A Study of Liposomal Irinotecan Plus 5-FU/LV HAIC With Lenvatinib and a PD-1 Inhibitor in Advanced ICC

A Prospective Study on the Efficacy and Safety of Liposomal Irinotecan, 5-Fluorouracil, and Leucovorin Hepatic Arterial Infusion Chemotherapy (HAIC) Combined With Lenvatinib and a PD-1 Inhibitor as First-Line Therapy for Advanced Intrahepatic Cholangiocarcinoma (ICC)

This is a prospective, single-center, single-arm clinical study. It aims to evaluate the efficacy and safety of a new combination therapy as a first-line treatment for patients with advanced intrahepatic cholangiocarcinoma (ICC) who cannot be treated with surgery. The combined therapy includes hepatic arterial infusion chemotherapy (HAIC) with Liposomal Irinotecan, 5-Fluorouracil, and Leucovorin, along with the oral targeted drug Lenvatinib and an intravenous PD-1 inhibitor (an immunotherapy). A total of 30 participants will be enrolled. The main goal of the study is to measure the Objective Response Rate (ORR), which is the percentage of patients whose cancer shrinks or disappears after treatment.

This study investigates a novel therapeutic strategy for unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma (ICC). Despite being the second most common primary liver malignancy, advanced ICC has a poor prognosis with limited effective first-line treatment options. The rationale for this combination regimen is based on the potential synergy between localized and systemic therapies. Hepatic arterial infusion chemotherapy delivers high concentrations of chemotherapy directly to the liver tumors, potentially improving local control while reducing systemic toxicity. The combination of Lenvatinib, a multi-targeted tyrosine kinase inhibitor, and a PD-1 inhibitor is designed to simultaneously inhibit tumor angiogenesis and enhance anti-tumor immunity. This study will explore whether combining these modalities (HAIC + targeted therapy + immunotherapy) can yield superior efficacy compared to historical data of standard chemotherapy. The liposomal formulation of irinotecan is utilized for its improved pharmacokinetic profile and targeted delivery, which may enhance efficacy and tolerability. Key assessments include tumor evaluation based on RECIST 1.1 criteria and safety monitoring per NCI CTCAE v5.0.

Inclusion Criteria:

1. Aged 18 to 75 years.
2. Histologically or cytologically confirmed unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma (ICC).
3. Liver function: Child-Pugh class A (score 5-6) or good class B (score ≤7).
4. At least one measurable lesion as defined by RECIST 1.1 criteria.
5. ECOG performance status of 0 or 1.
6. Life expectancy greater than 12 months.
7. No prior systemic therapy for unresectable locally advanced or metastatic ICC. Prior adjuvant or neoadjuvant chemotherapy is allowed if completed >6 months before recurrence.
8. Adequate bone marrow function: Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L, Hemoglobin ≥90 g/L, Platelet count (PLT) ≥100×10⁹/L, White Blood Cell count (WBC) ≥3.0×10⁹/L.
9. Adequate renal function: Serum creatinine (Cr) ≤1.5 × ULN or Creatinine Clearance (CCr) ≥60 mL/min (calculated by Cockcroft-Gault formula).
10. Adequate coagulation function: Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), and International Normalized Ratio (INR) ≤1.5 × ULN.
11. No active or suspected infection.
12. Not pregnant or lactating. Female and male participants of childbearing potential must use effective contraception during the study and for 6 months after the last dose.
13. Good compliance, ability to understand the study procedures, and provision of signed informed consent.

Exclusion Criteria:

1. History of other malignancies within the past 5 years (except cured carcinoma in situ or basal cell skin cancer).
2. Significant clinical bleeding symptoms or tendency within 3 months prior to treatment (e.g., >30 mL bleeding, hematemesis, melena, hematochezia), hemoptysis (>5 mL of fresh blood within 4 weeks). Venous/thrombotic events within the past 6 months (e.g., cerebrovascular accident, deep vein thrombosis, pulmonary embolism). Requirement for long-term anticoagulation (e.g., warfarin, heparin) or antiplatelet therapy (Aspirin ≥300 mg/day or Clopidogrel ≥75 mg/day).
3. Extensive distant metastasis (e.g., peritoneal metastasis, multiple bone/brain metastases).
4. Use of strong CYP3A4 inducers within 3 weeks prior to first dose, or use of strong CYP3A4 inhibitors or strong UGT1A1 inhibitors within 3 weeks prior to first dose.
5. Major organ surgery within 4 weeks prior to treatment (excluding needle biopsy, central venous catheter placement, port implantation, biliary stenting, percutaneous transhepatic biliary drainage, cholecystostomy) or planned elective surgery.
6. Active cardiac disease within 6 months prior to treatment, including myocardial infarction, severe/unstable angina. Left ventricular ejection fraction (LVEF) <50% by echocardiogram, or poorly controlled arrhythmia.
7. Congenital or acquired immunodeficiency (e.g., HIV infection), or active hepatitis (abnormal liver enzymes; for Hepatitis B: HBV DNA ≥1000 IU/mL; for Hepatitis C: HCV RNA ≥1000 IU/mL). Chronic HBV carriers with HBV DNA <2000 IU/ml can be enrolled if they receive concurrent antiviral therapy during the trial.
8. Any other disease, metabolic disorder, physical examination finding, or laboratory abnormality that, in the investigator's judgment, contraindicates the use of the study drug, may affect result interpretation, or places the patient at high risk.
9. Bowel obstruction (except incomplete obstruction manageable with enteral nutrition) or patients at risk of bowel perforation (e.g., acute diverticulitis, abdominal abscess, history of abdominal cancer).
10. Pregnant or lactating female participants.