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    Summary
    EudraCT Number:2018-001693-25
    Sponsor's Protocol Code Number:AG221-CL-MDS-GFM-13217(IDEAL)
    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:2019-09-03
    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 number2018-001693-25
    A.3Full title of the trial
    A single-arm phase II multicenter study of IDH2 (AG 221) inhibitor in patients with IDH2 mutated myelodysplastic syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    study of the efficacy of treatment with AG-221 in patients with myelodysplastic syndrome and mutation IDH2
    A.4.1Sponsor's protocol code numberAG221-CL-MDS-GFM-13217(IDEAL)
    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 SponsorGroupe Francophone des Myelodysplasies
    B.1.3.4CountryFrance
    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
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGroupe Francophone des Myelodysplasies
    B.5.2Functional name of contact pointHabiba ATTALAH
    B.5.3 Address:
    B.5.3.1Street AddressHôpital Saint Louis Service Hématologie Séniors 1 Avenue Claude Vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75475
    B.5.3.4CountryFrance
    B.5.4Telephone number+33171 20 70 55
    B.5.5Fax number+33171 20 70 38
    B.5.6E-mailhabiba.attalah@aphp.fr
    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 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.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 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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myelodysplastic syndromes, mutation IDH-2, inhibitor IDH-2
    E.1.1.1Medical condition in easily understood language
    Myelodysplastic syndromes
    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 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10025309
    E.1.2Term Haematological and lymphoid tissue therapeutic procedures
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Cohorts A and B : To determine the response rate (CR+PR + stable disease with HI according to IWG 2006 criteria) of the administration of AG221 in each group (A and B) of patients.
    Cohort C : To determine the safety and tolerability of AG-221. We will use CTCAE Version 4.03
    E.2.2Secondary objectives of the trial
    •To determine the response rate (CR+PR+ stable disease with HI according to IWG 2006 criteria) of the administration of AG221 in each group of patients with IDH2 mutation (Cohort C).
    •To determine the response duration, time to IPSS progression, and loss of RBC transfusion independence in responders
    •To determine the rate and interval to AML evolution
    •T o determine overall survival
    •To identify prognostic and predictive factors of response, including IPSS-R, IPSS-karyotype and somatic mutations
    •To assess the evolution of IDH2 VAF on therapy
    •Safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Myelodysplastic syndrome according to WHO classification including non-proliferative AML up to 29% of BM blast
    • Age ≥ 18 years
    • Belonging to one of the following categories
    1. Higher risk MDS (IPSS int-2, high) without response to azacitidine (CR,PR, stable disease with HI) after at least 6 cycles , or relapsing after a response but without overt progression (defined by at least doubling of marrow blasts, compared to pre azacitidine bone marrow, or AML progression beyond 30% blasts)
    2. Untreated higher risk MDS (IPSS int-2, high) without life threatening cytopenia including ANC <500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom
    3. Lower risk MDS with resistance or loss of response to a previous treatment with epoetin alpha/ beta (>=60000 U/w) or Darbopoetin (>=250 ug/w) given for at least 12 weeks and RBC transfusion requirement at least 2 U/8 weeks in the previous 16 weeks.
    • Presence of IDH2 mutation in either blood or marrow prior to start of therapy
    • Normal renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance (Modification of diet in renal disease) (MDRD) ≥ 50 mL/min.
    • Normal liver function, defined by total bilirubin < 2.0 mg/dl (exception permitted in patients with Gilbert’s Syndrome) and transaminases less than 1.5 times the upper limit of normal.
    • Adequate cardiac ejection fraction (>40%)
    • Patient is not known to be refractory to platelet transfusions.
    • Written informed consent.
    • Patient must understand and voluntarily sign consent form.
    • Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements.
    • ECOG performance status 0-2 at the time of screening.
    • Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
    • Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
    Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 120 365 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as: hormonal oral contraceptives, injectables, patches, intrauterine devices. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal)
    - progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable)
    - intrauterine device (IUD)
    - intrauterine hormone-releasing system ( IUS)
    - bilateral tubal occlusion
    - vasectomised partner
    • -sexual abstinence

    •Male patients must :
    -Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment.
    -Agree to learn about the procedures for preservation of sperm before starting treatment
    E.4Principal exclusion criteria
    • Severe infection or any other uncontrolled severe condition.
    • Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months.
    • Less than 14 days since prior treatment with growth factors (EPO, G-CSF).
    • Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before the study entry with the exception of hydroxyurea.
    •The patient must have recovered from all acute toxicity from any previous therapy.
    • Subject has a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study.
    • Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast.
    • Patient already enrolled in another therapeutic trial of an investigational drug.
    • Known HIV infection or active hepatitis B or C (test prior to inclusion required).
    • Women who are or could become pregnant or who are currently breastfeeding.
    • Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form.
    • Patient eligible for allogeneic stem cell transplantation.
    • Known allergies to AG-221 or any of its excipients.
    • No affiliation to a health insurance system.
    E.5 End points
    E.5.1Primary end point(s)
    Overall hematological response at 3 and 6 months ( Including CR, PR, Stable disease with HI according to IWG 2006 ) for cohort A, B and safety for cohort C of treatment with Enasidenib
    All patients with one of the following responses after 3 and 6 cycles are defined as responder:
    • CR, PR, SD as defined in chapter 20.1.1 of the trial protocol
    • Hematologic improvement as defined in chapter 20.1.1 of the trial protocol
    E.5.2Secondary end point(s)
    - Duration of response
    - Progression-free survival
    - overal survival
    - Time to treatment failure
    - Toxicity as measured by NCI CTCAE 5.0
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 68
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 68
    F.4.2.2In the whole clinical trial 68
    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)
    patient responders to the treatment beyond 24 months, an extension could be proposed to evaluate the long term effectiveness of Enasidenib (AG-221).
    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 Decision2020-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-14
    P. End of Trial
    P.End of Trial StatusOngoing
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