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

Safety and Efficacy of Hepatic Arterial Infusion Chemotherapy (GP Regimen) and Intra-arterial Infusion of Envafolimab Combined With Lenvatinib for Unresectable Advanced First-line Biliary Tract Cancer: A Multicenter, Phase Ib/II, Single-arm Clinical Study

Advanced biliary tract cancer has a poor prognosis and limited efficacy with current regimens. This multicenter single-arm phase Ib/II trial explores the efficacy and safety of HAI-GP chemotherapy combined with intraoperative arterial envafolimab and lenvatinib as first-line therapy for unresectable BTC. It conducts dose exploration to confirm the optimal dosage and evaluates clinical outcomes, aiming to establish a better comprehensive treatment strategy.

Inclusion Criteria:

Patients must meet all of the following inclusion criteria:

1. Age between 18 years and [missing value] years, inclusive.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

3. Histologically or cytologically confirmed biliary tract carcinoma, deemed unsuitable for radical surgical resection.

4. At least one measurable lesion as determined by the investigator in accordance with mRECIST or RECIST version 1.1.

5. Estimated life expectancy greater than 3 months.

6. No prior systemic therapy or local anti-tumor treatment, except for surgery (biliary drainage is permitted).

7. Patients who experience relapse more than 6 months after completion of postoperative adjuvant therapy may be enrolled.

8. Child-Pugh score of [missing value] points.

9. Adequate organ function to meet the criteria for chemotherapy:

   1. Bone marrow function: absolute neutrophil count ≥ [missing value]/L; platelet count ≥ [missing value]; hemoglobin ≥ [missing value];
   2. 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;
   3. 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;
   4. 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.

10. 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:

1. Known hypersensitivity to the investigational drug(s).

2. 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.

3. 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.

4. 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).

5. History of solid organ or hematopoietic stem cell transplantation.

6. Any condition requiring systemic corticosteroids (equivalent to prednisone or above) or other immunosuppressive therapy within 14 days prior to randomization.

7. Active autoimmune disease or history of autoimmune disease with potential for recurrence.

8. Radiographic evidence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or prior noninfectious pneumonitis identified on screening chest computed tomography (CT).

9. Severe infection within 4 weeks prior to randomization, including but not limited to hospitalization due to infectious complications, bacteremia, or severe pneumonia.

10. Severe chronic or active infection (including tuberculosis) requiring systemic (oral or intravenous) antibiotic therapy within 14 days prior to randomization.

11. 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.

12. Concurrent participation in another therapeutic clinical trial.

13. Presence of obstructive jaundice (enrollment permitted following active intervention such as biliary drainage or stenting and subsequent normalization of liver function).

14. Meeting any of the following cardiovascular criteria:

    1. New York Heart Association (NYHA) Class II or higher heart failure within 3 months prior to initiation of study treatment;
    2. Major cardiovascular events including myocarditis, myocardial infarction, cerebrovascular events, unstable arrhythmia, or unstable angina within 6 months prior to initiation of study treatment;
    3. Symptomatic pulmonary embolism within [missing value] months prior to randomization;
    4. Known artery disease or left ventricular ejection fraction (LVEF) < 40%.

15. Lactating women.

16. Women of childbearing potential unwilling to use contraception.

17. Vulnerable populations other than elderly or illiterate individuals, including those with mental illness, cognitive impairment, or critical illness.

18. Any other reason deemed by the investigator to render the subject unsuitable for study participation.