Sintilimab Plus NALIRIFOX or Gemcitabine-Cisplatin as First-Line Treatment for Metastatic Biliary Tract Cancer

This randomized, noncomparative, open-label, exploratory clinical study will enroll approximately 54 patients with metastatic biliary tract cancer who have not received prior systemic anticancer therapy for metastatic disease. Eligible participants will be randomized in a 1:1 ratio to Group A or Group B.

Participants assigned to Group A will receive sintilimab in combination with NALIRIFOX. NALIRIFOX consists of liposomal irinotecan (II), 5-fluorouracil (5-FU)/leucovorin (LV), and oxaliplatin. The NALIRIFOX chemotherapy regimen will be administered every 2 weeks, while sintilimab will be administered every 3 weeks. Participants who remain free of disease progression after 12 cycles of combination therapy will enter maintenance treatment with liposomal irinotecan (II), 5-FU/LV, and sintilimab.

Participants assigned to Group B will receive sintilimab in combination with gemcitabine and cisplatin (GP), administered on a 3-week treatment schedule. Participants who remain free of disease progression after 8 cycles of combination therapy will subsequently receive maintenance treatment with gemcitabine and sintilimab.

Maintenance treatment will continue until disease progression, unacceptable toxicity, a concomitant condition that precludes further treatment, investigator decision to discontinue study treatment, noncompliance with study treatment or study procedures, or another protocol-specified reason for discontinuation, whichever occurs first.

Tumor response will be assessed according to RECIST version 1.1. The primary endpoint is objective response rate (ORR). Secondary efficacy endpoints include disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety will also be evaluated throughout the study, including adverse events, vital signs, laboratory assessments, electrocardiograms, and echocardiography, with adverse events graded according to NCI-CTCAE version 5.0.

Inclusion criteria

• Aged 18 to 75 years, inclusive, at the time of signing the informed consent form, regardless of sex.
• Histologically and/or cytologically confirmed biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.
• Presence of distant metastasis at the current disease stage.
• No prior anticancer treatment for biliary tract cancer at the current disease stage, including radiotherapy, chemotherapy, immunotherapy, or biologic therapy.
• At least one measurable lesion according to RECIST version 1.1. The measurable lesion must not have received prior radiotherapy or other local treatment.
• Expected survival of at least 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic, hepatic, renal, cardiac, and coagulation function within 14 days before initiation of study treatment, meeting all of the following requirements:

• Hematologic function:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;
• Platelet count ≥ 100 × 10^9/L;
• Hemoglobin ≥ 90 g/L (9.0 g/dL);
• No blood transfusion or hematopoietic growth factor support for correction within 14 days before screening.
• Biochemical function:

• Serum albumin ≥ 30 g/L (3.0 g/dL);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN);
• Total bilirubin ≤ 1.5 × ULN;
• Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 60 mL/min as calculated using the Cockcroft-Gault formula.
• Cardiac function:

• Normal 12-lead electrocardiogram or abnormalities considered clinically insignificant by the investigator, with QTcF < 470 ms;
• Left ventricular ejection fraction (LVEF) ≥ 50%.
• Coagulation function:

• Prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;
• International normalized ratio (INR) ≤ 1.5 × ULN in participants not receiving anticoagulant therapy. Participants receiving a stable dose of anticoagulant therapy, such as low-molecular-weight heparin or warfarin, may be eligible if the INR is within the expected therapeutic range.
• Willing and able to participate voluntarily, provide written informed consent, and comply with the scheduled study visits and other protocol requirements.

Exclusion criteria

• Tumor- and treatment-related criteria:

• History of a malignancy other than biliary tract cancer within 5 years before screening, except for adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other malignancies considered by the investigator to have a low risk of metastasis and death.
• Known central nervous system (CNS) metastases. Participants with suspected CNS metastases must undergo contrast-enhanced CT or MRI within 28 days before initiation of study treatment to exclude CNS metastases.
• Prior treatment with an immune checkpoint inhibitor, including anti-PD-1, anti-PD-L1, anti-CTLA-4 therapy, or any cellular immunotherapy.
• Prior irinotecan- or liposomal irinotecan-based chemotherapy.
• Use of strong inhibitors or inducers of CYP3A4, CYP2C8, or UGT1A1 within 14 days before initiation of study treatment.
• Participation in another interventional drug clinical trial within 4 weeks before initiation of study treatment, except for observational (non-interventional) studies or follow-up of an interventional clinical study.
• Medical history or concomitant diseases:

• Severe gastrointestinal dysfunction documented clinically, including bleeding or obstruction, inflammation of NCI-CTCAE version 5.0 grade >2, diarrhea of NCI-CTCAE version 5.0 grade >1, or other conditions considered by the investigator to potentially affect drug intake, transit, or absorption, including inability to swallow, prior small-bowel resection, or total gastrectomy.
• Pleural effusion or ascites requiring clinical intervention (NCI-CTCAE version 5.0 grade ≥2).
• Serious concomitant conditions that may interfere with study treatment, including any of the following:

• Uncontrolled serious medical disease considered by the investigator to impair the participant's ability to receive protocol-specified treatment, including severe cardiac disease, cerebrovascular disease, uncontrolled diabetes mellitus, uncontrolled hypertension, or active peptic ulcer disease;
• Arterial or venous thrombotic events within 1 year before screening, including cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism, except for catheter-related venous thrombosis from prior chemotherapy that has resolved according to the investigator;
• Tumor involvement of major blood vessels on imaging, or a very high risk, in the investigator's judgment, of tumor invasion into major blood vessels during treatment resulting in potentially fatal hemorrhage;
• History of interstitial lung disease, or noninfectious pneumonitis requiring oral or intravenous corticosteroid therapy;
• Poorly controlled cardiac symptoms or disease, including heart failure greater than New York Heart Association (NYHA) class II, unstable angina, myocardial infarction within 6 months, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention;
• Positive hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) antibody.
• Severe infection (NCI-CTCAE version 5.0 grade >2) within 4 weeks before screening, such as severe pneumonia requiring hospitalization, bacteremia, or other serious infectious complications; or signs or symptoms of infection requiring intravenous antibiotic therapy within 2 weeks before initiation of study treatment, except for prophylactic antibiotic use.
• Other criteria:

• Known allergy or intolerance to any study drug or its excipients, or any contraindication to any study drug.
• Women who are planning pregnancy, are pregnant, or are breastfeeding.
• Any other condition that, in the investigator's judgment, warrants exclusion from the study, including factors that may lead to premature study discontinuation, such as another serious disease (including psychiatric illness) requiring concomitant treatment, severe laboratory abnormalities, or family or social factors that could affect participant safety or the collection of study data or samples.