Tauroursodeoxycholic Acid Combined With PD-1/PD-L1 Immunotherapy in Advanced Hepatocellular Carcinoma: A Prospective Study

Official title

Prospective Study on the Synergistic Effect of Tauroursodeoxycholic Acid Combined With Immunotherapy in Hepatocellular Carcinoma

Overview

This is a clinical trial that aims to evaluate whether adding a bile acid called tauroursodeoxycholic acid (TUDCA) can improve the effects of immunotherapy in patients with advanced liver cancer (hepatocellular carcinoma). Immunotherapy has shown promise in treating this type of cancer, but not all patients respond well. TUDCA is known to help protect liver cells and may improve the liver's immune environment, potentially making immunotherapy more effective. In this study, 300 patients with advanced liver cancer will be randomly assigned to receive either immunotherapy alone or immunotherapy combined with TUDCA. Researchers will look at how well the cancer responds, whether the treatment helps more patients become eligible for surgery, and how safe the combination is. The goal is to find a more effective and better tolerated treatment for patients with liver cancer.

Detailed description

This prospective, randomized, controlled clinical trial investigates the efficacy and safety of combining tauroursodeoxycholic acid (TUDCA) with immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC).

Immunotherapy using PD-1 or PD-L1 inhibitors has become a cornerstone in treating advanced HCC. However, a significant proportion of patients exhibit limited response or develop resistance. One contributing factor may be the immunosuppressive liver tumor microenvironment, which impairs T cell activation and infiltration. TUDCA is a hydrophilic bile acid that exhibits cytoprotective and anti-inflammatory effects, and may enhance the immune response by improving liver immune homeostasis.

In this study, 300 patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC will be enrolled and randomly assigned to receive either PD-1/PD-L1 inhibitor monotherapy or combination therapy with TUDCA. The treatment cycle will last for 6 months, with a follow-up period of at least 6 months after treatment completion.

The primary outcome is objective response rate (ORR) as measured by RECIST 1.1 and mRECIST criteria. Secondary endpoints include progression-free survival (PFS), overall survival (OS), conversion to surgical eligibility, and biomarker dynamics.

Safety and tolerability will be closely monitored throughout the study. Dose-limiting toxicities, adverse events, and liver function parameters will be assessed regularly. The trial will also explore immune and inflammatory biomarkers associated with response to treatment.

This study aims to determine whether the addition of TUDCA can enhance the efficacy of ICIs in HCC and provide a novel treatment strategy for patients with advanced disease.

Interventions

• Drug TUDCA (Tauroursodeoxycholic Acid) Supplementation
  TUDCA administered orally according to protocol-defined dosage.
• Drug Immune checkpoint inhibitor (ICI)
  Administered intravenously according to standard practice or protocol.

Primary outcome measures

• Overall Survival (OS) [Time frame: Up to 12 months]
• Progression-Free Survival (PFS) [Time frame: Up to 12 months]

Secondary outcome measures (5)

• Disease Control Rate (DCR) [Time frame: up to 12 months]
• Change in Renal Function Indicators [Time frame: From baseline to 12 weeks (every 4-6 weeks)]
• Change in Hematologic Parameters [Time frame: From baseline to 12 weeks (every 4-6 weeks)]
• Change in Immune Inflammatory Markers [Time frame: From baseline to 12 weeks (every 4-6 weeks)]
• Change in Serum Bile Acid Levels [Time frame: From baseline to 12 weeks (every 4-6 weeks)]

Eligibility criteria

Inclusion criteria

Histologically or cytologically confirmed diagnosis of primary hepatocellular carcinoma (HCC).

Unresectable advanced HCC classified as Barcelona Clinic Liver Cancer (BCLC) stage C.

Age ≥ 18 years.

No prior systemic anti-tumor therapy for HCC before first dose of study treatment.

