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    Summary
    EudraCT Number:2017-000318-40
    Sponsor's Protocol Code Number:Pevonedistat-3001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-22
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-000318-40
    A.3Full title of the trial
    A Phase 3, Randomized, Controlled, Open-Label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line
    Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
    Studio clinico di fase III, randomizzato, controllato, in aperto su pevonedistat più azacitidina rispetto ad azacitidina in monoterapia come trattamento di prima linea in pazienti affetti da sindromi mielodisplastiche ad alto rischio, leucemia mielomonocitica cronica o leucemia
    mieloide acuta oligoblastica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes,
    Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
    Pevonedistat più azacitidina rispetto ad azacitidina in monoterapia come trattamento di prima linea in pazienti affetti da sindromi mielodisplastiche ad alto rischio, leucemia mielomonocitica cronica o leucemia mieloide acuta oligoblastica
    A.3.2Name or abbreviated title of the trial where available
    PANTHER
    PANTHER
    A.4.1Sponsor's protocol code numberPevonedistat-3001
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03268954
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:P-3001Number:P-3001 (Norme informale abbreviato del codice prot
    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 SponsorMILLENNIUM PHARMACEUTICALS, INC.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMillennium Pharmaceuticals, Inc. (Takeda)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number0015107402412
    B.5.5Fax number0018008816092
    B.5.6E-mailmedical@mlnm.com
    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 [MLN4924 (TAK-924)]
    D.3.4Pharmaceutical form 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 INNPevonedistat Hydrochloride
    D.3.9.1CAS number 1160295-21-5
    D.3.9.2Current sponsor codeMLN4924-003
    D.3.9.3Other descriptive namePEVONEDISTAT
    D.3.9.4EV Substance CodeSUB179279
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 RoleComparator
    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 Vidaza
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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/3/07/509, EU/3/01/084
    D.3 Description of the IMP
    D.3.1Product nameAZACITIDINA
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINA
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameAZACITIDINE
    D.3.9.4EV Substance CodeSUB05624MIG
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Higher-Risk Myelodysplastic Syndromes (MDS)
    Chronic Myelomonocytic Leukemia (CMML)
    Low-Blast Acute Myelogenous Leukemia (AML)
    Sindromi mielodisplastiche ad alto rischio (SMD):
    Leucemia mielomonocitica cronica (CMML)
    Leucemia mieloide acuta (AML) oligoblastica
    E.1.1.1Medical condition in easily understood language
    Myelodysplastic syndromes (MDS) are characteristed by changes to blood composition including reductions in red and white blood cells and platelets. Leukaemia is cancer of the white blood cells.
    Le sindromi mielodisplastiche (MDS) sono caratterizzate da alterazioni nella composizione del sangue, incluse diminuzioni di globuli rossi e bianchi e piastrine.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10009018
    E.1.2Term Chronic myelomonocytic 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 LLT
    E.1.2Classification code 10024348
    E.1.2Term Leukemia myelogenous
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10024330
    E.1.2Term Leukemia acute
    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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10054350
    E.1.2Term Chronic myelomonocytic 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 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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10028536
    E.1.2Term Myelodysplastic syndromes
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067387
    E.1.2Term Myelodysplastic syndrome transformation
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether the combination of pevonedistat and azacitidine improves overall response rate (ORR) by Cycle 6, when compared to
    single-agent azacitidine. (Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast
    AML is defined as CR+CRi+PR).
    To determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared to single-agent
    azacitidine. (An event is defined as death or transformation to acute myeloid leukemia (AML) in patients with MDS or CMML, whichever occurs first, and is defined as death in patients with low-blast AML).
    • Determinare se la combinazione di pevonedistat e azacitidina migliori il tasso di risposta globale (ORR) entro il Ciclo 6 rispetto ad azacitidina in monoterapia. (Il tasso di risposta globale nei pazienti affetti da HR MDS o CMML è definito da CR+PR; la risposta globale nei pazienti affetti da AML oligoblastica è definita da CR+remissione completa con recupero incompleto della conta ematica [CRi]+PR.
