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    Summary
    EudraCT Number:2017-002932-18
    Sponsor's Protocol Code Number:42756493-BLC3001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-02-09
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-002932-18
    A.3Full title of the trial
    A Phase 3 Study of Erdafitinib Compared with Vinflunine or Docetaxel or Pembrolizumab in Subjects with Advanced Urothelial Cancer and Selected FGFR Gene Aberrations
    Étude de phase 3 évaluant l’erdafitinib par rapport à la vinflunine, au docétaxel ou au pembrolizumab chez des patients atteints d’un cancer urothélial avancé et présentant des altérations pré-sélectionnées des gènes FGFR.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Erdafitinib Compared with Vinflunine or Docetaxel or Pembrolizumab in Subjects with Advanced Urothelial Cancer
    L'étude de l'Erdafitinib Comparée à la vinflunine, au docétaxel ou au pembrolizumab chez des patients atteints d’un cancer urothélial avancé
    A.3.2Name or abbreviated title of the trial where available
    THOR
    A.4.1Sponsor's protocol code number42756493-BLC3001
    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 SponsorJanssen-Cilag International NV
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPAREXEL International LLC
    B.5.2Functional name of contact point
    B.5.6E-mailclinicaltrial.enquiries@parexel.com
    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 nameErdafitinib
    D.3.2Product code JNJ-42756493
    D.3.4Pharmaceutical form Film-coated 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 INNErdafitinib
    D.3.9.1CAS number 1346242-81-6
    D.3.9.2Current sponsor codeJNJ-42756493
    D.3.9.3Other descriptive nameERDAFITINIB
    D.3.9.4EV Substance CodeSUB167731
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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.IMP: 2
    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 nameErdafitinib
    D.3.2Product code JNJ-42756493
    D.3.4Pharmaceutical form Film-coated 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 INNErdafitinib
    D.3.9.1CAS number 1346242-81-6
    D.3.9.2Current sponsor codeJNJ-42756493
    D.3.9.3Other descriptive nameERDAFITINIB
    D.3.9.4EV Substance CodeSUB167731
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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.IMP: 3
    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 nameErdafitinib
    D.3.2Product code JNJ-42756493
    D.3.4Pharmaceutical form Film-coated 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 INNErdafitinib
    D.3.9.1CAS number 1346242-81-6
    D.3.9.2Current sponsor codeJNJ-42756493
    D.3.9.3Other descriptive nameERDAFITINIB
    D.3.9.4EV Substance CodeSUB167731
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name JAVLOR®
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameVinflunine
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINFLUNINE
    D.3.9.1CAS number 162652-95-1
    D.3.9.4EV Substance CodeSUB00063MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name TAXOTERE®
    D.2.1.1.2Name of the Marketing Authorisation holderAventis Pharma S.A.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameDocetaxel
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDOCETAXEL
    D.3.9.1CAS number 114977-28-5
    D.3.9.4EV Substance CodeSUB12492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 namePembrolizumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced Urothelial Cancer
    cancer urothélial avancé
    E.1.1.1Medical condition in easily understood language
    Advanced Urothelial Cancer
    cancer urothélial avancé
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077840
    E.1.2Term Urothelial cancer of renal pelvis
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate efficacy of erdafitinib versus chemotherapy or pembrolizumab in subjects with advanced urothelial cancer harboring selected FGFR aberrations who have progressed after one prior treatment. The primary endpoint of overall survival will be evaluated in 2 cohorts:
    - Cohort 1: erdafitinib versus chemotherapy (docetaxel or vinflunine) [subjects who have received prior anti-PD(L)1 agent]
    - Cohort 2: erdafitinib versus pembrolizumab [subjects who have not received prior antiPD-(L)1 agent]
    L’objectif principal de cette étude est d’évaluer l’efficacité de l’erdafitinib par rapport à la chimiothérapie
    ou au pembrolizumab chez des patients présentant un cancer urothélial avancé porteur d’altérations présélectionnées
    de FGFR, et ayant progressés après une première ligne de traitement. Le critère
    d’évaluation principal est la survie globale et sera évaluée dans les 2 cohortes :
    • Cohorte 1 : erdafitinib versus chimiothérapie (docétaxel ou vinflunine) [patients ayant reçu
    précédemment un agent anti-PD(L)1]
    • Cohorte 2 : erdafitinib versus pembrolizumab [patients n’ayant pas reçu d’agent anti-PD(L)1]
    E.2.2Secondary objectives of the trial
    - To evaluate progression-free survival (PFS) of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
    - To evaluate the objective response rate (ORR) of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
    - To evaluate the health-related quality of life of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
