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    Summary
    EudraCT Number:2008-002298-11
    Sponsor's Protocol Code Number:NO21895
    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:2008-07-23
    Trial results View 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 number2008-002298-11
    A.3Full title of the trial
    Open-label, multicenter, dose-escalation Phase I/II study to evaluate safety, pharmacokinetics and activity of RO5126766, a dual Raf and MEK inhibitor, administered orally as monotherapy in patients with advanced tumors.
    A.4.1Sponsor's protocol code numberNO21895
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameCKI 27 (2) Inhibitor
    D.3.2Product code RO5126766/F02
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNnot yet available
    D.3.9.1CAS number 946128-90-1
    D.3.9.2Current sponsor codeRO5126766-002
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 nameCKI 27 (2) Inhibitor
    D.3.2Product code RO5126766/F03
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNnot yet available
    D.3.9.1CAS number 946128-90-1
    D.3.9.2Current sponsor codeRO5126766-002
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.1
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 nameCKI 27 (2) Inhibitor
    D.3.2Product code RO5126766/F04
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNnot yet available
    D.3.9.1CAS number 946128-90-1
    D.3.9.2Current sponsor codeRO5126766-002
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.15
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 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 nameCKI 27 (2) Inhibitor
    D.3.2Product code RO5126766/F05
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNnot yet available
    D.3.9.1CAS number 946128-90-1
    D.3.9.2Current sponsor codeRO5126766-002
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.8
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    To investigate RO5126766 single agent activity in patients with metastatic or advanced solid tumor.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10007050
    E.1.2Term Cancer
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part I of the study (Dose Escalation):
    - To determine the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicities (DLT) of RO5126766 administered on an oral continuous daily schedule.
    Part II of the study (Expansion Cohort):
    - To investigate RO5126766 single agent activity in patients with metastatic or advanced solid tumor.
    E.2.2Secondary objectives of the trial
    1. To determine the safety and tolerability profiles of RO5126766;
    2. To determine the pharmacokinetic (PK) of RO5126766;
    3. To determine the pharmacodynamic (PD) effect of RO5126766 in tumor by pERK inhibition and PET imaging, and in surrogate tissues with skin biopsy and peripheral blood samples;
    4. To explore the PK/PD relationship and relate this to any disease response obtained;
    5. To define a Minimal Biological Dose (MBD) and an Optimal Biological Dose (OBD).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Roche Sample Repository Research Project in association with protocol NO21895: Open-label, multicenter, dose-escalation Phase I/II study to evaluate safety, pharmacokinetics and activity of RO5126766, a dual Raf and MEK inhibitor, administered orally as monotherapy in patients with advanced tumors.

    Protocol NO21895RG version A dated July 3, 2008

    Objectives : To obtain a single blood sample from consenting patients enrolled in associated study NO21895 for pharmacogenetic and genetic research analysis.
    E.3Principal inclusion criteria
    1. Patients must have histologically or cytologically confirmed diagnosis of cancer which is not amenable to curative therapy (i.e., advanced and/or metastatic disease).
    •Part I (Dose Escalation): Patients with any tumor type or histology may be included.
    •Part II (Expansion Cohort): Patients with the following tumor types will be enrolled: malignant melanoma, pancreatic cancer, non small cell lung cancer. If emerging Part I data suggest that a particular tumor type or specific tumor histology might be responsive to treatment, then this tumor type or histology would be considered as preferred disease for inclusion.
    2. Prior Therapy :
    •The number of prior systemic therapies given for metastatic disease will not be limited (for both Part I and Part II of the study).
    3. Age ≥ 18 years.
    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    5. Life expectancy of ≥12 weeks.
    6. Disease measurability:
    •Part I (Dose Escalation): Patients must have a measurable (as per RECIST criteria) and/or evaluable disease (e.g., cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST criteria for measurable disease).
    •Part II (Expansion Cohort): Patients must have at least one measurable disease lesion as per the RECIST criteria.