    • Determinare se la combinazione di pevonedistat e azacitidina migliori l’EFS rispetto ad azacitidina in monoterapia. (Un evento è definito come decesso o trasformazione in AML nei pazienti affetti da MDS o CMML, a seconda dell’evento che si verifica prima, ed è definito come decesso nei pazienti affetti da AML oligoblastica.)
    E.2.2Secondary objectives of the trial
    To determine whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent
    azacitidine.
    To determine whether the combination of pevonedistat and azacitidine improves 6-month and 1-year survival rates when compared to single-agent azacitidine.
    To determine in patients with HR MDS or CMML whether the combination of pevonedistat and azacitidine delays time to AML transformation when
    compared to single-agent azacitidine.
    (Please refer to protocol for detailed list).
    Determinare se la combinazione di pevonedistat e azacitidina migliori l’OS rispetto ad azacitidina in monoterapia.
    Determinare se la combinazione di pevonedistat e azacitidina migliori il tasso di sopravvivenza a 6 mesi e a 1 anno rispetto ad azacitidina in monoterapia.
    Determinare se, nei pazienti affetti da HR MDS o CMML, la combinazione di pevonedistat e azacitidina ritardi la trasformazione in AML rispetto ad azacitidina in monoterapia.
    (Si prega di fare riferimento al protocollo per un elenco dettagliato).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female patients 18 years or older.
    2.Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with WBC <13,000/µL) or low-blast AML based on 1 of the following:
    French-American-British (FAB) Classifications:
    - RAEB, defined as having 5% to 20% myeloblasts in the bone marrow.
    - CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
    OR
    World Health Organization (WHO) Classifications.
    3. All patients with MDS or CMML must also have one of the following Prognostic Risk Category, based on the Revised International Prognostic
    Scoring System (IPSS-R):
    - Very high (>6 points),
    - High (>4.5 – 6 points), or
    - Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of
    =5% bone marrow myeloblasts.
    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
    5. Patients with AML (20%-30% blasts) must have a TRM score =4 for intensive, induction chemotherapy as calculated using the simplified
    model described by Walter and coworkers
    6. Female patients who:
    - Are postmenopausal for at least 1 year before the Screening visit, OR
    - Are surgically sterile, OR
    - If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier)
    method, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
    - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods],
    withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should
    not be used together.)
    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    - Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long
    half-life, for 90 days plus five half-lives) after the last dose of study drug, or
    - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods],
    withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should
    not be used together.)
    7. Ability to undergo the study-required bone marrow sample collection procedures.
    8. Suitable venous access for the study-required blood sampling (ie, including PK and pharmacodynamic sampling).
    9. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):
    - Albumin >2.7 g/dL.
    - Total bilirubin less than the upper limit of the normal range (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's
    syndrome may enroll if direct bilirubin =1.5×ULN of the direct bilirubin.
    - ALT and AST =2.5×ULN.
    - Creatinine clearance =50 mL/min.
    - Hemoglobin >8 g/dL. Patients may be transfused to achieve this value.
    Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
    10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the
    understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    1. Pazienti di sesso maschile o femminile di età pari o superiore a 18 anni.
    2. Una diagnosi morfologicamente confermata di MDS o CMML non proliferativa (ossia una conta dei globuli bianchi <13.000/µl) o AML oligoblastica basata su 1 dei seguenti criteri:
    Classificazione francese-americana-britannica.
    3.Tutti i pazienti affetti da MDS o CMML devono presentare inoltre le seguenti Categorie prognostiche di rischio, sulla base dell'IPSS-R [1]:
    -Molto alto (>6 punti).
    -Alto (>4,5-6 punti).
    -Intermedio (>3–4,5 punti): un paziente classificato nella categoria prognostica di rischio Intermedio è ammissibile solo in uno scenario con presenza =5% di mieloblasti midollari.