    - To evaluate the duration of response (DOR) for subjects treated with erdafitinib versus chemotherapy or pembrolizumab
    - To characterize the safety profile of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
    - To evaluate the population PK of erdafitinib
    Évaluer la survie sans progression (SSP) chez les patients traités par erdafitinib comparativement aux patients traités par chimiothérapie ou pembrolizumab
    • Évaluer le TRO chez les patients traités par erdafitinib comparativement aux patients traités par chimiothérapie ou pembrolizumab
    • Évaluer la qualité de vie liée à la santé chez les patients traités par erdafitinib comparativement aux patients traités par chimiothérapie ou pembrolizumab
    • Évaluer la durée de la réponse (DdR) chez les patients traités par erdafitinib comparativement aux patients traités par chimiothérapie ou pembrolizumab
    • Caractériser le profil de tolérance chez les patients traités par erdafitinib comparativement aux patients traités par chimiothérapie ou pembrolizumab
    • Évaluer la Pharmacocinétique (PK) chez les patients traités par erdafitinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
    2. Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components (<50% overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable
    3. Stage IV disease (metastatic or surgically unresectable, cT4b, N+, or M+ cancer)
    4. Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization
    5. Only one line of prior treatment for metastatic urothelial cancer. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression (as defined in criterion 4), within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting
    Cohort 1: prior chemotherapy and anti-PD(L)1 [in combination or in maintenance setting] (anti-PD(L)1 alone is allowed only for subjects with documented cisplatin ineligibility)
    Cohort 2: prior chemotherapy (no prior anti-PD(L)1 treatment)
    6. Subjects must meet appropriate molecular eligibility criteria (as determined by central laboratory screening): Tumors must have at least 1 of the following translocations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C
    7. ECOG performance status Grade 0, 1, or 2 (Attachment 1)
    8. Adequate bone marrow, liver, and renal function:
    a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2 weeks):
    Absolute neutrophil count (ANC) >1,500/mm3
    Platelet count >75,000/mm3
    Hemoglobin >8.0 g/dL (without transfusion or demonstrate stability, i.e., no significant decline in hemoglobin, for 2 weeks after transfusion)
    b. Liver function:
    Total bilirubin <1.5 x institutional upper limit of normal (ULN), unless known to have Gilbert's disease [≤1xULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy]
    Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x institutional ULN [ALT and AST both ≤1.5xULN and alkaline phosphatase ≤2.5xULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy]
    c. Renal function: Creatinine clearance >30 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using Cockcroft-Gault (Attachment 2)
    d. Electrolytes: Potassium within institutional normal limits
    e. Phosphate: <ULN within 14 days of treatment and prior to Cycle 1 Day 1 (medical management allowed)
    9. Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
    10. A woman of childbearing potential who is sexually active must have a negative pregnancy test (ß-human chorionic gonadotropin [ß-hCG]) at Screening (urine or serum)
    11. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies
    For women of childbearing potential:
    • practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
    Examples of highly effective contraceptives include
    - user-independent methods:
    implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence
    - user-dependent methods:
    combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable
    • agrees to remain on a highly effective method throughout the study and for at least 6 months after the last dose of study drug
    • agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug
    • not breast-feeding, not planning to become pregnant within 6 months after the last dose of study drug
    For men who are sexually active with women of childbearing potential:
    • agrees to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository)
    • agrees to not donate sperm during the study and for at least 6 months after the last dose of study drug
    • not planning to father a child during the study or within 6 months after the last dose of study drug
    Les patients potentiels doivent présenter tous les critères suivants pour être inclus dans l’étude :
    1. Âge ≥ 18 ans
    2. Démonstration histologique d’un carcinome à cellules transitionnelles de l’urothélium. La présence de
    composantes mineures de variants histologiques tels qu’une différenciation glandulaire ou squameuse, ou d’une évolution vers des phénotypes plus agressifs tels que présentant une modification sarcomatoïde ou micropapillaire est acceptable
    3. Atteinte de stade IV de la maladie
    4. Progression documentée de la maladie, définie comme toute progression nécessitant un changement de
    traitement, avant la randomisation.
