Internal strategy change. Not related to safety concerns.

This study is an open-label, phase II study of irinotecan liposome injection in patients with advanced biliary tract cancer. The purpose of this study is to evaluate the safety, efficacy and pharmacokinetics of irinotecan liposome injection in patients with advanced biliary tract cancer.

This is an open-label, parallel, multicentre, phase II study to evaluate the efficacy and safety of irinotecan liposome injection. Eligible patients will be divided into two cohorts according to the criteria for the corresponding cohort. The patients in cohort 1 will receive irinotecan liposome injection combined with 5-Fluorouracil (5-FU) and Leucovorin (LV). The patients in cohort 2 will receive irinotecan liposome injection combined with a PD-1 inhibitor, 5-Fluorouracil and Leucovorin.

Inclusion Criteria:

• 1. At least 18 years of age, regardless of gender. 2.Histologically or cytologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of biliary tract, including intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC) and gallbladder carcinoma (GBC).

  3.At least one measurable lesion according to RECIST 1.1. 4.Previous first-line standard system chemotherapy failed. First-line standard chemotherapy is defined as gemcitabine combined with capecitabine or platinum.

  5.Patients with prior local treatment (embolization, chemoembolization, radiofrequency ablation, or radical radiotherapy) must be completed at least 4 weeks before the first administration of the study drug, palliative decompensated radiotherapy (such as bone metastases) must be completed at least 2 weeks before the first administration of the study drug.

  6.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. 7.Life expectancy >3 months. 8.Adverse reactions must recover to grade 1 or baseline according to CTCAE 5.0 (except for toxicity such as alopecia, grade 2 or less sensory neuropathy, etc., which have been judged no safety risk by investigators).

  9.Patients should not receive cell growth factors or blood and platelet transfusion within 7 days before the initiate administration of study drug, and laboratory test should meet the following criteria: neutrophile count ≥1.5×10^9/L;platelet count ≥90×10^9/L; hemoglobin ≥90 g/L or ≥5.6 mmol/L;serum creatinine ≤1.5×ULN or creatinine clearance rate must be ≥ 50 mL/min when serum creatinine >1.0×ULN;total bilirubin ≤1.5×ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN or ≤2.5×ULN if intrahepatic lesions exist;Albumin ≥3 g/dL.

  10. Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR) and prothrombin time (PT) ≤1.5 × ULN for patients not receiving therapeutic anticoagulation.

  11.Patients with biliary obstruction or no evidence of persistent infection should receive adequate biliary drainage; active or suspected infections are not allowed.

  12. Female patients with reproductive potential must agree to use adequate contraception from the signing of informed consent to at least 6 months after the study completion and have a negative serum pregnancy test within 7 days before enrollment, and must be non-lactating. Male patients must agree to use medically approved contraception during the study and for 6 months after the study period.

  13. Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• 1. Patients with definite positive NTRK fusion gene. 2. Patients who have received any investigational drug within 4 weeks prior to the first dose of irinotecan liposomes injection.

  3. Patients with definite metastatic encephalopathy. 4. Patients who have received liver transplantation or liver metastases accounted for 50% or more of the total liver volume.

  5. Patients with hepatic encephalopathy. 6. Uncontrolled third lacunar effusion other than ascites (e.g., large pleural or pericardial effusion).

  7. Previous malignancies in the past five years (except radically resected and non-recurring basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder carcinoma, local prostate carcinoma, carcinoma in situ of cervical, or other carcinoma in situ).

  8. History of serious cardiovascular disease. 9. Patients with uncontrolled active bleeding. 10. Gastrointestinal diseases of clinical significance, such as bleeding, inflammation, obstruction, >grade 1 diarrhea, etc.

  11. Patients with definite Gilbert syndrome. 12. Patients who have concomitant use of strong CYP3A4 inducers within 2 weeks prior to the first dose, or strong CYP3A4 inhibitors or strong UGT1A1 inhibitors within 1 week prior to the first dose.

  13. Patients who received systemic glucocorticoids or other immunosuppressive agents within 14 days before the first dose of the study drug.

  14. Patients who have undergone major organ surgery within 4 weeks prior to the first dose of the study drug.

  15. Patients who are hypersensitivity to any component of irinotecan liposome injection or other liposome products.

  16. Patients who are allergic to gemcitabine, cisplatin, fluorouracil or leucovorin or its components.

Additional exclusion criteria for cohort 2:

1. Patients who have received any other antibodies or drugs that act on T-cell synergetic stimulation or checkpoint pathways (including PD-1, PD-L1, CTLA-4 inhibitors, etc.).
2. Patients with a history of severe allergic reactions to monoclonal antibodies and uncontrolled allergic asthma.
3. Patients with active autoimmune disease or a history of autoimmune diseases.
4. History of primary immunodeficiency.
5. Patients who occurred immune related adverse events.
6. History of allogeneic organ or hematopoietic stem cell transplantation.
7. Received live attenuated vaccine within 14 days before screening period or planned to received it during the study period.