    4. Stato di performance ECOG pari a 0, 1 o 2.
    5. I pazienti con AML (20%-30% di blasti) devono presentare un punteggio di mortalità correlata al trattamento (TRM) =4 per chemioterapia intensiva di induzione calcolato utilizzando il modello semplificato descritto da Walter e collaboratori; consultare l’Appendice A.
    6. Pazienti di sesso femminile che:
    - Sono in post-menopausa da almeno 1 anno prima della visita di screening, OPPURE - Sono chirurgicamente sterili, OPPURE
    - Se sono in età fertile, accettano di utilizzare contemporaneamente un metodo contraccettivo altamente efficace e un ulteriore metodo (a barriera) efficace, dal momento della firma del consenso informato fino a 4 mesi dopo l’ultima dose di farmaco in studio, OPPURE
    - Accettano di praticare l'astinenza totale, se questo è in linea con lo stile di vita consueto e preferibile del soggetto. (L’astinenza periodica [per esempio metodi basati su calendario, ovulazione, sintotermici, postovulazione], il coito interrotto, l'uso di soli spermicidi e il metodo dell'amenorrea da lattazione (LAM) non sono metodi di contraccezione accettabili. I preservativi maschile e femminile non devono essere utilizzati insieme.)
    Pazienti di sesso maschile, anche se sterilizzati chirurgicamente (ossia in condizione di post-vasectomia), che:
    - Accettano di utilizzare contraccettivi efficaci a barriera durante l’intero periodo di assunzione del trattamento in studio e per 120 giorni (o se il farmaco ha un’emivita molto lunga, per 90 giorni più cinque emivite) dopo l’ultima dose dl farmaco in studio, oppure
    - Accettano di praticare l'astinenza totale, se questo è in linea con lo stile di vita consueto e preferibile del soggetto. (L’astinenza periodica [per esempio metodi basati su calendario, ovulazione, sintotermici, postovulazione], il coito interrotto, l'uso di soli spermicidi e il metodo dell'amenorrea da lattazione (LAM) non sono metodi di contraccezione accettabili. I preservativi maschile e femminile non devono essere utilizzati insieme.)
    7. Capacità di sottoporsi alle procedure di prelievo dei campioni di midollo osseo previste dallo studio.
    8. Accesso venoso idoneo per i prelievi di sangue previsti dallo studio (ovvero, incluso il prelievo di campioni per le analisi di farmacocinetica e farmacodinamica).
    9 e 10. Per questioni di spazio non è possibile inserire questi criteri, fare riferimento al testo EN del protocollo e alla sinossi.
    E.4Principal exclusion criteria
    1. Previous treatment for HR MDS or low-blast AML with chemotherapy or other antineoplastic agents including HMAs such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
    2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
    3. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
    - Age >75.
    - Comorbidities.
    - Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% blasts and TRM =4).
    - Physician decision (eg, lack of available stem cell donor).
    The reason a patient is not eligible should be documented in the electronic case report form (eCRF).
    4. Patients with either clinical evidence of or history of central nervous system involvement by AML.
    5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit expected patient survival to less than 6
    months.
    6. Treatment with any antileukemic/anti-MDS therapies (eg, cytarabine, anthracyclines, purine analogs) or with any investigational products
    within 14 days before the first dose of any study drug.
    7. Known hypersensitivity to mannitol.
    8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
    9. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery.
    10. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
    11. Life-threatening illness unrelated to cancer.
    12. Prothrombin time (PT) or aPTT >1.5×ULN or active uncontrolled coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
    13. Known human immunodeficiency virus (HIV) seropositive.
    14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
    15. Known hepatic cirrhosis or severe preexisting hepatic impairment.
    16. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
    17. Treatment with strong CYP3A inducers within 14 days before the first dose of pevonedistat.
    18. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive
    urine pregnancy test on Day 1 before first dose of study drug.
    19. Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
    20. Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
    1. Precedente trattamento per HR MDS o AML ologoblastica con chemioterapia o altri agenti anti-neoplastici, inclusi agenti ipometilanti quali decitabina o azacitidina. È ammesso il trattamento precedente con idrossiurea e con lenalidomide, ad esclusione della somministrazione di lenalidomide nelle 8 settimane precedenti la somministrazione della prima dose di farmaco in studio.