    5. Antécédent d’une seule ligne de traitement systémique pour un cancer urothélial métastasique. Les
    patients ayant reçu une chimiothérapie néoadjuvante ou adjuvante et ayant présenté une progression de la
    maladie dans les 12 mois suivant la dernière dose sont considérés comme ayant reçu une chimiothérapie systémique pour le traitement d’un cancer métastasique.
    Cohorte 1 : traitement antérieur par chimiothérapie et anti-PD(L)1 [en association ou en
    traitement d’entretien] (un traitement par anti-PD(L)1 seul n’est autorisé que chez les patients
    présentant une inéligibilité documentée pour un traitement par cisplatine)
    Cohorte 2 : traitement antérieur par chimiothérapie
    6. Présence de critères d’éligibilité moléculaire appropriés : Les tumeurs devront présenter au moins 1 des translocations suivantes : FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1 ou 1 des mutations géniques de FGFR3
    suivantes : R248C, S249C, G370C, Y373C.
    7. Indice de performances ECOG de grade 0, 1, ou 2
    8. Fonction médullaire, hépatique et rénale appropriée :
    a. Fonction médullaire :
    - Numération absolue des neutrophiles > 1 500/mm3
    - Numération des plaquettes > 75 000/mm3
    - Hémoglobine > 8,0 g/dl
    b. Fonction hépatique :
    - Bilirubine totale ≤ 1,5 x la limite supérieure de la normale (LSN) de l’l’hôpital, à moins
    qu’il existe une maladie de Gilbert’ connue [≤ 1 x LSN pour les patients de la Cohorte 1
    dans les centres choisissant la chimiothérapie par docétaxel]
    - Alanine aminotransférase (ALAT) et aspartate aminotransférase (ASAT) ≤ 2,5 x LSN de l’établissement [ALAT et ASAT ≤ 1,5 x LSN et phosphatases alcalines ≤ 2,5 x LSN
    pour les patients de la Cohorte 1 dans les centres choisissant la chimiothérapie par docétaxel]
    c. Fonction rénale : Clairance de la créatinine (ClCr) > 30 ml/min/1,73 m2 mesurée directement grâce au recueil des urines de 24 heures ou calculée à l’aide de la formule de Cockcroft-Gault.
    d. Électrolytes : Potassium dans les limites de la normale pour l’établissement.
    e. Phosphate : < LSN dans les 14 jours précédant le traitement et avant le Jour 1 du Cycle 1
    9. Signature ( d’un formulaire de consentement éclairé (FCE) indiquant que le patient/la patiente comprend l’objectif de l’étude et les procédures requises pour l’étude, et accepte d’y participer.
    10. Chez une femme en âge de procréer sexuellement active, test de grossesse négatif (dosage de
    gonadotrophine chorionique humaine [βhCG]) à la sélection (urinaire ou sérique).
    11. L’utilisation d’une contraception par les hommes ou les femmes doit être compatible avec les réglementations locales en vigueur concernant l’utilisation de moyens de contraception chez les sujets participant à une étude clinique.
