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    Summary
    EudraCT Number:2014-001876-75
    Sponsor's Protocol Code Number:HOVON103AMLSelinexor
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-09-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2014-001876-75
    A.3Full title of the trial
    A randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral selinexor (KPT-330) to standard induction chemotherapy in AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) in patients aged >= 66 years .

    A study in the frame of the masterprotocol of parallel randomized phase II studies in elderly AML
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study for patients with leukemic cells in their bone marrow
    A.3.2Name or abbreviated title of the trial where available
    HOVON 103 AML Selinexor
    A.4.1Sponsor's protocol code numberHOVON103AMLSelinexor
    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 supportHOVON Foundation
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportKaryopharm Therapeutics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC Cancer Institute, Clinical Trial Center
    B.5.2Functional name of contact pointHOVON Data Center
    B.5.3 Address:
    B.5.3.1Street AddressP.O. Box 2040
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3000 CA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31107041560
    B.5.5Fax number+31107041028
    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 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 nameselinexor (20 mg)
    D.3.2Product code KPT-330
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNselinexor
    D.3.9.2Current sponsor codeKPT-330
    D.3.9.3Other descriptive nameKPT-330
    D.3.9.4EV Substance CodeSUB168135
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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
    patients ≥ 66 years with:
    - a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
    - acute leukemia's of ambiguous lineage according to WHO 2008 or
    - a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5
    E.1.1.1Medical condition in easily understood language
    Leukemia, cancer of bone marrow
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10037803
    E.1.2Term RAEB
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid leukaemia
    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
    For part A of the study (if applicable):
    1. To assess the safety and tolerability of selinexor added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) and select the feasible dose level for part B
    2. To assess in a randomized comparison the effect of selinexor on the CR rate.


    For part B:
    1. To assess the safety and tolerability of selinexor added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of selinexor
    2. To assess in a randomized comparison the effect of selinexor on the CR rate.
    E.2.2Secondary objectives of the trial
    For part B:
    1. To determine the efficacy profile (event free survival (EFS) disease free survival (DFS) and overall survival (OS)) associated with the two therapy regimens.
    2. To measure MRD by immunophenotyping in relation to clinical response parameters.
    3. To identify potential biomarkers predictive of response, EFS, DFS and OS by exploratory genomic analysis (microarray, gene mutations)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients eligible for standard chemotherapy.
    • Patients 66 years and older
    • Patients with:
    - a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
    - acute leukemia’s of ambiguous lineage according to WHO 2008 or
    - a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5
    • Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
    - Serum creatinine ≤1.0 mg/dL (≤88.7 µmol/L); if serum creatinine >1.0 mg/dL (>88.7 µmol/L), then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where the Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if patient is female) x (1.212 if patient is black)
    NOTE: if serum creatinine is measured in µmol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 µmol/L and use the above mentioned formula.
    - Serum bilirubin ≤ 2.5 x upper limit of normal (ULN)
    - Aspartate transaminase (AST) ≤ 2.5 x ULN
    - Alanine transaminase (ALT) ≤ 2.5 x ULN
    - Alkaline phosphatase ≤ 2.5 x ULN
    • WHO performance status 0, 1 or 2 (see Appendix F)
    • Written informed consent.
    • Male and female patients must use an effective contraceptive method if relevant during the study and for a minimum of 6 months after study treatment.
    E.4Principal exclusion criteria
    • Acute promyelocytic leukemia
    • Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is allowed
    • Concurrent history of active malignancy in the two past years prior to diagnosis except for:
    - Basal and squamous cell carcinoma of the skin
    - in situ carcinoma of the cervix
    • Blast crisis of chronic myeloid leukemia
    • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera)
    • Cardiac dysfunction as defined by:
    - Myocardial infarction within the last 6 months of study entry, or
    - Reduced left ventricular function with an ejection fraction < 50% ad measured by MUG scan or echocardiogram or
    - Unstable angina or
    - New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix I) or
    - Unstable cardiac arrthythmias
    • 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.
    • Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
    • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
    E.5 End points
    E.5.1Primary end point(s)
    • Incidence of DLT (part A)
    • The effect of selinexor on the CR rate (part B of study)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analysis of the primary endpoints will be done one year after last patient is registered in the selinexor arm
    E.5.2Secondary end point(s)
    • Overall survival (time from registration till the death of the patient.)
    • Event free survival (i.e., time from registration to induction failure (i.e. no CR on induction), death or relapse whichever occurs first)
    • Disease free survival (time from CR on protocol treatment until relapse or death, whichever comes first)
    • Prognostic value of molecular markers and gene expression profiles of the leukemia assessed at diagnosis
    • Prognostic value of minimal residual disease (MRD) measurements following therapy by standardized sampling of marrow/blood
    E.5.2.1Timepoint(s) of evaluation of this end point
    The final analysis of the secondary endpoints will be done one year after the last patient is registered in the selinexor arm
    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
    addition of selinexor
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Netherlands
    Norway
    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
    see protocol
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months2
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 230
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 185
    F.4.2.2In the whole clinical trial 230
    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)
    see protocol
    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 Decision2016-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-29
    P. End of Trial
    P.End of Trial StatusOngoing
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