PD-L1 Antibody Combined With CTLA-4 Antibody for Patients With Advanced Intrahepatic Cholangiocarcinoma Who Progressed After Standard Treatment

Inclusion Criteria:

1. For unresectable or metastatic or postoperative recurrence, histologically confirmedadvanced ICC, provide enough tissue samples for PD-L1, CTLA-4 immunohistochemistry,and exome sequencing

2. The standard systemic treatment of advanced ICC (gemcitabine or platinum orfluorouracil) failed due to disease progression or toxicity

3. There are measurable lesions defined by RECIST standard v1.1

4. For patients with a history of liver chemoembolization, radiofrequencyablation/intervention, or radiotherapy, there must be measurable lesions outside thechemoembolization or radiotherapy area or measurable progression lesions at thechemoembolization or radiotherapy site

5. ECOG physical strength status ≤ 1

6. Life expectancy> 3 months

7. Adequate renal function: creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN) orglomerular filtration rate (GFR) ≥ 60mL/min/1.73 m2

8. Sufficient liver function: bilirubin ≤ 1.5 × ULN and alanine aminotransferase (ALT)and aspartate aminotransferase (AST) ≤ 5 × ULN

9. Sufficient bone marrow reserve: absolute value of neutrophils (ANC)> 1500/mcl,platelets (Plts)> 75,000/mcl, hemoglobin (Hgb) ≥ 9.0g/dl

10. Prothrombin time/activated partial thromboplastin time (PT/PTT) <1.5 × ULN

11. Age ≥18 years old

12. HBV infected persons must meet the following criteria to be eligible to participatein the study: Chronic hepatitis B virus (HBV) infection (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable HBV DNA) subjects must have HBV viral load below 2000 IU/ml before the first dose of the study intervention. Active HBV-treatedsubjects with a viral load of less than 2000 IU/ml should receive antiviral therapythroughout the study intervention period and check the HBV viral load every 6 weeks.Subjects whose HBV infection is clinically cured (defined as HBsAg negative andanti-HBc positive) and whose HBV viral load cannot be detected during screeningshould be checked for HBV viral load every 6 weeks. If the viral load exceeds 2000IU/ml, HBV treatment should be carried out. Antiviral treatment after completing theresearch intervention should follow local guidelines.

13. The toxicity of the previous treatment has been restored to ≤1 grade (if there issurgery, the wound has completely healed)

14. Female subjects of childbearing age must undergo a pregnancy test within 2 weeksbefore starting the study medication, and the result is negative, and are willing touse a medically approved high-efficiency contraceptive method during the studyperiod and within 24 weeks after the last study drug administration (Such asintrauterine device, contraceptive pills or condoms); for male subjects whosepartners are females of childbearing age, they should agree to use effective methodsof contraception during the study period and within 24 weeks after the last studyadministration

15. Subjects voluntarily joined the study, signed an informed consent form, had goodcompliance, and cooperated with follow-up.

Exclusion Criteria:

1. Past treatment with CTLA-4 mAb

2. Hilar cholangiocarcinoma or extrahepatic cholangiocarcinoma or periampullarycarcinoma or gallbladder cancer

3. Major surgery or radiotherapy within 4 weeks before enrollment

4. Active, known, or suspected autoimmune diseases

5. Congestive heart failure or symptomatic coronary artery disease within 3 monthsbefore enrollment

6. Cerebrovascular accident occurred in the past 6 months

7. Clinically significant bleeding, bleeding event, or thromboembolic disease occurredwithin 6 months

8. History of bowel perforation

9. A history of (non-infectious) pneumonia requiring steroid treatment or currentpneumonia

10. Known history of human immunodeficiency virus (HIV) infection

11. History of severely impaired lung function or interstitial lung disease

12. Diagnosed concurrent malignant tumors in the past 5 years (except for fully treatednon-melanoma skin cancer, superficial transitional cell carcinoma of the bladder andcervical carcinoma in situ [CIS]) or any currently active malignant tumors

13. HCV RNA positive test indicates the active period

14. Patients who have previously received allogeneic bone marrow transplantation orsolid organ transplantation

15. Uncontrollable or symptomatic hypercalcemia

16. Known uncontrollable or symptomatic active central nervous system (CNS) metastasis

17. Symptomatic advanced patients who are at risk of life-threatening complications inthe short term (including patients with uncontrollable large amounts of exudate [thoracic cavity, pericardium, abdominal cavity])

18. Known allergies to study drugs or excipients or known severe allergic reactions toany monoclonal antibody

19. Severe infections during screening, including but not limited to infectiouscomplications requiring hospitalization, bacteremia, severe pneumonia, etc.

20. Have received any other experimental drug treatment or participated in anotherinterventional clinical study within 4 weeks before signing the ICF

21. Live attenuated vaccine within 4 weeks before enrollment or planned during the studyperiod and 60 days after the end of study drug treatment

22. Known mental illness, alcohol abuse, inability to quit smoking, drug or drug abuse,etc.

23. Past or current evidence indicates that any conditions, treatments, or laboratoryabnormalities that may confuse the research results, interfere with the subject'sparticipation in the entire research process, or the researcher believes thatparticipating in this research is not in the subjects' best interests.