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    Summary
    EudraCT Number:2017-000318-40
    Sponsor's Protocol Code Number:Pevonedistat-3001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-11-03
    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 ConcernedSpain - AEMPS
    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
    Estudio clínico de fase 3, abierto, aleatorizado y controlado de pevonedistat más azacitidina frente a azacitidina en monoterapia como tratamiento de primera línea en pacientes con síndromes mielodisplásicos de alto riesgo, leucemia mielomonocítica crónica o leucemia mielógena aguda pobre en blastos
    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 más azacitidina frente a azacitidina en monoterapia como tratamiento de primera línea en pacientes con síndromes mielodisplásicos de alto riesgo, leucemia mielomonocítica crónica o leucemia mielógena aguda pobre en blastos
    A.3.2Name or abbreviated title of the trial where available
    PANTHER
    A.4.1Sponsor's protocol code numberPevonedistat-3001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03268954
    A.5.4Other Identifiers
    Name:P-3001Number:Informal shortened named of protocol code
    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. (Takeda)
    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 number+34900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 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 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 nameAzacitidine
    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 INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    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 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
    Higher-Risk Myelodysplastic Syndromes (MDS)
    Chronic Myelomonocytic Leukemia (CMML)
    Low-Blast Acute Myelogenous Leukemia (AML)
    Síndromes mielodisplásicos (SMD) de alto riesgo
    Leucemia mielomonocítica crónica (LMMC)
    Leucemia mielógena aguda (LMA) pobre en blastos
    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
    Los MDS se caracterizan por cambios en la composición sanguínea que incluyen reducciones en glóbulos rojos y blancos y plaquetas.
    La leucemia es cáncer de los glóbulos blancos
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 20.0
    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 20.0
    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 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 20.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 20.0
    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 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.)
    Determinar si la combinación de pevonedistat y azacitidina mejora la tasa de respuesta global (TRG) en el ciclo 6 en comparación con azacitidina en monoterapia. En los pacientes con SMD-AR o LMMC, la respuesta global se define como RC+RP y en los pacientes con LMA pobre en blastos, como RC+remisión completa con recuperación incompleta del hemograma [RCi]+RP.
    Determinar si la combinación de pevonedistat y azacitidina mejora la SSE en comparación con azacitidina en monoterapia. (Un episodio se define como la muerte o transformación en LMA en los pacientes con SMD o LMMC, lo que antes ocurra, y como la muerte en los pacientes con LMA pobre en blastos.)
    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)
    Determinar si la combinación de pevonedistat y azacitidina mejora la SG en comparación con azacitidina en monoterapia.
    Determinar si la combinación de pevonedistat y azacitidina mejora las tasas de supervivencia a los seis meses y un año en comparación con azacitidina en monoterapia.
    Determinar, en los pacientes con SMD-AR o LMMC, si la combinación de pevonedistat y azacitidina prolonga el tiempo transcurrido hasta la transformación en LMA en comparación con azacitidina en monoterapia.
    (Refiérase al Protocolo para más detalles)
    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:
    - Refractory anemia with excess blasts-1 (RAEB-1), defined as having 5%-9% myeloblasts in the bone marrow.
    - Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-19% blasts in the blood.
    - Chronic Myelomonocytic Leukemia-2 (CMML-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-19% blasts in the blood.
    - Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these patients may enroll only if bone marrow blasts ≥5%).
    - WHO-defined AML with 20%-30% myeloblasts in the bone marrow (defined in this protocol as low-blast AML) and ≤30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine-based therapy.

    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
    Calculation of TRM score:
    - 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age ≥71 years).
    - + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
    - + 0 for (platelets <50), +1 for (platelets ≥50).

    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. Pacientes de ambos sexos, de 18 años de edad en adelante
    2. Diagnóstico confirmado morfológicamente de SMD, LMMC no proliferativa (es decir, con un recuento de leucocitos < 13.000/μl) o LMA pobre en blastos basándose en una de las siguientes clasificaciones:
    Clasificación franco-americano-británica (FAB):
    - AREB, definida como la presencia de un 5%-20% de mieloblastos en la médula ósea.
    - LMMC con un 10%-19% de mieloblastos en la médula ósea o un 5%-19% de blastos en la sangre.
    O BIEN
    Clasificación de la Organización Mundial de la Salud (OMS):
    -Anemia refractaria con exceso de blastos-1 (AREB-1), definida como la presencia de un 5%-9% de mieloblastos en la médula ósea.
    -Anemia refractaria con exceso de blastos-2 (AREB-2), definida como la presencia de un 10%-19% de mieloblastos en la médula ósea o de un 5%-19% de blastos en la sangre.
    -Leucemia mielomonocítica crónica-2 (LMMC-2), definida como la presencia de un 10%-19% de mieloblastos en la médula ósea o de un 5%-19% de blastos en la sangre.