    Pour les femmes en âge de procréer :
    • utiliser un moyen de contraception hautement efficace
    Les exemples de contraceptions hautement efficaces incluent :
    - méthodes indépendantes de l’utilisatrice :
    contraception hormonale exclusivement progestative implantable associée à une inhibition de l’ovulation ; dispositif intra-utérin (DIU) ; système intra-utérin (SIU) à libération hormonale ; partenaire vasectomisé ; abstinence sexuelle - méthodes dépendantes de l’utilisatrice :
    contraception hormonale combinée associée à une inhibition de l’ovulation : orale, intravaginale et transdermique ; contraception hormonale exclusivement progestative associée à une inhibition de l’ovulation : orale et injectable
    • accepter d’utiliser un moyen de contraception hautement efficace pendant toute l’étude et pendant
    au moins 6 mois après la dernière dose de médicament de l’étude
    • accepter de ne pas faire de don d’ovules pour une procréation assistée, pendant l’étude et
    pendant au moins 6 mois après la dernière dose de médicament de l’étude
    • ne pas allaiter, ni prévoir de grossesse pendant les 6 mois suivant la dernière dose de médicament de l’étude
    Pour les hommes sexuellement actifs avec des femmes en âge de procréer :
    • accepter d’utiliser une méthode de contraception mécanique (« barrière »)
    • accepter de ne pas effectuer de don de sperme pendant l’étude et pendant au moins 6 mois après la
    dernière dose de médicament de l’étude
    • accepter de ne pas engendrer d’enfant pendant l’étude et pendant les 6 mois après la dernière dose de médicament à l’étude
    E.4Principal exclusion criteria
    For All Subjects
    1. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to randomization
    2. Active malignancies (ie, requiring treatment change in the last 24 months) other than urothelial cancer (except skin cancers within the last 24 months that is considered completely cured)
    3. Symptomatic central nervous system metastases
    4. Received prior FGFR inhibitor treatment
    5. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
    6. Corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.:
    a. History of central serous retinopathy (CSR) or retinal vascular occlusion (RVO)
    b. Active wet, age-related macular degeneration (AMD)
    c. Diabetic retinopathy with macular edema (non-proliferative)
    d. Uncontrolled glaucoma (per local standard of care)
    e. Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration.
    7. History of uncontrolled cardiovascular disease including:
    a. unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V (Attachment 3) within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months
    b. QTc prolongation as confirmed by triplicate assessment at screening (Fridericia; QTc >480 milliseconds)
    c. Pulmonary embolism or other venous thromboembolism (VTE) within the preceding 2 months
    8. Known active AIDS (human immunodeficiency virus (HIV) infection), unless the subject has been on a stable anti retroviral therapy regimen for the last 6 months or more, has had no opportunistic infections in the last 6 months, and has CD4 count >350
    9. Known active hepatitis B or C infection (subjects with history of hepatitis C infection but negative hepatitis C virus polymerase chain reaction[(PCR] test and subjects with JNJ42756493 (Erdafitinib) hepatitis B with positive hepatitis B surface antibody are allowed)
    10. Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, Grade 1 neuropathy, Grade 1-2 hearing loss)
    11. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
    12. Major surgery within 4 weeks before randomization
    13. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Examples include poorly controlled diabetes (hemoglobin A1c >8), or ongoing active infection requiring intravenous antibiotics

    For Cohort 1 Subjects
    14. Depending on the chemotherapy regimen to be used at the participating site, has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to either docetaxel or to other drugs formulated with polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids

    For Cohort 2 Subjects
    15. Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren's syndrome will not be excluded from the study
    16. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor
    17. Evidence of interstitial lung disease or active non-infectious pneumonitis
    18. Active infection requiring systemic therapy
    19. Received a live virus vaccine within 30 days of first dose
    20. Known allergies, hypersensitivity, or intolerance to pembrolizumab or its excipients
    Tout(e) patient(e) potentiel(le) répondant à un des critères suivants sera exclu(e) de la participation à
    l’étude :
    1. Traitement par un autre agent expérimental ou participation à une autre étude clinique à visée thérapeutique dans les 30 jours précédant la randomisation.
    2. Présence de cancers actifs autres qu’un cancer urothélial
    3. Métastases symptomatiques du système nerveux central
    4. Traitement antérieur pas inhibiteur de FGFR
    5. Présence connue d’allergies, hypersensibilité ou intolérance à l’erdafitinib ou ses excipients
    6. Anomalie cornéenne ou rétinienne susceptible d’augmenter le risque de toxicité oculaire, c’est-à-dire :
    a. Antécédents de rétinopathie séreuse centrale ou d’occlusion vasculaire rétinienne
    b. DMLA (dégénérescence maculaire liée à l’âge) humide active
    c. Rétinopathie diabétique avec oedème maculaire (non proliférative)
    d. Glaucome non contrôlé
    e. Pathologie de la cornée telle qu’une kératite, une kératoconjonctivite, une kératopathie, une abrasion, une inflammation ou une ulcération cornéenne.
