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

Randomized Phase II Trial of Fluorouracil and Folinic Acid With or Without Liposomal Irinotecan (ONIVYDE) for Patients With Metastatic Biliary Tract Cancer Which Progressed Following Gemcitabine Plus Cisplatin

The purpose of this study is to evaluate the efficacy and safety of combination of fluorouracil/folinic acid and liposomal irinotecan(Onivyde) compared with fluoruracil/folinic acid in patients with metastatic biliary tract cancer which progressed on 1st line gemcitabine/cisplatin.

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:

1. Signed and written informed consent form
2. ≥ 19 years of age
3. Histologically or cytologically confirmed cholangiocarcinoma
4. Documented metastatic disease
5. At least one measurable lesion according to the RECIST v1.1
6. Disease progression on gemcitabine-cisplatin combination therapy
7. 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.
8. Adequate hepatic, renal and hematological function AST(Aspartate Aminotransferase), ALT(Alanine Aminotransferase) ≤ 100 IU/L (100 U/L), Cr(Creatinine) ≤ 1.5mg/dL
9. Eastern Cooperative Oncology Group (ECOG) Performance status 0-1

Exclusion Criteria:

1. Serum total bilirubin ≥2 x ULN(upper limit of normal) (biliary drainage is allowed for biliary obstruction)

2. Severe renal impairment (Clcr ≤ 30 ml/min)

3. 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

4. ECOG performance status 2-4

5. Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment

6. Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 2

7. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months

8. 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

9. Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician's opinion might compromise the patient's health

10. Current use or any use in last two weeks of strong CYP3A-enzyme inducers/inhibitors and/or strong UGT1A inhibitors

11. Known hypersensitivity to any of the components of Onivyde other liposomal irinotecan formulations, irinotecan, fluoropyrimidines, or leucovorin.

12. 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.

13. Previous treatment with combination drug tegafur, gimeracil, and oteracil potassium with seven days before enrollment.

14. Current treatment with Sorivudine.

15. Severe fatigue or bone marrow depression after prior radiotherapy or antineoplastic therapy

16. Pregnancy or women with child-bearing potential or lactating

17. Non-malignant severe co-morbidity

18. Previous second-line anti-cancer therapy (e.g., Tegafur)

19. 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)

20. History or current eveidence of brain metastasis