Purpose: This phase II clinical trial evaluates whether a combination of liver-directed local therapies (HAIC and DEB-TACE) with immunotherapy (toripalimab) and targeted therapy (lenvatinib) is safe and effective for patients with unresectable intrahepatic cholangiocarcinoma (a type of liver cancer that cannot be removed by surgery). Participants: Adults aged 18-85 years with pathologically confirmed unresectable intrahepatic cholangiocarcinoma, no prior immune checkpoint inhibitor therapy, and adequate organ function. Study details include: Study Duration: Up to 24 months per participant Treatment Duration: Up to 6 cycles (each cycle is 21 days) of combination therapy, followed by maintenance therapy with toripalimab and lenvatinib until disease progression or unacceptable toxicity Visit Frequency: Every 3 weeks during the treatment phase; tumor imaging assessments every 6-8 weeks Primary endpoints: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Safety will be assessed by monitoring adverse events graded according to NCI-CTCAE v5.0. Toripalimab and lenvatinib are not available through an expanded access program.
Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy. Most patients are diagnosed at locally advanced or metastatic stages, precluding curative surgical resection. For unresectable ICC, conventional chemotherapy offers limited efficacy, with a 5-year survival rate below 10%. Emerging evidence suggests that combining locoregional therapies with immunotherapy and targeted therapy may improve outcomes. Study Design: This is a prospective, single-arm, single-center, phase II exploratory clinical trial. Approximately 29 evaluable patients will be enrolled at Zhongshan Hospital, Fudan University. Intervention: Participants will receive a comprehensive treatment regimen consisting of: HAIC (Hepatic Arterial Infusion Chemotherapy): Oxaliplatin 85 mg/m² and gemcitabine (total 1000 mg/m², with a portion used for DEB-TACE loading) administered via hepatic artery infusion over ≥2 hours on Day 1 of each 21-day cycle, for up to 6 cycles. DEB-TACE (Drug-Eluting Beads Transarterial Chemoembolization): Small-sized (40-90 μm) drug-eluting beads loaded with gemcitabine, performed on Day 1 of each cycle as needed (required in Cycle 1, thereafter based on tumor vascularity and imaging assessment). Toripalimab: 200 mg intravenous infusion on Day 1 of each 21-day cycle. Lenvatinib: Oral daily dosing (8 mg/day for body weight \<60 kg; 12 mg/day for body weight ≥60 kg), continued throughout the study. After completion of up to 6 cycles, patients without disease progression will enter a maintenance phase receiving toripalimab plus lenvatinib until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision to terminate. Efficacy Assessments: Tumor response will be evaluated by investigators using RECIST 1.1 and mRECIST criteria every 6-8 weeks. Primary efficacy endpoints include objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Safety Monitoring: Adverse events will be monitored throughout the study and graded according to NCI-CTCAE v5.0. Safety visits will be conducted before each TACE procedure. Statistical Considerations: The primary analysis will be descriptive. Sample size (approximately 29 patients) was calculated using a single-stage exact design based on an expected ORR of 40% versus a null rate of 15%, with α=0.05 and power=90%. Survival outcomes will be analyzed using Kaplan-Meier methods.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Small-sized (40-90 μm) drug-eluting beads loaded with gemcitabine, administered via transarterial chemoembolization into the hepatic artery to occlude tumor blood vessels and deliver localized chemotherapy. Performed on Day 1 of each 21-day cycle as needed (required in Cycle 1, thereafter based on tumor vascularity and imaging assessment).
200 mg administered as an intravenous infusion on Day 1 of each 21-day cycle. Toripalimab is a humanized anti-PD-1 monoclonal antibody that blocks PD-1/PD-L1 interaction, restoring T-cell anti-tumor immune activity.
Oral daily dosing: 8 mg/day for body weight \<60 kg; 12 mg/day for body weight ≥60 kg. Lenvatinib is a multi-target tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, thereby reducing tumor angiogenesis and suppressing tumor cell proliferation.
Total dose 1000 mg/m² administered via hepatic artery infusion (HAIC) on Day 1 of each 21-day cycle, for up to 6 cycles. A portion of the dose is used for DEB-TACE drug loading; the remainder is administered via HAIC. Gemcitabine is a pyrimidine nucleoside analog that inhibits DNA synthesis and induces tumor cell apoptosis.
85 mg/m² administered via hepatic artery infusion (HAIC) on Day 1 of each 21-day cycle, for up to 6 cycles. Oxaliplatin is a third-generation platinum-based chemotherapeutic agent that forms DNA crosslinks, blocking DNA replication and transcription, and inducing tumor cell apoptosis.
Objective Response Rate (ORR)
Proportion of participants achieving a confirmed complete response (CR) or partial response (PR) according to RECIST 1.1 and mRECIST criteria, assessed by the investigator. This is the primary efficacy endpoint used for sample size calculation.
Time frame: From the start of treatment until disease progression, up to 24 months
Progression-Free Survival (PFS)
Time from enrollment to first documented disease progression per RECIST 1.1 and mRECIST criteria, or death from any cause, whichever occurs first.
Time frame: From enrollment until disease progression or death, assessed up to 24 months
Overall Survival (OS)
Time from enrollment to death from any cause.
Time frame: From enrollment until death, assessed up to 24 months
Disease Control Rate (DCR)
Proportion of participants achieving a confirmed complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1 and mRECIST criteria, assessed by the investigator.
Time frame: From the start of treatment until disease progression, up to 24 months
Duration of Response (DoR)
Time from first documented response (CR or PR) to first documented disease progression per RECIST 1.1 and mRECIST criteria, or death from any cause, whichever occurs first.
Time frame: From first response until disease progression or death, assessed up to 24 months
Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and laboratory abnormalities. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Time frame: From the time of informed consent until 30 days after the last dose of study treatment, or until resolution/return to baseline, assessed up to 24 months
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