    2. Leucemia promielocitica acuta come diagnosticata dall'esame morfologico del midollo osseo mediante ibridazione in situ fluorescente o citogenetica del sangue periferico o del midollo osseo, o mediante altre analisi accettate.
    3. Eleggibilità per chemioterapia intensiva e/o trapianto allogenico di cellule staminali.
    4. Pazienti che presentano evidenza clinica di o anamnesi di coinvolgimento del sistema nervoso centrale da parte dell’AML.
    5. Ogni malattia medica o psichiatrica seria che potrebbe, secondo l'opinione dello Sperimentatore, interferire potenzialmente con il completamento delle procedure dello studio o potrebbe limitare la sopravvivenza prevista dei pazienti a meno di 6 mesi.
    6. Trattamento con terapie anti-leucemiche /anti-MDS o con qualsiasi prodotto sperimentale entro 14 giorni prima della somministrazione della prima dose di qualsiasi farmaco in studio.
    7. Nota ipersensibilità al mannitolo.
    8. Infezione incontrollata attiva o grave malattia infettiva.
    9. Intervento chirurgico significativo nei 14 giorni precedenti la prima dose o intervento chirurgico pianificato durante il periodo dello studio.
    10.Diagnosi di o trattamento per un altro tumore maligno nei 2 anni precedenti la randomizzazione o precedente diagnosi di un altro tumore maligno ed evidenza di malattia residua. I pazienti con carcinoma cutaneo non melanomatoso o carcinoma in situ di qualsiasi tipo non sono esclusi qualora siano stati sottoposti a resezione.
    11. Malattia potenzialmente fatale non correlata al tumore.
    12. Tempo di protrombina (PT) o tempo di tromboplastina parziale attivata >1,5xULN o coagulopatia incontrollata attiva o disturbo emorragico. I pazienti che assumono anticoagulanti a scopo terapeutico come warfarina, inibitori diretti della trombina, inibitori diretti del fattore Xa o eparina sono esclusi dall’arruolamento
    13. Nota sieropositività al virus dell'immunodeficienza umana (HIV).
    14. Nota sieropositività all'antigene di superficie dell'epatite B oppure nota o sospetta infezione da epatite C attiva. Nota: i pazienti che hanno isolato l'anticorpo anti-core dell'epatite B positivo (ovvero in caso di antigene di superficie dell'epatite B negativo e anticorpo di superficie dell'epatite B negativo) devono avere un carico virale di epatite B non rilevabile.
    15. Nota cirrosi epatica o grave compromissione epatica pre-esistente.
    16. Nota patologia cardiopolmonare definita come angina instabile, aritmia clinicamente significativa, insufficienza cardiaca congestizia (New York Heart Association di Classe III o IV), e/o infarto miocardico negli ultimi 6 mesi prima della prima dose, o grave ipertensione polmonare. Ad esempio, una fibrillazione atriale ben controllata non comporterebbe un'esclusione mentre la fibrillazione atriale non controllata la comporterebbe.
    17. Trattamento con forti induttori del citocromo P-450 3A nei 14 giorni precedenti la somministrazione della prima dose di pevonedistat
    18. Pazienti di sesso femminile che allattano o hanno un test di gravidanza su siero positivo nel periodo dello screening o un test di gravidanza sulle urine positivo il Giorno 1 prima della prima dose del farmaco in studio.
    19. Pazienti di sesso femminile che intendano donare i loro ovuli (cellule uovo) nel corso di questo studio o 4 mesi dopo aver ricevuto l'ultima dose di farmaco/i in studio.
    20. Pazienti di sesso maschile che intendano donare il loro sperma nel corso di questo studio o 4 mesi dopo aver ricevuto l'ultima dose di farmaco/i in studio.
    E.5 End points
    E.5.1Primary end point(s)
    - ORR by Cycle 6 (Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is
    defined as CR+CRi+PR.)