    7. Antécédents de maladie cardiovasculaire non contrôlée incluant :
    a. angor instable, infarctus du myocarde, fibrillation ventriculaire, torsades de pointes, arrêt cardiaque
    ou insuffisance cardiaque congestive connue de Classe III-V au cours des 3 mois précédents ; accident
    vasculaire cérébral ou accident ischémique transitoire au cours des 3 mois précédents.
    b. Allongement de l’intervalle QTc, confirmé par une triple évaluation lors de la sélection
    c. Embolie pulmonaire ou autres thrombo-embolies veineuses au cours des 2 mois précédents
    8. SIDA actif connu, sauf si le patient/la patiente a reçu un traitement anti-rétroviral à dose stable depuis au moins 6 mois, n’a pas présenté(e) d’infections opportunistes au cours des 6 mois précédentes et à un nombre de CD4 > 350
    9. Infection active connue par le virus de l’hépatite B ou C
    10. Toxicité réversible non résolue d’un précédent traitement anticancéreux
    11. Troubles de la capacité de cicatrisation des plaies, définis comme des escarres/ulcères de décubitus,
    ulcères chroniques des membres inférieurs, des ulcères gastriques connus ou des incisions non cicatrisées
    12. Intervention chirurgicale majeure dans les 4 semaines précédant la randomisation.
    13. Toute pathologie pour laquelle, d’après l’investigateur, la participation à l’étude n’est pas dans le
    meilleur intérêt du patient ou est susceptible d’empêcher ou de limiter les évaluations spécifiées dans le protocole ou de constituer un facteur de confusion pour ces évaluations. Les exemples incluent un diabète mal contrôlé ou infection active en cours nécessitant une antibiothérapie intraveineuse.
    Critères de non inclusion pour les patients de la Cohorte 1
    14. Outre les critères de non-inclusion mentionnés ci-dessus, tout patient potentiel de la Cohorte 1
    répondant aux critères suivants sera exclus de la participation à l’étude :
    Selon la chimiothérapie utilisée dans l’hôpital participant, antécédents de réaction d’hypersensibilité
    sévère vis-à-vis du docétaxel ou d’autres médicaments contenant de l’huile de ricin polyoxyéthylée dans leur composition, ou vis-à-vis de la vinflunine ou d’autres vinca-alcaloïdes.
    Critères de non inclusion pour les patients de la Cohorte 2
    Outre les critères de non-inclusion mentionnés ci-dessus, tout patient potentiel de la Cohorte 2 répondant à
    l’un des critères suivants sera exclus de la participation à l’étude :
    15. Maladie auto-immune active nécessitant un traitement systémique au cours des 3 mois précédents ou antécédents documentés de maladie auto-immune cliniquement sévère ou de syndrome nécessitant des
    agents systémiques ou immunosuppresseurs. Les patients présentant un vitiligo, un diabète de type I ou
    un asthme/une atopie infantile constituent une exception à cette règle. Les patients nécessitant
    l’utilisation intermittente de bronchodilatateurs, de corticoïdes par inhalation ou de corticoïdes en
    injections locales ne sont pas exclus de l’étude. Les patients présentant une hypothyroïdie stable sous
    hormonothérapie de substitution ou un syndrome de Sjøgren ne seront pas exclus de l’étude
    16. Diagnostic d’immunodéficience ou traitement en cours par corticothérapie ou toute autre forme de
    traitement immunosuppresseur au cours des 7 jours précédant la première dose de traitement à l’étude.
    L’utilisation de corticostéroïdes à doses physiologiques peut être approuvée après consultation du
    promoteur.
