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    The EU Clinical Trials Register currently displays   44339   clinical trials with a EudraCT protocol, of which   7369   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-005626-30
    Sponsor's Protocol Code Number:REACHIN
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-005626-30
    A.3Full title of the trial
    Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (non resectable) and metastatic cholangiocarcinoma: a randomized double-blinded phase II trial.
    Evaluation des effets de l'administration de Regorafenib chez des patients présentant une tumeur des voies biliaires non opérable et/ou métastatique en progression après gemcitabine et dérivé du platine: une étude de phase II randomisée en double aveugle.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessment of the effects of an oral chemotherapy (Regorafenib) after failure of previous treatments for non-operable patients suffering from a particular type of biliary tract cancer.
    Evaluation des effets d'une chimiothérapie par voie orale (Regorafenib) après échec des traitements antérieurs pour les patients non opérables souffrant d'un type particulier de cancer des voies biliaires.
    A.3.2Name or abbreviated title of the trial where available
    REACH IN
    A.4.1Sponsor's protocol code numberREACHIN
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCUB Erasme Hospital
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer SA-NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCUB Erasme Hospital
    B.5.2Functional name of contact pointAnne Demols
    B.5.3 Address:
    B.5.3.1Street AddressRoute de Lennik 808
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1070
    B.5.3.4CountryBelgium
    B.5.4Telephone number+32 2555 58 67
    B.5.5Fax number+322555 82 36
    B.5.6E-mailanne.demols@erasme.ulb.ac.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRegorafenib
    D.3.2Product code BAY 73-4506
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNREGORAFENIB
    D.3.9.1CAS number 755037-03-7
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    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
    Cancer des voies biliaires intra-hépatiques, extra-hépatiques ou du hile hépatique (appelé cholangiocarcinome) localement avancé (non-résécable) et/ou métastatique, déjà traité par des chimiothérapies incluant de la gemcitabine et un dérivé du platine –cisplatine ou oxaliplatine
    E.1.1.1Medical condition in easily understood language
    Particular type of bile duct cancer non operable and/or metastatic, and having been treated by several chemotherapies that have failed to control the disease.
    Type particulier de cancer des voies biliaires non opérable et/ou qui présente des métastases, et ayant déjà été traité par plusieurs chimiothérapies qui n’ont pas permis de contrôler la maladie.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).
    Le principal objectif est d'investiguer l'efficacité du Régorafénib en démontrant de manière prospective une amélioration de la survie médiane sans progression chez des patients traités pour un cholangiocarcinome des voies biliaires intrahépatiques ou hilaire, localement avancé (non-opérable) et/ou métastatique ou extra-hépatique métastatique avec le Régorafénib combiné à des soins de soutien, en comparaison à ceux traités par un placebo et des soins de soutien. Les patients doivent être en progression après l'échec de chimiothérapies précédentes incluant de la gemcitabine et un dérivé du platine –cisplatine ou oxaliplatine.
    E.2.2Secondary objectives of the trial
    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
    Analyse de différents biomarqueurs impliqués dans les mécanismes de résistance au Régorafénib, l'inhibition de l'angiogénèse durant le traitement, l'évaluation de la densité microvasculaire et sa corrélation avec des paramètres de perfusion obtenus par IRM et leur modification potentielle en cours de traitement, et la modulation de la formation du stroma
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (<5x ULN for patients with liver involvement of their cancer).
    o Amylase and lipase ≤1.5x ULN.
    o Alkaline phosphatase (ALP) ≤ 2.5x ULN (≤5x ULN for patients with liver involvement of their cancer and /or have bone metastases)
    o Platelets count ≥100.000/mm³, hemoglobin (Hb) ≥9 g/dL, absolute neutrophil count (ANC) ≥1500/mm³
    o Internation normalized ratio (INR) ≤1.5x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g. heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.
    - life expectancy of at least 12 weeks
    - effective contraception for both male and female patients must be used for at least 8 weeks after the last study drug administration if the risk of conception exists
    - negative pregnancy test, only applicable if there is a risk of conception
    - negative proteinuria on dipstick or 24 hours proteinuria<1000mg
    E.4Principal 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
    E.5 End points
    E.5.1Primary end point(s)
    Median PFS: improvement from 6 weeks to 12 weeks in Regorafenib+BSC group
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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
    E.5.2.1Timepoint(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 overall survival: at one-year
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state66
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-12-03
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