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    Summary
    EudraCT Number:2019-001416-30
    Sponsor's Protocol Code Number:IDH2-Post-Allo-Trial
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-03-23
    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 ConcernedGermany - BfArM
    A.2EudraCT number2019-001416-30
    A.3Full title of the trial
    IDH2-Post-Allo-Trial: Enasidenib as consolidation or salvage therapy for patients with IDH2 mutated AML or MDS following allogeneic blood stem cell transplantation
    IDH2-Post-Allo-Trial: Enasidenib als Konsolidierungs- oder Salvage-Therapie für Patienten mit IDH2-mutierter AML oder MDS nach allogener Blutstammzelltransplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial evaluating the safety and efficacy of Enasidenib for the treatment of recurrence or prophylactic treatment of certain forms of leukemia following blood stem cell transplantation.
    Studie zur Bewertung der Sicherheit und Wirksamkeit von Enasidenib zur Behandlung von Rückfällen oder zur vorbeugenden Behandlung bestimmter Formen von Leukämie nach einer Blutstammzelltransplantation.
    A.4.1Sponsor's protocol code numberIDH2-Post-Allo-Trial
    A.5.4Other Identifiers
    Name:Celgene Protocol CodeNumber:AG221-CL-AML-PI-13299
    Name:HHU Sponsor NumberNumber:SP-2019-32
    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 SponsorHeinrich-Heine-University Düsseldorf represented by the Coordinating Investigator
    B.1.3.4CountryGermany
    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 supportCelgene International II Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Düsseldorf, Dept. of Hematology, Oncology and Clinical Immunology
    B.5.2Functional name of contact pointCoordinating Investigator
    B.5.3 Address:
    B.5.3.1Street AddressMoorenstraße 5
    B.5.3.2Town/ cityDüsseldorf
    B.5.3.3Post code40225
    B.5.3.4CountryGermany
    B.5.4Telephone number+492118118524
    B.5.5Fax number+492118118522
    B.5.6E-mailthomas.schroeder@med.uni-duesseldorf.de
    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 numberAML: EU/3/316/1640
    D.3 Description of the IMP
    D.3.1Product nameEnasidenib
    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 INNENASIDENIB
    D.3.9.1CAS number 1650550-25-6
    D.3.9.4EV Substance CodeSUB189438
    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
    Patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or acute myelogenous leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) and with an IDH2 mutation (IDH2 R172 or R140 mutation)
    Patienten mit myelodysplastischem Syndrom (MDS), chronischer myelomonozytärer Leukämie (CMML) oder akuter myeloischer Leukämie (AML) nach allogener Stammzelltransplantation (allo-SCT) und einer IDH2-Mutation (IDH2 R172 oder R140-Mutation)
    E.1.1.1Medical condition in easily understood language
    Patients with certain forms of leukemia after stem cell transplantation
    Patienten mit bestimmten Formen von Leukämie nach Stammzelltransplantation
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10024329
    E.1.2Term Leukemia
    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
    Consolidation arm:
    • To evaluate the safety and feasibility of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation

    Salvage arm:
    • To evaluate the safety and feasibility of Enasidenib (investigational drug) – optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT
    E.2.2Secondary objectives of the trial
    Consolidation arm:
    • To descriptively assess the efficacy of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation

    Salvage arm:
    • To descriptively assess the efficacy of Enasidenib (investigational drug) - optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Consolidation arm:
    • Patients with myeloid malignancy (AML, MDS and CMML) and known IDH2 mutation (IDH2 R172 or R140 mutation) at diagnosis prior to first allo-SCT
    • molecular CR after allo-SCT determined during screening period between day+25 and day +35 (detected by the local laboratory of the respective center; the report has to be sent to the principle investigator for review at screening to include the patient; a sample will be stored for central retesting, which will be performed in batch during the course of the study)
    • Hematopoietic recovery after transplantation indicated by an absolute neutrophil count of at least 1.000/microliter and platelet count of at least 50.000/microliter

    Salvage arm:
    • First hematological or molecular relapse (reoccurrence or persistence of IDH2 mutation) of de novo or therapy related AML, MDS or CMML according to WHO 2016 classification after first allo-SCT (HLA-identical related or matched unrelated donor [≥9/10], haploidentical donor)
    • IDH2 R172 or R140 mutation at the time of relapse after allo-SCT (detected by the local laboratory of the respective center, the report has to be sent to the principle investigator for review at screening to include the patient; a sample will be stored for central retesting, which will be performed in batch during the course of the study)
    • Possibility of DLI (no cord blood)
    • no previous therapy for relapse after allo-SCT except for hydroxyurea for a maximum of 14 days during screening phase prior start of study medication

    Both arms:
    • no previous therapy with Enasidenib or any other IDH2 inhibitor
    • ECOG performance status ≤ 2 at study entry (s. Appendix)
    • no active, steroid refractory GvHD treated with additional systemic immunosuppression within 4 weeks before inclusion
    • no uncontrolled infection at inclusion
    • Understand and voluntarily sign an informed consent form.
    • Age ≥18 years at the time of signing the informed consent form.
    • Able to adhere to the study visit schedule and other protocol requirements.
    • Female of childbearing potential (FCBP) must:
    • Understand that Enasidenib can cause embryo-fetal harm when administered to a pregnant woman
    • Agree to have a medically supervised pregnancy test prior to starting of Enasidenib
    • Use effective contraception during treatment with Enasidenib and for at least 2 months after the last dose
    • Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives
    • Avoid becoming pregnant while receiving Enasidenib
    • Notify her study doctor immediately if there is a risk of pregnancy
    • Agree to abstain from breastfeeding during study participation and for at least 30 days after study drug discontinuation
    • Understand that Enasidenib may impair fertility in females of reproductive potential and this effect may be not reversible