    17. Présence d’une pneumopathie interstitielle ou d’une pneumonite non infectieuse active
    18. Infection active nécessitant un traitement systémique.
    19. Vaccination par un virus vivant au cours des 30 jours précédant la première dose
    20. Présence connue d’allergies, hypersensibilité ou intolérance au pembrolizumab ou ses excipients
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is overall survival (OS). Overall survival is measured from the date of randomization to the date of the subject’s death. If the subject is alive or the vital status is unknown, the subject will be censored at the date the subject was last known to be alive

    Le critère d’évaluation principal est la SG. La SG est mesurée à partir de la date de la randomisation jusqu’à la date du décès du patient. Si le patient/la patiente est en vie ou si le statut vital est inconnu, le patient/la patiente sera recensé(e) à la dernière date à laquelle il/elle était connu(e) comme étant vivant(e).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study
    E.5.2Secondary end point(s)
    - PFS: duration in days from the date of randomization to the date of disease progression (assessed per RECIST v1.1 by the investigator) or relapse from CR or death, whichever is reported first. For subjects who do not have disease progression and are alive, as well as for subjects with unknown disease progression or unknown survival status as of the clinical cutoff date, PFS will be censored at the date of the last adequate disease assessment. If there is no postbaseline tumor assessment for a subject, PFS will be censored on the date of randomization. Refer to the Statistical Analysis Plan (SAP) for further details regarding censoring rules. Adequate disease assessment is defined as having sufficient evidence to indicate correctly that progression has or has not occurred
    - ORR: the proportion of subjects who achieve complete response or partial response, as assessed per RECIST v1.1 by the investigator
    - Change from baseline in patient-reported health status and physical functioning scales of the Functional Assessment of Cancer Therapy – Bladder Cancer (FACT-Bl), Patient-Global Impression of Severity (PGIS), and utility and visual analog scale of the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)
    - DOR: for responders, duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death. The censoring is similar to PFS
    - Safety: collection of adverse event, clinical laboratory values, electrocardiograms, vital signs, ophthalmologic evaluations, physical examinations
    - Oral clearance, area under the plasma concentration-time curve (and other parameters, as needed and as data permits) will be estimated using a population approach
    • SSP : durée en jours depuis la date de la randomisation jusqu’à la date de la progression de la maladie (évaluée par l’investigateur selon les critères d’évaluation de la réponse dans les tumeurs solides (RECIST, Response Evaluation Criteria in Solid Tumors) version 1.1) ou de la récidive après une réponse complète (RC) ou du décès, selon la première occurrence. Pour les patients ne présentant pas de progression de la maladie et qui sont vivants, ainsi que pour les patients ayant un statut inconnu de progression de la maladie ou de survie à la date limite de recueil des données cliniques, la SSP sera considérée à la date de la dernière évaluation appropriée de la maladie. Si on ne dispose pas d’évaluation tumorale après l’inclusion d’un patient, la SSP sera recensée à la date de la
    randomisation.
    • TRO : la proportion de patients parvenant à une réponse complète ou partielle, évaluée selon les critères RECIST v1.1 par l’investigateur..
    • Changement par rapport aux valeurs initiales, de l’état de santé rapporté par le patient/la patiente et des échelles de fonctionnement physique FACT-BI (Functional Assessment of Cancer Therapy – Bladder Cancer, Evaluation Fonctionnelle du Traitement du Cancer – Cancer de la vessie), PGIS (Patient-Global Impression of Severity, impression globale de sévérité établie par le patient/la patiente), ainsi que de l’échelle analogique visuelle et d’utilité du questionnaire EQ-5D-5L (European Quality of Life-5 Dimensions-5 Levels Questionnaire, questionnaire européen de qualité de vie à 5 dimensions et 5 niveaux).
    • DdR : pour les patients ayant répondu, durée en jours depuis la date de la documentation initiale d’une réponse à la date de la première mise en évidence documentée d’une progression de la maladie (ou d’une récidive pour les patients ayant une RC pendant l’étude) ou du décès.
    • Tolérance : recueil des événements indésirables, résultats des analyses biologiques cliniques, électrocardiogrammes, signes vitaux, évaluations ophtalmologiques, examens cliniques
    • La clairance orale, l’aire sous la courbe de concentrations plasmatiques en fonction du temps (et d’autres paramètres, selon les besoins et selon ce que permettent les données) seront estimées à l’aide d’une approche de population.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned21
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    France
    Germany
    Greece
    Hungary
    India
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Portugal
    Russian Federation
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    dernière visite du dernier patient
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial 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: 315
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 315
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 237
    F.4.2.2In the whole clinical trial 630
    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)
    The Sponsor will ensure that subjects benefiting from treatment will be able to continue treatment after the end of the study
    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 Decision2018-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-02
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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