Liposomal Irinotecan Plus 5-FU/LV and Sintilimab With Sequential SBRT for Locally Advanced Biliary Tract Cancer

A Prospective, Single-Arm, Exploratory Clinical Study of Liposomal Irinotecan (II) Plus 5-Fluorouracil/Leucovorin and Sintilimab With Sequential Stereotactic Body Radiation Therapy as First-Line Treatment for Locally Advanced Biliary Tract Cancer

This is a prospective, single-arm, exploratory interventional study designed to evaluate the efficacy and safety of liposomal irinotecan (II) plus fluorouracil/leucovorin (5-FU/LV) and sintilimab with sequential stereotactic body radiation therapy (SBRT) as first-line treatment for patients with unresectable locally advanced biliary tract cancer (BTC) who have not received prior systemic anticancer therapy for their current disease.

Approximately 31 participants will be enrolled. Participants will receive liposomal irinotecan (II), 5-FU/LV, and sintilimab. Participants without disease progression after initial systemic treatment will receive sequential SBRT to the primary biliary tract tumor. After eight administrations of chemotherapy (approximately 16 weeks), resectability will be assessed by a multidisciplinary team. Participants considered eligible for surgery will undergo radical surgical resection followed by adjuvant treatment, whereas those who remain unresectable will continue the study treatment until disease progression or another protocol-defined reason for discontinuation.

The primary endpoint is objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), surgical conversion rate (SCR), and safety.

Eligible participants will initiate study treatment within 72 hours after enrollment. The systemic treatment regimen consists of liposomal irinotecan (II) 60 mg/m² administered intravenously on Day 1 every 2 weeks (Q2W), leucovorin 200 mg/m² administered intravenously on Day 1 Q2W, fluorouracil (5-FU) 2000 mg/m² administered as a continuous intravenous infusion over 46 hours on Day 1 Q2W, and sintilimab 200 mg administered intravenously on Day 1 every 3 weeks (Q3W).

After four administrations of chemotherapy, participants without disease progression will proceed to sequential stereotactic body radiation therapy (SBRT), which will be delivered between the sixth and seventh chemotherapy administrations to the primary biliary tract tumor. The prescribed SBRT doses are 50 Gy in 10 fractions to the planning gross tumor volume (PGTV) and 30 Gy in 10 fractions to the planning target volume (PTV).

After eight administrations of chemotherapy (approximately 16 weeks), each participant will undergo multidisciplinary evaluation for surgical resectability. Participants considered suitable for surgery will undergo radical surgical resection followed by protocol-specified adjuvant treatment. Participants who remain unresectable will continue the original treatment regimen until disease progression, unacceptable toxicity, a concomitant condition precluding further treatment, investigator decision, noncompliance with study treatment or procedures, or another protocol-specified reason for discontinuation.

Tumor response will be assessed according to RECIST version 1.1. The primary efficacy endpoint is objective response rate (ORR). Secondary efficacy endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and surgical conversion rate (SCR). Surgical conversion is considered successful when conversion therapy results in R0 or R1 resection. Safety will be assessed throughout the study, and adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 6.0.

Inclusion Criteria:

1. Aged 18 to 80 years, inclusive, at the time of signing the informed consent form, regardless of sex.

2. Histologically and/or cytologically confirmed biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

3. Unresectable locally advanced disease at the current disease stage, as determined by a multidisciplinary team (MDT).

4. No prior anticancer treatment for biliary tract cancer at the current disease stage, including radiotherapy, chemotherapy, immunotherapy, or biologic therapy.

5. At least one measurable lesion according to RECIST version 1.1. The measurable lesion must not have received prior radiotherapy or other local treatment.

6. Expected survival of at least 12 weeks.

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

8. Adequate hematologic, hepatic, renal, cardiac, and coagulation function within 14 days before initiation of study treatment, meeting all of the following requirements:

   1. 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); and no blood transfusion or hematopoietic growth factor support for correction within 14 days before screening.
   2. 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; and serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min as calculated using the Cockcroft-Gault formula.
   3. Cardiac function: normal 12-lead electrocardiogram or abnormalities considered clinically insignificant by the investigator, with QTcF <470 ms; and left ventricular ejection fraction (LVEF) ≥50%.
   4. Coagulation function: prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN and 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.

9. Willing to participate voluntarily, provide written informed consent, and comply with scheduled study visits and other protocol requirements.

Exclusion Criteria:

1. History of a malignancy other than biliary tract cancer within 5 years before screening, except for cured basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other malignancies considered by the investigator and multidisciplinary team to have a low risk of metastasis and death.

2. 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.

3. Prior treatment with an immune checkpoint inhibitor, including anti-PD-1, anti-PD-L1, anti-CTLA-4 therapy, or any cellular immunotherapy.

4. Prior irinotecan- or liposomal irinotecan-based chemotherapy.

5. Use of strong inhibitors or inducers of CYP3A4, CYP2C8, or UGT1A1 within 14 days before initiation of study treatment.

6. 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.

7. Severe gastrointestinal dysfunction documented clinically, including bleeding or obstruction, inflammation of NCI-CTCAE version 6.0 grade >2, diarrhea of NCI-CTCAE version 6.0 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.

8. Pleural effusion or ascites requiring clinical intervention (NCI-CTCAE version 6.0 grade ≥2).

9. Serious concomitant conditions that may interfere with study treatment, including any of the following:

   1. 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.
   2. 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.
   3. 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.
   4. History of interstitial lung disease, or noninfectious pneumonitis requiring oral or intravenous corticosteroid therapy.
   5. 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.
   6. Positive hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) antibody.

10. Severe infection (NCI-CTCAE version 6.0 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.

11. Known allergy or intolerance to any study drug or its excipients, or any contraindication to any study drug.

12. Women who are planning pregnancy, are pregnant, or are breastfeeding.

13. 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.