive and HCV-RNA above the lower limit of detection) are excluded.
• Concurrent participation in another therapeutic clinical trial.
• Presence of obstructive jaundice (enrollment permitted following active intervention such as biliary drainage or stenting and subsequent normalization of liver function).
• Meeting any of the following cardiovascular criteria:

• New York Heart Association (NYHA) Class II or higher heart failure within 3 months prior to initiation of study treatment;
• Major cardiovascular events including myocarditis, myocardial infarction, cerebrovascular events, unstable arrhythmia, or unstable angina within 6 months prior to initiation of study treatment;
• Symptomatic pulmonary embolism within [missing value] months prior to randomization;
• Known artery disease or left ventricular ejection fraction (LVEF) < 40%.
• Lactating women.
• Women of childbearing potential unwilling to use contraception.
• Vulnerable populations other than elderly or illiterate individuals, including those with mental illness, cognitive impairment, or critical illness.
• Any other reason deemed by the investigator to render the subject unsuitable for study participation.