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    Summary
    EudraCT Number:2018-000047-31
    Sponsor's Protocol Code Number:HOVON155
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-31
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-000047-31
    A.3Full title of the trial
    A randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to 10-day decitabine in UNFIT (i.e. HCT-CI ≥ 3) adult AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) patients.

    A study in the frame of the masterprotocol of parallel randomized phase II studies in UNFIT- AML/high-risk MDS patients.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized study to assess the tolerability and efficacy of the addition of midostaurin to 10-day decitabine treatment in patients with AML and high risk myelodysplasia (MDS), UNFIT for intensive chemotherapy. ,
    A.3.2Name or abbreviated title of the trial where available
    HOVON 155 AML/SAKK
    A.4.1Sponsor's protocol code numberHOVON155
    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 SponsorHOVON Foundation
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDutch Cancer Society
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportNovartis
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportJanssen
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC, HOVON Data Center
    B.5.2Functional name of contact pointHOVON Data Center
    B.5.3 Address:
    B.5.3.1Street Addresswytemaweg 80
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 CN
    B.5.3.4CountryNetherlands
    B.5.6E-mailhdc@erasmusmc.nl
    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 Yes
    D.2.1.1.1Trade name Rydapt
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/214
    D.3 Description of the IMP
    D.3.1Product nameMidostaurin
    D.3.4Pharmaceutical form Capsule
    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 INNmidostaurin
    D.3.9.1CAS number 120685-11-2
    D.3.9.3Other descriptive nameMIDOSTAURIN
    D.3.9.4EV Substance CodeSUB21040
    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 Yes
    D.2.1.1.1Trade name Dacogen
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Ciliq International NV
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/370
    D.3 Description of the IMP
    D.3.1Product nameDecitabine
    D.3.4Pharmaceutical form Powder for 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 INNDECITABINE
    D.3.9.1CAS number 2353-33-5
    D.3.9.4EV Substance CodeSUB06932MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Meyloid Leukemia and high risk myelodysplastic syndromes
    E.1.1.1Medical condition in easily understood language
    Acute Meyloid Leukemia and high risk myelodysplastic syndromes
    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 10000886
    E.1.2Term Acute myeloid leukemia
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10028533
    E.1.2Term Myelodysplastic syndrome
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess in a randomized comparison the effect of midostaurin added to 10-day decitabine treatment on the cumulative CR/CRi rate during 3 cycles.
    E.2.2Secondary objectives of the trial
    - To assess the safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards to the selected dose level of the study.
    - To determine the efficacy profile: response rate (CRMRD-, CR, CRi, MLFS, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens.
    - To measure MRD by immunophenotyping and PCR in relation to clinical response parameters.
    - To identify gene mutations as potential biomarkers predictive of response, EFS and OS by exploratory analysis.
    - To evaluate the prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL)) on treatment outcome.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with:
    - a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
    - a diagnosis of myelodysplastic syndrome with excess of blasts (MDS) and IPSS-R > 4.5
    • Patients 18 years and older.
    • Patients NOT eligible for standard chemotherapy, defined as HCT-CI ≥ 3. (Appendix G)
    or
    Patients NOT eligible for standard chemotherapy for other reasons (wish of patient).
    • WBC ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment)
    • Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
    - Serum creatinine ≤ 221.7 µmol/L (≤ 2.5 mg/dL ), unless considered AML-related
    - Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert’s syndrome
    - Alanine transaminase (ALT) ≤ 2.5 x ULN, unless considered AML-related
    • WHO performance status 0, 1 or 2 (see Appendix D).
    • Patient is willing and able to use adequate contraception during and until 5 months after the last protocol treatment.
    • Written informed consent.
    • Patient is capable of giving informed consent.

    E.4Principal exclusion criteria
    • Acute promyelocytic leukemia.
    • Acute leukemia's of ambiguous lineage according to WHO 2016
    • Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement)
    • Blast crisis of chronic myeloid leukemia.
    • Diagnosis of any previous or concomitant malignancy is an exclusion criterion:
    - except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization. OR
    - except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
    • Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period ( ≤ 5 days) with Hydroxyurea is allowed
    • Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea
    • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
    • Cardiac dysfunction as defined by:
    - Myocardial infarction within the last 3 months of study entry, or
    - Reduced left ventricular function with an ejection fraction < 40% as measured by MUGA scan or echocardiogram or
    - Unstable angina or
    - New York Heart Association (NYHA) grade IV congestive heart failure (see Appendix I) or
    - Unstable cardiac arrhythmias.
    • History of stroke or intracranial hemorrhage within 6 months prior to randomization.
    • Patient has a history of human immunodeficiency virus (HIV) or active infection with Hepatitis C or B.
    • Patients known to be pregnant
    • Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
    • Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.
    • Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
    • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule


    E.5 End points
    E.5.1Primary end point(s)
    Cumulative CR/CRi rate during 3 cycles
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoints will be evaluated when relevant data for all patients are available
    E.5.2Secondary end point(s)
    Secundary endpoints:
    • Safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (type, frequency, severity and relationship of adverse events to study treatment).
    • Efficacy profile (response rate after each first three cycles and best response during three cycles and after 9 months (CRMRD-, CR, CRi, MLFS, PR))
    • Event free survival (EFS)
    • Overall survival (OS)). (see Appendix B and 13.4 for definition of the survival endpoints)
    • Days of staying in hospital and transfusion needs during three cycles.
    • Prognostic value of MRD (by flowcytometry or PCR).
    • Gene mutations predictive of response, EFS and OS by exploratory analysis.
    • Prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL) on treatment outcome.

    Translational endpoints:
    To identify potential biomarkers (molecular) that predict for response to decitabine and/or midostaurin.

    E.5.2.1Timepoint(s) of evaluation of this end point
    These endpoints will be evaluated when relevant data for all patients are available
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Decitabine treatment without midostaurin
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Germany
    Ireland
    Netherlands
    Switzerland
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 126
    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 state63
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 140
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation HOVON Foundation
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-30
    P. End of Trial
    P.End of Trial StatusOngoing
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