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    Summary
    EudraCT Number:2018-000588-99
    Sponsor's Protocol Code Number:BLU-285-2203
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-12-18
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2018-000588-99
    A.3Full title of the trial
    A 3-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib (BLU-285), a Selective KIT Mutation-Targeted Tyrosine Kinase Inhibitor, in Indolent and Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Avapritinib in Patients with Indolent and Smoldering Systemic Mastocytosis
    A.3.2Name or abbreviated title of the trial where available
    Pioneer
    A.4.1Sponsor's protocol code numberBLU-285-2203
    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 SponsorBlueprint Medicines Corporation
    B.1.3.4CountryUnited States
    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 supportBlueprint Medicines Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyneos Health, LLC
    B.5.2Functional name of contact pointProject Director, Global Oncology
    B.5.3 Address:
    B.5.3.1Street Address1030 Sync Street,
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1512904 4317
    B.5.6E-mailsara.hoffman@syneoshealth.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2074
    D.3 Description of the IMP
    D.3.1Product nameAvapritinib
    D.3.2Product code BLU-285, C-366, C366, 70C366, X720776, BLU112317
    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 INNAvapritinib
    D.3.9.2Current sponsor codeBLU-285
    D.3.9.4EV Substance CodeSUB178877
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2074
    D.3 Description of the IMP
    D.3.1Product nameAvapritinib
    D.3.2Product code BLU-285, C-366, C366, 70C366, X720776, BLU112317
    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 INNAvapritinib
    D.3.9.2Current sponsor codeBLU-285
    D.3.9.4EV Substance CodeSUB178877
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    D.8 Placebo: 2
    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
    Indolent Systemic Mastocytosis (ISM)
    E.1.1.1Medical condition in easily understood language
    Mastocytosis
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10042949
    E.1.2Term Systemic mastocytosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10056452
    E.1.2Term Indolent systemic mastocytosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1 - to determine the RP2D of avapritinib in patients with ISM for use
    in Part 2 and Part 3 of the study.
    Part 2 - to determine the proportion of avapritinib-treated patients with
    ISM achieving a ≥30% reduction in TSS from Baseline to C7D1,
    compared to placebo.
    Part 3 - to assess the long-term safety and efficacy of avapritinib in ISM
    patients.
    E.2.2Secondary objectives of the trial
    Key Secondary (Part 2 Only)
    To determine from Baseline to C7D1, compared to placebo:
    - proportion of avapritinib-treated patients with a ≥50% reduction in
    serum tryptase
    - proportion of patients with a ≥50% reduction in peripheral blood KIT
    D816V allele fraction or undetectable (<0.02%) for patients with
    detectable mutation at Baseline
    - mean change in ISM-SAF TSS in patients
    - proportion of patients with a ≥50% reduction in bone marrow mast
    cells or no aggregates for patients with aggregates at Baseline
    Additional Secondary
    Assess change in:
    - measures of mast cell burden in each treatment cohort (serum
    tryptase, KIT D816V allele burden in blood, bone marrow mast cells)
    - best supportive care usage for SM symptoms
    Assess change in other Patient-Reported Outcomes and Quality of Life
    measures
    Assess the safety and tolerability of avapritinib, as assessed by AEs, vital
    signs, electrocardiograms, and laboratory tests
    Assess the PK of avapritinib (Part 1 and 2 only)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients who are ≥ 18 years of age.
    2. Patient must have SM, confirmed by Central Pathology Review of BM
    biopsy, and central review of B- and C-findings by WHO diagnostic
    criteria.
    3. Patient must have moderate-to-severe symptoms based on minimum
    mean TSS over the 14-day eligibility screening period for assessment of
    TSS and ≥ 1 symptom in skin or GI domains of the ISM-SAF at Baseline.
    Minimum TSS for eligibility is ≥ 28.
    4. Patient must have failed to achieve adequate symptom control for 1 or
    more Baseline symptoms, as determined by the Investigator, with at
    least 2 of the following symptomatic therapies: H1 blockers, H2 blockers,
    proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium,
    corticosteroids, or omalizumab.