    •Males must:
    • Understand that Enasidenib can cause embryo-fetal harm
    • Use effective contraception during treatment with Enasidenib and for at least 2 months after the last dose of Enasidenib if engaged in sexual activity with a pregnant female or a female with childbearing potential
    • Agree to notify the investigator immediately, if pregnancy or a positive pregnancy test occurs in his partner during study participation
    E.4Principal exclusion criteria
    Consolidation arm:
    • Any evidence of activity of the underlying IDH2-mutated myeloid malignancy (AML, MDS and CMML) determined during screening period until start of treatment
    • Any previous prophylactic therapy given within the interval between allo-SCT and screening period
    • Patients with myeloid malignancy (AML, MDS and CMML) and known IDH2 mutation (IDH2 R172 or R140 mutation) after second allo-SCT

    Salvage arm:
    • No IDH2 R172 or R140 mutation at the time of relapse
    • Relapse after second allogeneic transplantation
    • Any previous therapy (chemotherapy, radiation or investigational drugs) administered as therapy for relapse after allo-SCT except for hydroxyurea for a maximum of 14 days during screening phase prior start of study medication
    • Non-infectious leukocytosis (WBC > 30x10^9/L)

    Both arms:
    • previous transplantation with cord blood
    • Active, steroid refractory GvHD treated with additional requiring systemic immunosuppression within the last 4 weeks
    • Uncontrolled infection
    • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
    • Pregnant or lactating females
    • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
    • Impaired renal function (GFR < 30 ml/min)
    • Impaired hepatic function, as follows:primar
    Aspartate aminotransferase ≥3 x ULN or Alanine aminotransferase (ALT) ≥3 x ULN or
    Total bilirubin ≥3 x ULN
    Alkaline Phosphatase ≥3 x ULN
    • Known hypersensitivity to Enasidenib or any other component of the treatment
    • Prior history of malignancy other than AML, MDS or CMML (except basal and squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3 years
    • Concurrent use of other anti-cancer agents or treatments
    • Known positive for HIV or infectious hepatitis, type A, B or C
    • Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study (in cases where the investigational product has an unusually long half-life (e.g. antibodies), the interval until study enrollment must be at least five times the plasma half-life of the investigational product)
    E.5 End points
    E.5.1Primary end point(s)
    Consolidation arm:
    • To evaluate the safety and feasibility of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation

    Salvage arm:
    • To evaluate the safety and feasibility of Enasidenib (investigational drug) – optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Annual Review of Safety Data by DMC, based on DSUR data
    2. Interim Analysis (as 10 patients will have been treated within each arm and the 10th patient in each arm has either completed 4 cycles or has discontinued treatment whichever occurs first. In case one of the two arms is recruiting significantly slower than the other arm, an independent interim analysis of the individual arms may be performed optionally.)
    3. End of Study
    E.5.2Secondary end point(s)
    Efficacy variables:

    Consolidation arm:
    • Number of patients who maintain remission (molecular/hematological) after allo-SCT
    • Overall survival
    • Relapse-free survival
    • Number of patients who require any cellular or pharmacological intervention due to pending or frank relapse (defined as treatment-failure)
    • Correlation of relapse-free survival and cytogenetics/molecular alterations

    Salvage arm:
    • Best response within the first 12 months of treatment according to the International Working Group (IWG) and European Leukemia Net (ELN) criteria
    • Time to response
    • Rate of and time to complete donor chimerism
    • Molecular response measured by IDH2 mutation burden and other disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 or WT1 mRNA expression)
    • Duration of remission and incidence of relapse
    • Overall survival
    • Correlation of response and cytogenetics/molecular alterations

    Safety variables:

    Both arms (if not otherwise indicated):
    • Incidence, course and severity of aGvHD and cGvHD
    • Number of hospitalizations
    • Number of patients who require dose reductions due to toxicity reasons
    • Number of patients who have to stop consolidation therapy due to toxicity (only consolidation arm)
    • Number of patients who can receive all 12 cycles of consolidation therapy (only consolidation arm)
    • Number of screened patients that can start consolidation therapy within the envisaged time frame (only consolidation arm)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Annual Review of Safety Data by DMC, based on DSUR data
    2. Interim Analysis (as 10 patients will have been treated within each arm and the 10th patient in each arm has either completed 4 cycles or has discontinued treatment whichever occurs first. In case one of the two arms is recruiting significantly slower than the other arm, an independent interim analysis of the individual arms may be performed optionally.)
    3. End of 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 No
    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 No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned10
    E.8.5The trial involves multiple Member States No
    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 No
    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
    Last visit of the last subject (after end of treatment phase plus 1 year 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 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state60
    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: routine care based on individual investigators decision
    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 Decision2020-06-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-18
    P. End of Trial
    P.End of Trial StatusOngoing
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