At least one measurable lesion according to RECIST v1.1, or a measurable lesion with clear progression after local treatment based on RECIST v1.1.

Adequate organ and bone marrow function within 7 days prior to enrollment, with no blood products, growth factors, albumin, or other intravenous/subcutaneous corrective treatment within 14 days prior to laboratory assessment:

Hematology:

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelet count (PLT) ≥ 75 × 10⁹/L Hemoglobin (Hb) ≥ 9.0 g/dL

Liver function:

Total bilirubin (TBil) ≤ 2 × ULN ALT and AST ≤ 5 × ULN Serum albumin ≥ 28 g/L

Alkaline phosphatase (ALP) ≤ 5 × ULN

Renal function:

Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 50 mL/min (calculated by Cockcroft-Gault formula) Urinalysis shows urine protein < 2+; if urine protein ≥ 2+, 24-hour urine collection must show protein < 1g/24h

Coagulation:

International Normalized Ratio (INR) ≤ 2.3 or prothrombin time (PT) prolongation ≤ 6 seconds

Estimated life expectancy of ≥ 12 weeks.

Exclusion criteria

History of hepatic encephalopathy or liver transplantation.

Acute cholecystitis, acute cholangitis, patients with frequent biliary colic attacks, complete biliary obstruction, or gallbladder dysfunction (inability to contract and empty).

Patients with Child-Pugh class C or decompensated cirrhosis, including those with a history of severe hepatic encephalopathy or refractory ascites due to liver disease.

Patients with a previous diagnosis of biliary atresia without adequate biliary drainage (e.g., failed biliary-enteric anastomosis).

Pregnant or breastfeeding women.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Tongji Medical college of HUST — Wuhan

Publications

• Lan X, Ma J, Huang Z, Xu Y, Hu Y. Akkermansia muciniphila might improve anti-PD-1 therapy against HCC by changing host bile acid metabolism. J Gene Med. 2024 Jan;26(1):e3639. doi: 10.1002/jgm.3639. Epub 2023 Dec 7. PMID 38058259
• Kusaczuk M. Tauroursodeoxycholate-Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives. Cells. 2019 Nov 20;8(12):1471. doi: 10.3390/cells8121471. PMID 31757001
• Latif MU, Schmidt GE, Mercan S, Rahman R, Gibhardt CS, Stejerean-Todoran I, Reutlinger K, Hessmann E, Singh SK, Moeed A, Rehman A, Butt UJ, Bohnenberger H, Stroebel P, Bremer SC, Neesse A, Bogeski I, Ellenrieder V. NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression. Gut. 2022 Dec;71(12):2561-2573. doi: 10.1136/gutjnl-2021-325013. Epub 2022 Apr 1. PMID 35365570
• Oura K, Morishita A, Tani J, Masaki T. Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review. Int J Mol Sci. 2021 May 28;22(11):5801. doi: 10.3390/ijms22115801. PMID 34071550
• Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025 Feb 7;10(1):35. doi: 10.1038/s41392-024-02075-w. PMID 39915447
• Cunningham M, Gupta R, Butler M. Checkpoint inhibitor hepatotoxicity: pathogenesis and management. Hepatology. 2024 Jan 1;79(1):198-212. doi: 10.1097/HEP.0000000000000045. Epub 2023 Jan 13. PMID 36633259
• Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2024 Apr 26;9(1):97. doi: 10.1038/s41392-024-01811-6. PMID 38664391
• Feng L, Zhang W, Shen Q, Miao C, Chen L, Li Y, Gu X, Fan M, Ma Y, Wang H, Liu X, Zhang X. Bile acid metabolism dysregulation associates with cancer cachexia: roles of liver and gut microbiome. J Cachexia Sarcopenia Muscle. 2021 Dec;12(6):1553-1569. doi: 10.1002/jcsm.12798. Epub 2021 Sep 28. PMID 34585527

Identifiers

NCT: NCT07064668 · TJ-IRB202505056

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