Chidamide Combined With Benmelstobart, Nab-paclitaxel, and SBRT as Second-Line Treatment for Advanced BTC

• 1.Voluntarily sign the informed consent form (ICF); fully understand and be informed about this study and sign the ICF; be willing to comply with and capable of completing all study procedures.
• 2.Male or female; aged 18 years or older.
• 3. Histologically or cytologically confirmed unresectable or metastatic biliary tract cancer (BTC).
• 4.Patients who have failed prior standard first-line therapy (gemcitabine plus cisplatin, gemcitabine plus oxaliplatin, or either regimen combined with a PD-1 monoclonal antibody). Failure of first-line therapy is defined as: disease progression during treatment or within 6 months after the last dose of treatment; or intolerance due to toxicity during treatment. Prior neoadjuvant or adjuvant chemotherapy is permitted. If disease progression or recurrence occurs during neoadjuvant/adjuvant therapy or within 6 months after completion of such therapy, the neoadjuvant/adjuvant therapy is considered to constitute failure of first-line therapy for progressive disease.
• 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.
• 6. Life expectancy ≥ 12 weeks.
• 7. At least 2 tumor lesions, of which at least 1 lesion must be a measurable lesion according to RECIST v1.1.
• 8. At least one tumor lesion is suitable for hypofractionated immunogenic radiotherapy at 5-8 Gy × 3 fractions, as assessed by a radiation oncologist.
• 9. Laboratory test values obtained within 7 days prior to initiation of treatment must meet the following criteria: a) Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; b) Platelets ≥ 50 × 10⁹/L; c) Hemoglobin ≥ 90 g/L (no packed red blood cell transfusion within 2 weeks); d) Serum creatinine ≤ 1.5 × upper limit of normal (ULN) and creatinine clearance ≥ 50 mL/min; e) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; f) Serum albumin ≥ 30 g/L; g) For patients not receiving anticoagulant therapy: INR or aPTT ≤ 1.5 × ULN. If the patient is receiving prophylactic anticoagulant therapy, enrollment is acceptable provided that INR ≤ 2 × ULN and aPTT is within the normal range within 14 days prior to initiation of study treatment; h) Serum bilirubin ≤ 1.25 × ULN.
• 10. Subjects with controlled hepatitis B are eligible to participate provided they meet the following criteria: HBV antiviral therapy must have been administered for at least 4 weeks, and the HBV viral load must be \< 100 IU/mL prior to the first dose of study drug. For subjects with a viral load below 100 IU/mL who are receiving anti-HBV therapy, the same treatment should be maintained throughout the study treatment period. Subjects who are positive for hepatitis B core antibody (anti-HBc), negative for hepatitis B surface antigen (HBsAg), negative or positive for hepatitis B surface antibody (anti-HBs), and have an HBV viral load below 100 IU/mL do not require prophylactic anti-HBV therapy.
• 11. Subjects must have good compliance.

Exclusion Criteria:

• 1. Prior receipt of HDAC inhibitor therapy or PD-L1-targeted therapy.
• 2. Active autoimmune disease (except psoriasis) requiring systemic therapy (i.e., use of corticosteroids or immunosuppressive agents) within the past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is permitted.
• 3. Anticipated major surgery during the study period, including the 28-day screening period (diagnostic surgical procedures are excluded). Major surgery is defined as surgery requiring at least 3 weeks of postoperative recovery before the subject is able to receive study treatment.
• 4. Known interstitial lung disease or presence of non-infectious pneumonitis requiring corticosteroid therapy.
• 5. History of human immunodeficiency virus (HIV) infection, or other acquired or congenital immunodeficiency disease, or 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, hepatic steatosis (fatty liver), hereditary liver disease, hepatic atrophy, portal hypertension, uncontrolled major seizure disorder, or superior vena cava syndrome.
• 7. Known prior hypersensitivity to macromolecular protein preparations, monoclonal antibodies, or to any chemotherapeutic agent used in this trial.
• 8. Participation in another clinical trial of an investigational agent within 4 weeks prior to the first dose (calculated from the date of last administration of the investigational agent).
• 9. Receipt of a live vaccine within 30 days prior to the first dose. Injected inactivated viral vaccines for seasonal influenza are permitted; however, intranasally administered live attenuated influenza vaccines are not permitted.
• 10. Receipt of liver-directed local therapy (transcatheter arterial chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiotherapy, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug. Note: subjects must show evidence of disease progression following local therapy in order to be eligible.
• 11. Receipt of prior radiotherapy to non-hepatic regions within 2 weeks prior to the first dose of study drug. Subjects must have recovered from all radiotherapy-related toxicities, must not require corticosteroids, and must not have experienced radiation pneumonitis. Palliative radiotherapy for non-CNS disease (≤ 2 weeks of radiotherapy) is permitted with a 2-week washout period.
• 12. Known additional malignancy that is currently progressing or has required active treatment within the past 3 years. Note: subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma in situ, cervical carcinoma in situ) that has received potentially curative therapy are permitted.
• 13. Alcohol dependence, or a history of drug abuse or substance abuse within the past 1 year.
• 14. Pregnancy or breastfeeding during the study period, i.e., from the screening visit until 120 days after the last dose of study treatment, or planning to become pregnant or to father a child.
• 15. Medical history or evidence of disease, treatment, or abnormal laboratory values that may interfere with the interpretation of study results or prevent the subject from participating in the entire study, or situations in which the investigator considers participation not to be in the subject's best interest.
• 16. Subjects considered by the investigator to be unsuitable for participation in this trial for any other reason.