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    Summary
    EudraCT Number:2019-004536-37
    Sponsor's Protocol Code Number:SHAPE
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-06-16
    Trial results View 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 number2019-004536-37
    A.3Full title of the trial
    Treatment of MDS/AML patients with an impending hematological relapse with azacitidine alone or in combination with pevonedistat - a randomized phase 2 trial
    Behandlung von MDS und AML Patienten mit drohendem hämatologischem Rezidiv mit Azacitidin alleine oder Azacitidin in Kombination mit Pevonedistat – eine randomisierte Phase 2 Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of MDS/AML patients with an impending hematological relapse with azacitidine alone or in combination with pevonedistat
    Behandlung von MDS/AML Patienten mit drohendem hämatologischem Rezidiv mit Azacytidin alleine oder Azacytidin in Kombination mit Pevonedistat
    A.3.2Name or abbreviated title of the trial where available
    SHAPE
    SHAPE
    A.4.1Sponsor's protocol code numberSHAPE
    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 SponsorLeipzig University
    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 supportMillennium Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZentrum für Klinische Studien Leipzig
    B.5.2Functional name of contact pointSusanne Melzer
    B.5.3 Address:
    B.5.3.1Street AddressHaertelstr.16-18
    B.5.3.2Town/ cityLeipzig
    B.5.3.3Post code04107
    B.5.3.4CountryGermany
    B.5.6E-mailsusanne.melzer@zks.uni-leipzig.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePevonedistat
    D.3.2Product code MLN4929
    D.3.4Pharmaceutical form Concentrate and solvent 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 INNPEVONEDISTAT
    D.3.9.1CAS number 905579-51-3
    D.3.9.2Current sponsor codeTAK-924/MLN4924
    D.3.9.3Other descriptive namePevonedistat hydrochloride
    D.3.9.4EV Substance CodeSUB179279
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 myeloid leukemia (AML) and Myelodysplastic syndromes (MDS) with impending hematological relapse
    Akute myeloische Leukämie (AML) und myelodysplastische Syndrome (MDS) mit drohendem hämatologischem Rezidiv
    E.1.1.1Medical condition in easily understood language
    Acute myeloid leukemia or Myelodysplastic syndromes
    Akute myeloische Leukämie und myelodysplastische Syndrome
    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 10000880
    E.1.2Term Acute myeloid leukaemia
    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 21.1
    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 show that pevonedistat and azacitidine are more effective compared to azacitidine alone with regard to achievement of MRD negativity after 3 months of treatment
    E.2.2Secondary objectives of the trial
    To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option:
    Time to event endpoints:
    - Overall Survival (OS): Time from randomization until death from any cause
    - Relapse Free Survival (RFS): Time from randomization until hematological relapse or death from any cause (whichever comes first)

    Time to event endpoints with competing risks:
    - Cumulative incidence of documented MRD negativity with death, hematological relapse and transplant as competing events
    - Cumulative incidence of hematological relapse with death and transplant as competing events
    - Quality of life
    - Rate and severity of adverse events for patients treated with pevonedistat and azacitidine
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - AML or MDS
    - continuing first CR after conventional intensive chemotherapy OR continuing CR after alloSCT
    - MRD positivity (assessed by local lab) as defined by:
    o NPM1mut status >1% in peripheral blood or bone marrow in NPM1 mutated patients at diagnosis or
    o Patients after allogeneic transplantation, who were NPM1 unmutated at diagnosis and have a blood or marrow CD34/CD117 chimerism <80%
    E.4Principal exclusion criteria
    Compliance with major study procedures
    - Patient does not accept bone marrow sampling during screening, primary end point visit and after the treatment.
    - Patient does not accept several blood sampling during screening, treatment (up to bi-daily) and after the treatment.

