Candonilimab in Combination With LM-302 for Claudin 18.2 Positive-advanced Biliary Tract Cancer After Failure of Standard of Chemotherapy and PD1/PD-L1 Antibody

Inclusion Criteria:

1. Advanced BTC that is not resectable or metastatic or recurred after surgery, histologically confirmed, and sufficient tissue specimens are provided for PD-L1, CTLA-4, Claudin18.2 immunohistochemistry and exon sequencing. Claudin18.2 expression is not required at the first stage. In the second stage, Claudin18.2-positive patients were required to be enrolled (≥40% immunohistochemical expression of Claudin18.2 was considered positive, <40% was considered negative, and two independent pathologists made the judgment. If there was any discrepancy, the third pathologist was asked to make the judgment together).
2. Failure of standard chemotherapy (gemcitabine or platinum or fluorouracil) and PD1/PD-L1 for advanced BTC due to disease progression or toxicity;
3. Measurable lesions;
4. For patients with a prior history of hepatic chemoembolization, radiofrequency ablation/intervention, or radiotherapy, measurable lesions outside the chemoembolization or radiotherapy area or measurable progression lesions at the chemoembolization or radiotherapy site must be present;
5. ECOG physical state ≤ 2;
6. Life expectancy > 3 months;
7. Adequate renal function: creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥ 60mL/min/ 1.73m2;
8. Adequate liver function: bilirubin ≤ 1.5 × ULN and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;
9. Adequate bone marrow reserve: absolute value of neutrophil (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, male or female;
12. Participants with a prior history or persistent hepatitis C virus (HCV) infection will be eligible to participate in the study. Participants receiving antiviral therapy must complete treatment at least 1 month before the start of the study intervention. For HCV subjects who have not received or have not completed antiviral therapy, treatment should be initiated only after liver function has remained stable for at least 3 months during the study intervention.

13. Hepatitis B controlled subjects are eligible to participate in the study as long as they meet the following criteria:

    Subjects with chronic hepatitis B virus (HBV) infection (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable HBV DNA) must have a HBV viral load of less than 2000 IU/ml prior to first dosing of the study intervention or a 10-fold reduction in HBV viral load with antiviral therapy. Subjects treated with active HBV with a viral load below 2000 IU/ml should receive antiviral therapy throughout the study intervention.

14. Subjects who are clinically cured of HBV infection (defined as HBsAg negative and anti-HBC positive) and whose HBV viral load is not detectable at screening should have their HBV viral load checked every 8 weeks and should be treated for HBV if the viral load exceeds 2000 IU/ml. Antiviral therapy after completion of the study intervention should follow local guidelines.

Exclusion Criteria:

• 1) Previous treatment with checkpoint inhibitor CTLA-4 monoclonal antibody, targeting Claudin18.2; 2) Major surgery or radiotherapy or intervention or ablation within 4 weeks before enrollment; 3) Active, known, or suspected autoimmune disease; 4) Congestive heart failure or symptomatic coronary artery disease within 3 months prior to enrollment; 5) Cerebrovascular accident occurred within the past 6 months; 6) Clinically significant bleeding, bleeding event, or thromboembolic disease within 6 months; 7) History of intestinal perforation; 8) Have a history of (non-infectious) pneumonia requiring steroid treatment or currently have pneumonia; 9) Known history of human immunodeficiency virus (HIV) infection; 10) A history of severely impaired lung function or interstitial lung disease; 11) Concurrent malignancies (other than adequately treated non-melanoma skin cancer, superficial transitional cell carcinoma of the bladder and cervical carcinoma in situ [CIS]) or any currently active malignancies have been diagnosed within the last 5 years; 12) Past or current evidence indicates any condition, treatment, or laboratory abnormality that may confuse the study results, interfere with the subject's participation throughout the study, or the investigator determines that participation in the study is not in the subject's best interest.