    - EFS: time from randomization to the date of an EFS event (defined as death or transformation to AML in patients with MDS or CMML, whichever occurs first, and defined as death in patients with low-blast AML).
    • ORR entro il Ciclo 6 (la risposta globale nei pazienti affetti da HR MDS o CMML è definita da CR+PR; la risposta globale nei pazienti affetti da AML oligoblastica è definita da CR+CRi+PR)
    • EFS: tempo dalla randomizzazione alla data di un evento di EFS (definito come decesso o trasformazione in AML nei pazienti affetti da MDS o CMML, a seconda dell’evento che si verifica prima, e definito come decesso nei pazienti affetti da AML oligoblastica).
    E.5.1.1Timepoint(s) of evaluation of this end point
    - EFS is defined as the time from randomization to the occurrence of an event.
    - ORR by cycle 6 (28 day cycles).
    - La EFS è definita come il tempo che intercorre tra la randomizzazione e la manifestazione di un evento.
    - ORR entro il ciclo 6 (cicli di 28 giorni).
    E.5.2Secondary end point(s)
    - OS.
    - 6-month and 1-year survival rates.
    - 30-day and 60-day survival rates.
    - Time to AML transformation in patients with HR MDS or CMML.
    - Rate of CR (CR in patients with HR MDS or CMML, CR+CRi in patients with low-blast AML), CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in patients with HR MDS or CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow CR+PR+HI (in patients
    with HR MDS or CMML), overall response, and overall response 2. Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as
    CR+PR+HI; overall response 2 in patients with low-blast AML is defined as CR+CRi+PR.
    - Duration of CR (CR for HR MDS or CMML, CR+CRi for low-blast AML), overall response (CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and overall response 2 (CR+PR+HI for HR MDS or CMML, CR+CRi+PR for low-blast AML).
    - Rates of RBC and platelet transfusion independence.
    - Duration of RBC transfusion independence, platelet transfusion independence, and platelet and RBC transfusion independence.
    - Time to first CR or PR.
    - Rates of HI in patients with HR MDS or CMML.
    - Patients who have inpatient hospital admission(s) related to HR MDS, CMML (collected through transformation to AML or until initiation of
    subsequent therapy, whichever occurs first) or low-blast AML (collected through initiation of subsequent therapy).
    - Time to PD, relapse after CR or PR, or death.
    - HRQOL assessed using the EORTC QLQ-C30.
    - Plasma concentration-time data for pevonedistat.
    - ORR, EFS and OS in patients that have TP53 mutations, 17p deletions and/or are determined to be in an adverse cytogenetic risk group in both
    treatment arms.
    • OS.
    • Tasso di sopravvivenza a sei mesi e 1 anno.
    • Tasso di sopravvivenza a trenta giorni e 60 giorni.
    • Tempo alla trasformazione in AML nei pazienti con HR MDS o CMML.
    • Tasso di CR (CR nei pazienti affetti da HR MDS o CMML, CR+CRi nei pazienti affetti da AML oligoblastica), CR+CR del midollo (nei pazienti affetti da HR MDS o CMML), CR+PR+HI (nei pazienti affetti da HR MDS o CMML), CR+CR del midollo+PR (nei pazienti affetti da HR MDS o CMML), CR+CR del midollo+PR+HI (nei pazienti affetti da HR MDS o CMML), risposta globale e risposta globale 2. La risposta globale nei pazienti affetti da HR MDS o CMML è definita da CR+PR; la risposta globale nei pazienti affetti da AML oligoblastica è definita da CR+CRi+PR. La risposta globale 2 nei pazienti affetti da HR MDS o CMML è definita da CR+PR+HI; la risposta globale 2 nei pazienti affetti da AML oligoblastica è definita da CR+CRi+PR.
    • Durata della CR (CR per HR MDS o CMML, CR+CRi per AML oligoblastica) risposta globale (CR+PR per HR MDS o CMML, CR+CRi+PR per AML oligoblastica) e risposta globale 2 (CR+PR+HI per MDS HR o CMML, CR+CRi+PR per AML oligoblastica).
    • Tasso di indipendenza da trasfusioni di piastrine e RCB.
