Regorafenib Versus Placebo to Treat Cholangiocarcinoma

Study Overview
=================
Brief Summary
-----------------
The study is a multicenter randomized (1:1) placebo-controlled, double-blinded phase II trial aiming to demonstrate an improvement of median PFS when treating locally advanced unresectable or metastatic patients suffering from an intra-hepatic or hilum (mass-forming) cholangiocarcinoma with Regorafenib as compared to placebo, and after progression after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum (CDDP or oxaliplatin)-based chemotherapy. The principal objective is to investigate Regorafenib efficacy by prospectively evaluating the PFS after the administration of Regorafenib combined with BSC as compared to placebo with BSC. Hypothesis is a 50% improvement in median PFS (from 6 weeks to 12 weeks in Regorafenib group).

Detailed Description
-----------------
The principal objective is to investigate Regorafenib efficacy by prospectively evaluating the PFS after the administration of Regorafenib combined with BSC as compared to placebo with BSC. Hypothesis is a 50% improvement in median PFS (from 6 weeks to 12 weeks in Regorafenib group).

Official Title
-----------------
REGORAFENIB AFTER FAILURE OF GEMCITABINE AND PLATINUM-BASED CHEMOTHERAPY FOR LOCALLY ADVANCED (NON RESECTABLE) AND METASTATIC INTRA-HEPATIC OR HILAR CHOLANGIOCARCINOMA: A Randomized Double-blinded Phase II Trial.

Conditions
-----------------
Cholangiocarcinoma

Intervention / Treatment
-----------------
* Drug: Regorafenib/active
* Drug: Regorafenib/placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: histologically proven intra-hepatic or hilum cholangiocarcinoma (mass forming, not liniting tumor), locally advanced unresectable or metastatic progression documented after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum-based (CDDP or oxaliplatin) chemotherapy age > 18 years ECOG PS 0/1 at study entry measurable disease according to RECIST version 1.1 Adequate bone marrow, liver and renal function as assessed by the following laboratory requirementsconducted within 7 days of starting to study treatment: oSerum creatinine <1.5x upper reference range oTotal bilirubin <1.5x ULN oAlanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5x ULN (<5x ULN forpatients with liver involvement of their cancer). oAmylase and lipase <1.5x ULN. life expectancy of at least 12 weeks effective contraception for both male and female patients if the risk of conception exists negative proteinuria on dipstick or 24 hours proteinuria<1000mg signed written informed consent Exclusion Criteria: unability to take oral medication any malabsorption condition patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg. Clarithromycin, indinavir,itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin,voriconazole) or strong CYP3A4 inducers (eg. Carbamazepine, phenobarbital, phenytoin, rifampin, St-John's Wort) (see section 8) persistent proteinuria >3.5g/24 hours measured by urine protein-creatinine ratio from a random urinesample (persistent proteinuria >3 non-healing woud, ulcer, or bone fracture any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of studymedication interstitial lund disease with ongoing signs and symptoms at the time of informed consent uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension history of myocardial infarction, deep venous or arterial thrombosis, cerebrovascular accident (CVA) during the last 6 months previous exposure to anti-VEGF targeting therapy (including Regorafenib) and to signal transduction inhibitors known hypersensitivity to any of the components of study treatments previous malignancy in the last past 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods medical or psychological conditions that would not permit the patient to complete the study or sign inform consent unstable angina, congestive heart failure ≥NYHA class II uncontrolled hypertension despite optimal management (systolic blood pressure >150 mmHg or diastolic pressure > 90mmHg) pheochromocytoma HIV infection active chronic hepatitis B or C with a need for antiviral treatment liver failure, cirrhosis Chil Pugh B or C brain metastasis major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of treatment intra-hepatic locoregional therapy (DC Beads, SIRT) history of organ allograft ongoing infection renal failure requiring dialysis patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regorafenib/active<br>Subjects randomized to be treated with Regorafenib (active product) will receive once a day 160 mg po (four tablets of 40 mg) for 3 weeks of every 4 weeks cycle (3 weeks on and 1 week off). Duration of one cycle is 28 days. | Drug: Regorafenib/active<br>* Subjects randomized to be treated with Regorafenib/active will receive once a day 160 mg po (four tablets of 40 mg) for 3 weeks of every 4 weeks cycle (3 weeks on and 1 week off) Duration of one cycle is 28 days<br>|
| Placebo Comparator: Regorafenib/placebo<br>Subjects randomized to be treated with Regorafenib (placebo) will receive once a day 160 mg po (four tablets of 40 mg) for 3 weeks of every 4 weeks cycle (3 weeks on and 1 week off). Duration of one cycle is 28 days. | Drug: Regorafenib/placebo<br>* Subjects randomized to be treated with Regorafenib/placebo will receive once a day 160 mg po (four tablets of 40 mg) for 3 weeks of every 4 weeks cycle (3 weeks on and 1 week off) Duration of one cycle is 28 days<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improve median PFS | The primary endpoint is to improve median PFS from 6 weeks to 12 weeks in Regorafenib group. | 6 to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of response rate | -Evaluation of tumor response will be done based on radiological RECIST criteria version 1.1 evaluation (thoraco-abdominal CT scan); | At pretreatment visit (14 to 1 days before treatment initiation), every 6 weeks for 3 times then every 8 weeks until progression | 
| Correlation between radiological response and metabolic response | Correlation between radiological response (using RECIST criteria version 1.1) and metabolic response using PET imaging (SUV max modifications). This will only be done if SUV max of the tumor inside the liver at pre-treatment visit is ≥ 175% of the SUV max of the normal liver. | At pretreatment visit (14 to 1 days before treatment initiation) | 
| Correlation between radiologic response rate and Dynamic tumor response rate | Correlation between radiologic response rate (RECIST criteria version 1.1) and Dynamic tumor response rate. Dynamic response rate is defined by a 20% modification of tumoral perfusion status determined by quantitative DCE-MRI after 14 days of treatment (D1 compared to D15 values); | At day 1 (pre-treatment) and day 15 of cycle 1 | 
| Correlation between dynamic tumor response rate and metabolic response rate | Correlation between dynamic tumor response rate and metabolic response rate (Pet CT) when first Pet CT is positive | At cycle 1 day 15 | 
| Evaluation of Overall Survival (OS) | Evaluation of OS at one year. | After 1 year (March 2015) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Intra-hepatic, Hilar, Locally Advanced, Non Resectable, Metastatic, Regorafenib, Placebo