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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Metastatic Biliary Tract Cancer

Intervention / Treatment
-----------------
* Drug: Onivyde
* Drug: 5-FU/LV


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-FU/LV/Onivyde<br>Onivyde 70 mg/m2 (90 minutes), dl-LV 400mg/m2 or l-LV 200mg/m2 (30 minutes), 5-FU 2400 mg/m2 (46 hours) IV every 2 weeks. | Drug: Onivyde<br>* The recommended dose and regimen of Onivyde is 70 mg/m2 intravenously over 90 minutes, followed by dl-LV 400mg/m2 or l-LV 200mg/m2 intravenously over 30 minutes, followed by 5-FU 2400 mg/m2 intravenously over 46 hours, administered every 2 weeks.<br>* Other names: Liposomal irinotecan;Drug: 5-FU/LV<br>* The recommended dose and regimen of dl-LV 400mg/m2 or l-LV 200mg/m2 intravenously over 30 minutes, followed by 5-FU 2400 mg/m2 intravenously over 46 hours, administered every 2 weeks<br>* Other names: Fluorouracil/Folinic acid;|
| Active Comparator: 5FU/LV<br>dl-LV 400mg/m2 or l-LV 200mg/m2 (30 minutes), 5-FU 2400 mg/m2 (46 hours) IV every 2 weeks. | Drug: 5-FU/LV<br>* The recommended dose and regimen of dl-LV 400mg/m2 or l-LV 200mg/m2 intravenously over 30 minutes, followed by 5-FU 2400 mg/m2 intravenously over 46 hours, administered every 2 weeks<br>* Other names: Fluorouracil/Folinic acid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival by independent central reviewer | Progression-free survival is the time from the date of enrollment to the earlier of the date of confirmed progression or death from any cause. | from the date of enrollment to the earlier of the date of confirmed progression or death from any cause. (assessed up to 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is the time from the date of enrollment to death from any cause | from the date of enrollment to death from any cause. (assessed up to 36 months) | 
| Response rates determined by the investigator according to the RECIST(Response Evaluation Criteria in Solid Tumors) v1.1 | The response rate is the proportion of eligible patients with measurable lesions with a overall response of CR(Complete Response) or PR(Partial Response) | from the date of enrollment to end of treatment. (assessed up to 36 months) | 
| EORTC-QLQ (European Organization for Research and Treatment of Cancer - Quality of life Questionnaire) C30 (version 3.0) | EORTC-QLQ C-30 questionnaires will be performed at screening visit, at pre-dose (Cycle 1 Day1) of every subsequent cycle, at the end of treatment visit. It is a 30-item questionnaire. It has 4-point scales for the item number 1 to 28. These are coded with the same response categories as items 1 to 28, namely not at all=1 a little=2 quite a bit=3 and very much=4 It has 7-point scale for question number 29 to 30. These are coded with the same response categories as items 29 to 30, namely worst=1 to best=7 Total score will be minimum 30 and maximum 126. | from the date of Screening to end of treatment. (assessed up to 36 months) | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Severity of adverse events will be graded by NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) v4.03 | from the date of enrollment to 30 days after last treatment. (assessed up to 36 months) | 
| Progression Free Survival by investigator assessment | Progression-free survival is the time from the date of enrollment to the earlier of the date of confirmed progression or death from any cause. | from the date of enrollment to the earlier of the date of confirmed progression or death from any cause. (assessed up to 36 months) | 
| Response rates determined by the independent central reviewer | The response rate is the proportion of eligible patients with measurable lesions with a overall response of CR(Complete Response) or PR(Partial Response) | from the date of enrollment to end of treatment. (assessed up to 36 months) |