    5. The patient's symptomatic SM therapies (eg, H1 and H2 blockers)
    must be stable (same dose, no new medications ≥14 days before
    beginning the 14-day ISM-SAF eligibility TSS assessment).
    6. If the patient is receiving corticosteroids, the dose must be ≤20
    mg/day prednisone or equivalent, and the dose must be stable for ≥14
    days before beginning the 14-day ISM-SAF eligibility TSS assessment.
    7. Patient must have an Eastern Cooperative Oncology Group
    Performance Status of 0 to 2.
    8. Patient must be able to give written informed consent.
    E.4Principal exclusion criteria
    1. Patient has been diagnosed with any of the following WHO SM
    subclassifications: Cutaneous mastocytosis only, SM-AHN, SSM, ASM,
    MCL, MC sarcoma.
    2. Patient has been diagnosed with another myeloproliferative disorder.
    3. Patient has any of the following organ damage C-findings attributable
    to SM: Cytopenia, Hepatomegaly with ascites and impaired liver function,
    Palpable splenomegaly with hypersplenism, Malabsorption with
    hypoalbuminemia and significant weight loss, Skeletal lesions: large
    osteolytic lesions with pathologic fractures, Life-threatening organ
    damage in other organ systems that is caused by MC infiltration in
    tissues.
    4. Patient meets any of the following laboratory criteria: Aspartate
    aminotransferase or alanine aminotransferase > 3.0 × ULN, Total
    bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease. (In the
    case of Gilbert's disease, a direct bilirubin > 2.0 × ULN is an exclusion.)
    Albumin < 1 × LLN, eGFR < 30 mL/min/1.73 m^2 or creatinine
    clearance or creatinine > 1.5 × ULN Absolute neutrophil count < 1.5 ×
    10^9/L, Hemoglobin < 10 g/dL, Platelet count < 100,000/μL
    5. Patient has received any of the following medications, therapies, or
    procedures in the timeframes listed: Any prior treatment with
    avapritinib, Any TKI, including but not limited to masitinib and
    midostaurin, or investigational agent for < 14 days or 5 half-lives of the
    drug (whichever is longer) before beginning the 14-day ISM-SAF
    eligibility TSS assessment, Any antineoplastic drug therapy < 28 days or
    5 half-lives of the drug (whichever is longer) before beginning the 14-
    day ISM-SAF eligibility TSS assessment, Radiotherapy or psoralen and
    ultraviolet A (PUVA) therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment, Any hematopoietic growth factor <
    14 days before beginning the 14-day ISM-SAF eligibility TSS assessment,
    Any major surgical procedure < 14 days before starting the ISM-SAF for
    determination of eligibility.
    6. Patient requires therapy with a concomitant medication that is a
    strong inhibitor, strong inducer, or moderate inducer of cytochrome
    P450 3A4 (CYP3A4) (see Appendix 6).
    7. Patient has a history of a malignancy that has been diagnosed or
    required therapy within 3 years before the first dose of study drug.
    Patients with a prior or concurrent malignancy whose natural history or
    treatment does not have the potential to interfere with the safety or
    efficacy assessment of the investigational agent may be included after
    approval by medical monitor.
    8. Patient has a QTcF > 480 msec.
    9. Patient has a history of a seizure disorder (eg, epilepsy) or requires
    antiseizure medication.
    10. Patient has a history of a cerebrovascular accident or transient
    ischemic attacks within 12 months before the first dose of study drug.
    11. Patient has a known risk or recent history (12 months before the
    first dose of study drug) of ICB (eg, brain aneurysm).
    12. Patient has a primary brain malignancy or metastases to the brain.
    13. Patient has clinically significant, uncontrolled cardiovascular disease,
    including Grade III or IV congestive heart failure greater than New York
    Heart Association classification II; myocardial infarction or unstable
    angina within the previous 6 months; clinically significant, uncontrolled
    arrhythmias, or uncontrolled hypertension.
