Efficacy and Safety of Irinotecan Liposome Injection Combined With 5-FU/LV± Immunotherapy in First-line Gemsitabine + Immunoprogressive Patients With Metastatic Biliary Tract Cancer

Inclusion Criteria:

1. The patient had good compliance, could understand the research process of the study,and signed a written informed consent;
2. Age ≥18 years, ≤75 years;
3. Histologically or cytologically confirmed cholangiocarcinoma;
4. Documented metastatic disease;
5. At least one measurable lesion according to RECIST v1.1;
6. Disease progression after gemcitabine + immunotherapy;
7. For patients whose disease recurred after curative resection (R0 or R1), previousadjuvant 5-FU-based chemotherapy is allowed if there is at least 6 month-intervalbetween the last dose of adjuvant chemotherapy and recurrence of disease;
8. Eastern Cooperative Oncology Group (ECOG) Performance status 0-1;
9. The expected survival time is greater than 3 months;
10. Having adequate organ function, as defined below:
11. Absolute neutrophil count (ANC) ≥1.5*109/L
12. Hemoglobin ≥90g/dL
13. Platelets (PLT) ≥100*109/L
14. Total bilirubin < 1.5 times Upper Normal Value (ULN)
15. Chemical examination of liver function index (AST&ALT) < 2.5 times Upper Limitof Normal (ULN)
16. Serum creatinine (Cr) ≤1.5×ULN
17. Non-pregnant or lactating women; Effective contraception should be used by women/menof childbearing age during the study period and for 6 months after the end of studytreatment-

Exclusion Criteria:

（1) Serum total bilirubin ≥2 x ULN (upper limit of normal) (biliary obstruction allowsbiliary drainage); （2）Severe renal impairment (Clcr ≤ 30 ml/min); （3）Any clinicallysignificant disorder impacting the risk-benefit balance negatively per physician'sjudgment； （4）Any clinically significant gastrointestinal disorder, including hepaticdisorders, bleeding, inflammation, occlusion, or diarrhea > grade 2; （5）Severe arterialthromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6months; （6） NYHA(New York Heart Association) Class III or IV congestive heart failure,ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG withclinically significant abnormal findings; （7） Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician's opinion might compromise thepatient's health; （8） Current use or any use in last two weeks of strong CYP3A-enzymeinducers/inhibitors and/or strong UGT1A inhibitors； （9） Known hypersensitivity to any ofthe components of Onivyde other liposomal irinotecan formulations, irinotecan,fluoropyrimidines, or leucovorin; （10）Breast feeding, known pregnancy, positive serumpregnancy test or unwillingness to use an effective method of contraception, during therapyand for 3 months following the last dose of Onivyde. Females of Childbearing Potential musteither agree to use and be able to take effective contraceptive birth control measures (Pearl Index < 1) or agree to practice complete abstinence from heterosexual intercourseduring the course of the study and for at least 3 months after last application of programtreatment. A female subject is considered to be of childbearing potential unless she is age ≥ 50 years and naturally amenorrhoeic for ≥ 2 years, or unless she is surgically sterile.Males must agree not to father a child (including not donating sperm) during the course ofthe trial and for at least 6 months after last administration of study drugs; （11） Previoustreatment with combination drug tegafur, gimeracil, and oteracil potassium with seven daysbefore enrollment; （12） Current treatment with Sorivudine; （13） Severe fatigue or bonemarrow depression after prior radiotherapy or antineoplastic therapy; （14）There are seriousconcomitant diseases, such as diabetes mellitus and can not be well controlled byhypoglycemic drugs, clinically serious (that is, active) heart disease, renal failure,liver failure, uncontrolled epilepsy, central nervous system disease or history of mentaldisorders, hemorrhagic peptic ulcer, intestinal paralysis, intestinal obstruction, etc.; （15） History of other malignancy with a disease-free interval <5 years (Registration ispermitted if it has minimal impact on prognosis, such as carcinoma in situ and papillarythyroid cancer); （16） History or current eveidence of brain metastasis; （17）Patients deemedunsuitable for this trial by the investigator.