    7. Patient ability to comply with the collection of tumor biopsies (at baseline, on day 15 of cycle 1, and at the time of disease progression, complete/partial response, or stable disease lasting for more than 4 months) for those eligible for that evaluation (mandatory for part II).
    8. Adequate bone marrow function as defined by: ANC of ≥1.5 x 10 exp9/L, platelet count of ≥100.0 x 10 exp9/L, and hemoglobin of ≥9 g/dL.
    9. Adequate liver function, as determined by: Serum total bilirubin ≤1.5 ULN, AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases); AP < 2.5 x ULN (< 5x ULN if liver metastases). There is no upper limit for alkaline phosphatase (AP) if elevations are due exclusively to bone metastases or if the patient has prostate cancer.
    10. Adequate renal function assessed by at least one of the following: 1) Serum creatinine ≤ 1.5 xULN or 2) creatinine clearance estimate of ≥60 mL/min in male and ≥50 mL/min in female (as calculated according to Cockroft-Gault formula).
    11. Serum calcium (corrected for albumin level) ≤1.0 x ULN.
    12. INR and PTT ≤ 1.5.
    13. Signed informed consent.
    14. Patient ability to comply with protocol requirements (visits and assessment schedules) and willingness to submit to blood sampling for the PK and PD analyses.
    15. Female patients must be postmenopausal (12 months of amenorrhea), surgically sterile or they must agree to use a physical method of contraception. Oral or injectable contraceptive agents can not be the sole method of contraception. Male patients must be surgically sterile or agree to use a barrier method of contraception.
    16. Female patients of child-bearing potential must have a negative urine pregnancy test within the seven days prior to the first study drug administration.
    E.4Principal exclusion criteria
    1. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
    2. Patients with known (past or present) Central Nervous System (CNS) metastases.
    3. Patients with history of gallbladder disorder or complication including cholelithiasis.
    4. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C). Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated.
    5. Prior toxicities from chemotherapy or radiotherapy which have not regressed to Grade ≤1 severity (NCI-CTCAE version 3.0).
    6. Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drug.
    7. Treatment with any investigational agent within 28 days of first receipt of study drug.
    8. Patients with acute or chronic infection. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding or any other medical condition that, in the opinion of the investigator, contraindicates the use of an investigational drug, or will impose excessive risk to the patient. Examples of such medical conditions include significant cardiovascular disease (such as NYHA Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or severe obstructive pulmonary disease .
    9. Patients with HIV, HBV and HCV infection.
    10. Patients exposed to CYP3A4 inhibitors within 7 days prior to the first dose and CYP3A4 inducers 14 days prior to the first dose (see Appendix°5 table for CYP3A4 inducers and inhibitors).
    11. History of any bowel disease including abdominal fistula, gastro-intestinal perforation, and diverticulitis.
    12. Major surgery within 28 days of first receipt of study drug.
    13. Pregnant or lactating women.
    14. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    This study is primarily designed in Part I to characterize DLTs and to determine the MTD (maximum tolerated dose) and OBD (optimal biological dose) of RO5126766. Response to treatment according to the RECIST criteria (complete/partial responses: CR/PR, stable disease: SD, for definition see Appendix 4 RECIST). In Part II of the study, safety, tolerability, and anti-tumor activity will be further assessed in the MTD and OBD. The Objective Response Rates (Objective Response Rate: CR+PR) and Clinical Benefit Rates (CBR: CR+PR+SD > 4 months), as well as median Progression Free Survival (PFS measured from the day of first administration of RO5126766 until the date of first documented disease progression or death by any cause) will be calculated for the MTD and OBD to evaluate the most likely effective dose for all tumor types combined and by tumor type.
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    MTD (maximum tolerated dose) and OBD (optimal biological dose); Biomarker analysis
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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 Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months26
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    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 Decision2008-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-11-14
    P. End of Trial
    P.End of Trial StatusOngoing
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