    14. Female patients who are unwilling, if not postmenopausal or
    surgically sterile, to abstain from sexual intercourse or employ highly
    effective contraception during the study drug administration period and
    for at least 6 weeks after the last dose of study drug. Men who are
    unwilling, if not surgically sterile, to abstain from sexual intercourse or
    employ highly effective contraception during the study drug
    administration period and for at least 6 weeks after the last dose of
    study drug.
    15. Pregnant women, as documented by a β-hCG pregnancy test
    consistent with pregnancy obtained within 7 days before the first dose of
    study drug.
    16. Women who are breast feeding.
    17. Patient is illiterate or otherwise unable or unwilling to complete daily
    ISM-SAF assessments in the eDiary.
    18. Patients with known hypersensitivity to avapritinib or to any of the
    excipients.
    19. Patients requiring anticoagulant therapy such as warfarin, or similar
    agents requiring therapeutic international normalized ratio (INR)
    monitoring.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    •The RP2D in patients with ISM.
    Part 2
    •Proportion of responders, defined as ≥30% reduction in ISM-SAF TSS,
    from Baseline to C7D1.
    Part 3
    •The long-term safety and efficacy of avapritinib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1 - weekly for the first 4 weeks, then every 4 weeks
    Part 2 - Patients will be assessed every 4 weeks through C7D1
    Part 3 - All patients in Part 3 will have study visits every 4 weeks until
    C7D1, then every 8 weeks until C13D1. After C13D1, patients will have
    visits every 12 weeks for a total study duration of up to 5 years,
    inclusive of Part 1 and Part 2.
    E.5.2Secondary end point(s)
    Key Secondary (Part 2 Only)
    • Proportion of patients with a ≥50% reduction in serum tryptase.
    • Proportion of patients with a ≥50% reduction in peripheral blood KIT
    D816V allele fraction or undetectable (<0.02%) for patients with
    detectable mutation at Baseline.
    • Mean change in ISM-SAF TSS.
    • Proportion of patients with a ≥50% reduction in bone marrow mast
    cells or no aggregates for patients with aggregates at Baseline.
    Additional Secondary
    • Change in measures of mast cell burden: serum tryptase, KIT D816V
    allele burden in blood, bone marrow mast cells.
    • Change in best supportive care usage.
    • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
    • Safety and tolerability of avapritinib, as assessed by AEs, vital signs,
    electrocardiograms, and laboratory tests.
    • Pharmacokinetics of avapritinib (Part 1 and 2 only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Key Secondary (Part 2 Only): from Baseline to C7D1
    • KIT D816V & Tryptase: C1D1/D15, C2D1, C4D1 (KIT), every visit
    through C4D1 (tryptase), every 4w until roll over (Part 1); every cycle
    through C7D1 (Part 2); every cycle through C7D1, every 8w during C7-
    13, and every 12w during C13 through EOT (Part 3)
    • Bone marrow biopsy: Screening, C4D1 (Part 1), C7D1 (Part 2); optional
    at approx. 1 year after end of Part 1 & 2 biopsy (Part 3)
    • ISM-SAF: daily through C13D1 in Part 3
    • QoL: each visit through C13D1 in Part 3
    • AE & BSC: throughout study
    • Vital signs, hematology & chemistry: every visit until EOT
    • ECG: Screening, D1 of every cycle (Part 1 & 2); D1 of every visit (Part
    3)
    • Sparse PK: before & after study drug dosing (Part 1 & 2)
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    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 trial4
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    Belgium
    Canada
    Denmark
    Germany
    Italy
    Netherlands
    Spain
    Switzerland
    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
    The end of the study is defined as the time that the last patient
    completes his/her last visit (LPLV), including assessments performed
    as part of safety follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 44
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 244
    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)
    Normal standard of care.
    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 Decision2021-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-16
    P. End of Trial
    P.End of Trial StatusOngoing
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