Locally advanced (non resectable) and metastatic histologically proven intra-hepatic or hilum cholangiocarcinoma + histologically proven metastatic extra-hepatic cholangiocarcinoma (common bile duct and gallbladder), progressing after gemcitabine-CDDP (or gemcitabine-oxaliplatin) or after gemcitabine alone followed or preceded by platinum-based chemotherapy
Conditions
Interventions
Product Name: Regorafenib
Product Code: BAY 73-4506
Pharmaceutical Form: Tablet
INN or Proposed INN: REGORAFENIB
CAS Number: 755037-03-7
Other descriptive name: REGORAFENIB
Concentration unit: mg mil
Sponsors
CUB Erasme Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - histologically proven locally advanced unresectable or metastatic intra-hepatic or hilum cholangiocarcinoma or histologically proven metastatic extra-hepatic cholangiocarcinoma (common bile duct and gallbladder) - progression documented after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum-based chemotherapy - signed written informed consent - Male or female = 18 years of age - 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 requirements conducted within 7 days of starting to study treatment: o Serum creatinine =1.5x upper reference range o Total bilirubin =1.5x ULN o Alanine transaminase (ALT) and aspartate aminotransferase (AST) = 3.0x ULN (=65 years) yes F.1.3.1 Number of subjects for this age range 22
Exclusion criteria
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) - persistent proteinuria >3.5g/24 hours measured by urine protein-creatinine ratio from a random urine sample (persistent proteinuria >3 non-healing woud, ulcer, or bone fracture - patients with evidence or history of any bleeding diathesis, irrespective of severity - any hemorrhage or bleeding event = CTCAE Grade 3 within 4 weeks prior to the start of study medication - interstitial lung disease with ongoing signs and symptoms at the time of informed consent - uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension - history of myocardial infarction (6 months before start of study drug) - arterial or venous thrombotic events such as cerebrovascular accident (CVA) (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication) - uncontrolled cardiac arrhythmias - 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) - pheochomocytoma - HIV infection - active chronic hepatitis B or C with a need for antiviral treatment - 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 > grade 2 NCI CTCAE - 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The principal objective is to investigate Regorafenib efficacy by prospectively demonstrating an improvement of median Progression-free survival (PFS) when treating locally advanced unresectable or metastatic patients suffering from an intra-hepatic or hilum (mass-forming) cholangiocarcinoma or metastatic extra-hepatic cholangiocarcinoma with Regorafenib combined with BSC as compared to placebo with BSC, and in progression after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum (CDDP or oxaliplatin)-based chemotherapy. Hypothesis is a 50% improvement in median PFS (from 6 weeks to 12 weeks in Regorafenib group). ;Secondary Objective: Biomarker analysis for mechanisms of resistance to Regorafenib, angiogenesis pathway inhibition during treatment, evaluation of microvascular density of the tumor and correlation with perfusion MRI and its potential modification during treatment and stromagenesis modulation during treatment;Primary end point(s): Median PFS: improvement from 6 weeks to 12 weeks in Regorafenib+BSC group;Timepoint(s) of evaluation of this end point: After at least 1 cycle of therapy. Every six weeks (three times), then every eight weeks, the patient condition will be evaluated by a complete blood sampling(including measurement of tumor factors) and a thoraco-abdominal scan, and this up to progression disease. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Evaluation of response rate: evaluation of tumor response will be done based on radiological modified RECIST criteria evaluation (thoraco-abdominal CT scan) - Correlation between radiological response (using modified RECIST criteria) 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 - Correlation between radiologic response rate (modified RECIST criteria) 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 valuess) - Correlation between dynamic tumor response rate and metabolic response rate (Pet CT) when first Pet CT is positive (as defined behind) - Evaluation of OS at one year - Translational analysis: Biomarker analysis for: mechanisms of resistance to Regorafenib: pAKT, pERK (on tumor sample if enough tissue); angiogenesis pathway inhibition during treatment: serum levels of CXCL 12, VEGF-C, HGF, PDGF-béta, iNO, Ang2, CXCR4; evaluation of microvascular density of the tumor (CD31 on tumor sample if enough tissue) and correlation with perfusion MRI, and its potential modification during treatment; stromagenesis modulation during treatment: evaluation of FGFR and PDGFR serum levels ;Timepoint(s) of evaluation of this end point: - For response rate, a thoraco-abdominal scan will be done every six weeks (three times), then every eight weeks until disease progression - For correlation between radiological response and metabolic response, a PET-scan will be done at pretreatment visit and a second one will be realized in Day 15 of first cycle only if the baseline (pre treatment) Pet CT was “positive”. - For correlation between radiologic response rate and “Dynamic tumor response rate”, a DCE-MRI will be done at Day 1 and Day 15 of first cycle - For ove | — |
Countries
Belgium
Contacts
Public ContactAnne Demols
CUB Erasme Hospital
Outcome results
None listed