Chidamide Combined With Chemotherapy and Immunotherapy as First-line Treatment for Advanced Intrahepatic Cholangiocarcinoma

Open-label, Phase II Clinical Study of Chidamide Combined With Chemotherapy and Immunotherapy as First-line Treatment for Advanced Intrahepatic Cholangiocarcinoma

This is a single-center, open-label, phase II clinical trial designed to evaluate the efficacy and safety of chidamide in combination with chemotherapy and immunotherapy as a first-line treatment for patients with advanced intrahepatic cholangiocarcinoma (ICC), a type of liver cancer.

The study will enroll approximately 35 patients with histologically or pathologically confirmed unresectable or metastatic ICC who have not received prior systemic therapy. All participants will receive chidamide, an oral HDAC inhibitor, in combination with gemcitabine, cisplatin, and an immune checkpoint inhibitor. Treatment will be administered in 21-day cycles until disease progression, unacceptable toxicity, or other withdrawal criteria are met.

The primary study endpoints are objective response rate (ORR), and safety, evaluated by the frequency and severity of adverse events. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), overall survival (OS), and exploratory biomarker analyses.

The study aims to assess whether the addition of chidamide to standard chemotherapy and immunotherapy can improve treatment outcomes in this patient population.

Inclusion Criteria:

1. Voluntarily sign the informed consent form (ICF), fully understand the study, and be willing to comply with and capable of completing all trial procedures.

2. Male or female, aged 18 to 75 years.

3. Patients with histologically or pathologically confirmed unresectable or metastatic intrahepatic cholangiocarcinoma (ICC). Patients with extrahepatic cholangiocarcinoma (EHCC) or gallbladder cancer (GBC) are excluded.

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

5. Laboratory test values within 7 days prior to the start of treatment must meet the following criteria:

   1. Neutrophils ≥ 1.5 × 10⁹/L;
   2. Platelets ≥ 50 × 10⁹/L;
   3. Hemoglobin ≥ 90 g/L (without packed red blood cell transfusion within the past 2 weeks);
   4. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) and creatinine clearance ≥ 50 mL/min;
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN;
   6. Serum albumin ≥ 30 g/L;
   7. For patients not receiving anticoagulation therapy: INR or aPTT ≤ 1.5 × ULN. Patients receiving prophylactic anticoagulation are eligible if INR ≤ 2 × ULN and aPTT is within the normal range within 14 days prior to the start of study treatment;
   8. Serum bilirubin ≤ 1.25 × ULN.

6. Life expectancy ≥ 12 weeks.

7. Presence of at least one measurable lesion as confirmed by RECIST version 1.1.

8. Patients with controlled hepatitis B are eligible if they meet the following criteria: HBV antiviral therapy must have been administered for at least 4 weeks, and HBV viral load must be less than 100 IU/mL prior to the first dose of study drug. Patients receiving anti-HBV treatment with a viral load below 100 IU/mL should maintain the same treatment throughout the study period. Patients who are positive for hepatitis B core antibody (HBcAb), negative for hepatitis B surface antigen (HBsAg), negative or positive for hepatitis B surface antibody (HBsAb), and have an HBV viral load below 100 IU/mL do not require prophylactic anti-HBV treatment.

9. Patients must have good compliance.

Exclusion Criteria:

• 1. Prior treatment with a histone deacetylase (HDAC) inhibitor. 2. Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment within the past 2 years (i.e., use of corticosteroids or immunosuppressive medications). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

  3. Anticipated major surgery during the study period, including the 28-day screening period (diagnostic surgical procedures are excluded). Major surgery is defined as a procedure requiring at least 3 weeks of recovery time before study treatment can be administered.

  4. Known history of interstitial lung disease or has non-infectious pneumonitis requiring corticosteroid treatment.

  5. Known history of human immunodeficiency virus (HIV) infection, other acquired or congenital immunodeficiency disorders, or a history of organ transplantation or stem cell transplantation.

  6. Known clinically significant liver disease, including active viral hepatitis, alcoholic hepatitis, or other hepatitis; severe cirrhosis, fatty liver, hereditary liver disease, liver atrophy, portal hypertension, uncontrolled major seizure disorder, or superior vena cava syndrome.

  7. Known history of allergy to macromolecular protein preparations/monoclonal antibodies or to the chemotherapeutic agents used in this trial.

  8. Participation in another clinical trial of an investigational drug within 4 weeks prior to the first dose of study drug (calculated from the last use of the investigational drug).

  9. Receipt of a live vaccine within 30 days prior to the first dose of study drug. Inactivated virus vaccines for seasonal influenza are permitted; however, intranasally administered live attenuated influenza vaccines are not permitted.

  10. Received prior local therapy to the liver (transcatheter chemoembolization, transcatheter embolization, hepatic arterial infusion, radiotherapy, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug. Note: Patients must have evidence of disease progression after local therapy to be eligible.

  11. Received prior radiotherapy to non-hepatic regions within 2 weeks prior to the first dose of study drug. Patients must have recovered from all radiotherapy-related toxicities, not require corticosteroids, and have no history of radiation pneumonitis. A 2-week washout period is permitted for palliative radiotherapy for non-central nervous system (CNS) disease (≤ 2 weeks of radiotherapy).

  12. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical carcinoma in situ) that have undergone potentially curative therapy are permitted.

  13. History of alcohol dependence, or history of drug abuse or substance abuse within the past 1 year.

  14. Is pregnant or breastfeeding, or plans to become pregnant or father a child during the study period, from the screening visit through 120 days after the last dose of study treatment.

  15. Has any condition (e.g., disease history or evidence, treatment, laboratory abnormality) that, in the investigator's judgment, could interfere with the trial results, preclude the patient's full participation in the study, or for which participation in the study is not in the patient's best interest.

  16. Patients deemed by the investigator to be unsuitable for participation in this trial for any other reason.