Nal-IRI(Nanoliposomal Irinotecan) Plus 5-FU/LV in Metastatic Biliary Tract Cancer

This study is a multicenter, open-label, randomized, phase II study comparing the efficacy and safety between fluorouracil/folinic acid plus liposomal irinotecan and fluoruracil/folinic acid monotherapy in patients with metastatic biliary tract cancer which progressed on 1st line gemcitabine/cisplatin.

Eligible patients will be included in this study and treated according to the protocol. Study treatment will be continued until disease progression, unacceptable toxicity, or patient's decision/consent withdrawal. Local investigators will determine disease progression, radiologic or clinical deterioration.

Inclusion criteria

• Signed and written informed consent form
• ≥ 19 years of age
• Histologically or cytologically confirmed cholangiocarcinoma
• Documented metastatic disease
• At least one measurable lesion according to the RECIST v1.1
• Disease progression on gemcitabine-cisplatin combination therapy
• For patients whose disease recurred after curative resection (R0 or R1), previous adjuvant 5-FU-based chemotherapy is allowed if there is at least 6 month-interval between the last dose of adjuvant chemotherapy and recurrence of disease.
• Adequate hepatic, renal and hematological function AST(Aspartate Aminotransferase), ALT(Alanine Aminotransferase) ≤ 100 IU/L (100 U/L), Cr(Creatinine) ≤ 1.5mg/dL
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-1

Exclusion criteria

• Serum total bilirubin ≥2 x ULN(upper limit of normal) (biliary drainage is allowed for biliary obstruction)
• Severe renal impairment (Clcr ≤ 30 ml/min)
• Inadequate bone marrow reserves as evidenced by:

• ANC(Absolute Neutrophile Count) ≤ 1,500 cells/μl; or
• Platelet count ≤ 100,000 cells/μl; or
• Hemoglobin ≤ 9 g/dL
• ECOG performance status 2-4
• Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment
• Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 2
• Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months
• NYHA(New York Heart Association) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings
• Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician's opinion might compromise the patient's health
• Current use or any use in last two weeks of strong CYP3A-enzyme inducers/inhibitors and/or strong UGT1A inhibitors
• Known hypersensitivity to any of the components of Onivyde other liposomal irinotecan formulations, irinotecan, fluoropyrimidines, or leucovorin.
• Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use an effective method of contraception, during therapy and for 3 months following the last dose of Onivyde. Females of Childbearing Potential must either agree to use and be able to take effective contraceptive birth control measures (Pearl Index < 1) or agree to practice complete abstinence from heterosexual intercourse during the course of the study and for at least 3 months after last application of program treatment. 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 of the trial and for at least 6 months after last administration of study drugs.
• Previous treatment with combination drug tegafur, gimeracil, and oteracil potassium with seven days before enrollment.
• Current treatment with Sorivudine.
• Severe fatigue or bone marrow depression after prior radiotherapy or antineoplastic therapy
• Pregnancy or women with child-bearing potential or lactating
• Non-malignant severe co-morbidity
• Previous second-line anti-cancer therapy (e.g., Tegafur)
• History of other malignancy with a disease-free interval <5 years (Registration is permitted if it has minimal impact on prognosis, such as carcinoma in situ and papillary thyroid cancer)
• History or current eveidence of brain metastasis