    • Durata dell'indipendenza da trasfusioni di RBC, indipendenza da trasfusioni di piastrine e indipendenza da trasfusioni di piastrine e RCB.
    • Tempo alla prima CR o PR.
    • Tasso di HI nei pazienti con HR MDS o CMML.
    • Pazienti che presentano ricovero/i ospedaliero/i correlato/i a HR MDS o CMML (dati raccolti fino a trasformazione in AML o fino all'inizio della terapia successiva qualunque di questi eventi si verifichi per primo) o AML oligoblastica (dati raccolti fino all'inizio della terapia successiva).
    • Tempo all'insorgenza di PD, recidiva dopo CR o PR, o decesso.
    • HRQOL valutata utilizzando il EORTC QLQ-C30.
    • Dati relativi alla concentrazione plasmatica nel tempo per pevonedistat.
    • ORR, EFS e OS nei pazienti che presentano mutazioni TP53 e delezioni 17p e/o classificati nel gruppo a rischio citogenetico avverso in entrambi i bracci di trattamento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Primary:
    - ORR by Cycle 6: The number and percentage of patients who achieved an objective response (CR+PR for patients with HR MDS or CMML,
    CR+CRi+PR for patients with low-blast AML) by Cycle 6. Up to 6 years
    - EFS: The time from randomization to the occurrence of an event. For patients with HR MDS/CMML, an event is defined as death or
    transformation to AML; for patients with low-blast AML, an event is defined as death. Up to 6 years
    Secondary:
    - OS: The time from randomization to death from any cause. Up to 6 years
    (Please refer to protocol for complete list)
    Primario:
    - ORR entro il ciclo 6: Il numero e la percentuale di pazienti che hanno raggiunto una risposta obiettiva (CR+PR per pazienti affetti da HR MDS o CMML, CR+CRi+PR per pazienti affetti da AML oligoblastica) entro il ciclo 6. Fino a 6 anni
    - EFS: Il tempo che intercorre tra la randomizzazione e la manifestazione di un evento. Per i pazienti affetti da HR MDS/CMML, un evento viene definito come decesso o trasformazione in AML; per i pazienti affetti da AML oligoblastica, un evento viene definito come decesso. Fino a 6 anni
    Secondario:
    - OS: Il tempo intercorso tra la randomizzazione e il decesso per qualsiasi causa. Fino a 6 anni
    (Si prega di fare riferimento al protocollo per un elenco completo)
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    IMP1 + IMP2 vs. IMP2
    PR1 + PR2 vs. PR2
    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 EEA73
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Canada
    Israel
    Japan
    Korea, Republic of
    Mexico
    Russian Federation
    Turkey
    United States
    Belgium
    Czechia
    France
    Germany
    Greece
    Italy
    Poland
    Spain
    Sweden
    United Kingdom
    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
    The study will be considered complete after the final analysis for OS has been completed or the study has been terminated by the sponsor.
    Lo studio sarà considerato completo dopo il completamento dell’analisi per la sopravvivenza globale (OS) o l’interruzione dello studio da parte dello Sponsor
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    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) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 243
    F.4.2.2In the whole clinical trial 450
    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)
    Following the EFS and response follow-up visits, or the EOT visit (for patients with HR MDS or CMML who discontinue study treatment because of transformation to AML, or patients with low-blast AML who discontinue study treatment because of PD), patients will enter OS follow-up and will be contacted every 3 months until death to
    document subsequent therapies and survival status.
    A seguito delle visite di follow-up della risposta e della EFS, o della visita EOT (per i pazienti affetti da MDS HR o CMML che interrompono il trattamento in studio a causa di trasformazione in AML, o i pazienti affetti da AML oligoblastica che interrompono il trattamento in studio a causa di PD), i pazienti entreranno nel follow-up per la OS e saranno contattati ogni 3 mesi fino al decesso per documentare le terapie successive e lo stato di sopravvivenza.
    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 Decision2018-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-19
    P. End of Trial
    P.End of Trial StatusCompleted
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