    Safety
    - Inadequate organ function as defined in the list below:
    o Absolute neutrophil count (ANC) < 1.5 Gpt/L
    o Platelets < 100 Gpt/L
    o Albumin < 2.7 g/dL
    o Creatinine clearance < 30 mL/min (Cockcroft und Gault formula)
    o Total bilirubin > 1.5xupper limit of normal (ULN)19 except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may be enrolled if direct bilirubin > 1.5x ULN of the direct bilirubin.
    o Both Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3.0 ULN
    - ECOG performance status of ≥2

    Concomitant Diseases
    - Liver cirrhosis or severe pre-existing hepatic impairment
    - Known severe cardiopulmonary disease (e.g. unstable angina, congestive heart failure NYHA III or IV, myocardial infarction within 6 months prior to screening, symptomatic cardiomyopathy, clinically significant arrhythmia20, clinically significant pulmonary hypertension requiring pharmacologic therapy)
    - Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)
    - Known prolonged rate corrected QT interval ≥ 500 msec, calculated according to institutional guidelines
    - Known left ventricular ejection fraction < 50% as assessed by echocardiogram or radionuclide angiography
    - Known moderate to severe symptomatic chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis
    - Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia
    - Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    - Known Human Immunodeficiency Virus (HIV 1/2 antibodies)
    - Known active Hepatitis B (i.e. HBsAg reactive) or Hepatitis C (i.e., HCV RNA [qualitative] is detected). NOTE: Patients who have isolated positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
    - Major surgery within 14 days of randomization or a scheduled surgery during study period
    - Known central nervous system (CNS) involvement
    - Diagnosis or treatment for another malignancy within 2 years before randomization. (NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. Prior diagnosis of myelodysplasia, myeloproliferative neoplasm, or aplastic anemia and treatment for that diagnosis does not lead to exclusion)
    - Any evidence of residual disease of another malignancy
    - Patients with uncontrolled coagulopathy or bleeding disorder
    - History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the in the best interest of the subject to participate, in the opinion of the treating investigator

    Prior unfavourable effect of HMA monotherapy
    - Prior HMA failure
    - Prior HMA treatment without subsequent allogeneic transplantation

    Interfering Treatments
    - Any ongoing therapy active against MDS or AML
    - BCRP inhibitors (for exceptions, see section 5.7.5) are not permitted during the study and should be stopped 14 days before first dose of the study drug

    Exclusion criteria regarding special restrictions for females of childbearing potential (see Protocol)

    Exclusion criteria regarding special restrictions for males, even if surgically sterilized (i.e. status post vasectomy), see Protocol

    Regulatory requirements
    - Age under 18 years at registration
    - Inability to provide written informed consent
    - Subject is unable to understand the nature, scope, significance and consequences of this clinical trial or has no legal capacity.
    - Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to SHAPE trial beginning
    E.5 End points
    E.5.1Primary end point(s)
    - Rate of documented MRD negativity after three cycles of treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients who do not receive three cycles for any reason (e.g. hematological relapse, toxicity), patients without valid MRD assessment after three cycles, as well as patients in whom the
    E.5.2Secondary end point(s)
    - Overall Survival (OS)
    - Relapse Free Survival (RFS)
    - Cumulative incidence of documented MRD negativity with death, hematological relapse and transplant as competing events
    - Cumulative incidence of hematological relapse with death and transplant as competing events
    - Rate of conversion to MRD negativity among patients crossing over from the control to the experimental arm after three crossed-over cycles
    - Rate and CTC graded severity of adverse events for patients treated with PEV and AZA combination therapy and with AZA alone
    - Impact on quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS = Time from randomization until death from any cause.
    RFS = Time from randomization until hematological relapse or death from any cause (whichever comes first).
    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 Yes
    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
    Azacitidine
    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 concerned17
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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 No
    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 years
    E.8.9.1In the Member State concerned months70
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months70
    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: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    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 state96
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 102
    F.4.2.2In the whole clinical trial 102
    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)
    Patients will be treated as usual after the individual’s trial completion
    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 Decision2020-09-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-19
    P. End of Trial
    P.End of Trial StatusCompleted
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