    -Leucemia mielomonocítica crónica-1 (aunque la LMMC-1 queda definida como la presencia de < 10% de mieloblastos en la médula ósea o < 5% de blastos en la sangre, estos pacientes podrán participar únicamente si presentan >= 5% de blastos en la médula ósea).
    -LMA definida por la OMS con un 20%-30% de mieloblastos en la médula ósea (definida en este protocolo como “LMA pobre en blastos”) y <= 30% de mieloblastos en la sangre periférica en la que el investigador considera indicado el tratamiento a base de azacitidina.
    3. Todos los pacientes con SMD o LMMC también deben pertenecer a una de las siguientes categorías de riesgo pronóstico basadas en el IPSS-R:
    -Muy alto (> 6 puntos).
    -Alto (> 4,5-6 puntos).
    -Intermedio (> 3-4,5 puntos): un paciente perteneciente a la categoría de riesgo pronóstico intermedio solo podrá participar en el contexto de la presencia de ≥ 5% de mieloblastos en la médula ósea.
    4. EF del ECOG de 0, 1 o 2.
    5. Los pacientes con LMA (20%-30% de blastos) deben tener una puntuación de mortalidad relacionada con el tratamiento (TRM) >= 4 respecto a la quimioterapia de inducción intensiva, calculada con el modelo simplificado descrito por Walter y cols.
    Cálculo de la puntuación TRM:
    - 0 para (edad < 61 años), + 2 para (edad 61-70 años), + 4 para (edad >= 71 años).
    - + 0 para (EF = 0), + 2 para (EF = 1), + 4 para (EF > 1).
    - + 0 para (plaquetas < 50.000/μl), +1 para (plaquetas > =50.000/μl).
    6. Pacientes mujeres que:
    - Son posmenopáusicas durante al menos 1 año antes de la visita de detección, O
    - Son quirúrgicamente estériles, O
    - Si están en edad fértil, acuerden practicar un método altamente efectivo de anticoncepción y un método efectivo (barrera) adicional en el mismo tiempo, desde el momento de la firma del consentimiento informado hasta 4 meses después del última dosis del medicamento del estudio, O
    - Acordar practicar la abstinencia verdadera, cuando esto esté en línea con el preferido y habitual
    estilo de vida del sujeto.
    Pacientes masculinos, incluso si están esterilizados quirúrgicamente (es decir, estado postvasectomía), que:
    - Acepten la práctica de la anticoncepción de barrera efectiva durante todo el período de tratamiento del estudio y hasta 120 días (o si el medicamento tiene una semivida muy larga, durante 90 días más cinco
    vidas medias) después de la última dosis del medicamento del estudio, o
    - Acepten practicar la abstinencia verdadera, cuando esto esté en línea con el preferido y habitual
    estilo de vida del sujeto.
    7. Capacidad para someterse a los procedimientos de recolección de muestras de médula ósea requeridas por el estudio.
    8. Acceso venoso adecuado para el muestreo de sangre requerido por el estudio (es decir, que incluye PK y
    muestreo farmacodinámico).
    9. Valores analíticos dentro de los siguientes parámetros (con repetición en los 3 días previos a la primera dosis del fármaco del estudio si los valores analíticos utilizados para la aleatorización se han obtenido más de 3 días antes de la primera dosis del fármaco del estudio):
    - Albúmina > 2,7 g/dl.
    - Bilirrubina total inferior al límite superior de la normalidad (LSN), salvo en los pacientes con síndrome de Gilbert. Los pacientes con síndrome de Gilbert podrán participar si presentan un valor de bilirrubina directa <=1,5 veces el LSN.
    - Alanina aminotransferasa y aspartato aminotransferasa <= 2,5 veces el LSN.
    - Aclaramiento de creatinina >= 50 ml/min.
    - Hemoglobina > 8 g/dl. Se podrá transfundir a los pacientes para conseguir este valor. Se permitirá la presencia de una bilirrubina indirecta elevada debida a hemólisis postransfusional.
    10. El consentimiento escrito voluntario debe darse antes de la realización de cualquier procedimiento relacionado con el estudio no forma parte de la atención médica estándar, con el entendimiento de que el consentimiento puede ser retirado por el paciente en cualquier momento sin perjuicio de la futura atención médica.
    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. Tratamiento previo por SMD-AR o LMA pobre en blastos con quimioterapia u otros antineoplásicos, incluidos hipometilantes, como decitabina o azacitidina. Se permitirá el tratamiento previo con hidroxicarbamida y lenalidomida, salvo que no podrá administrarse lenalidomida en las 8 semanas previas a la primera dosis del fármaco del estudio.
    2. Leucemia promielocítica aguda, diagnosticada mediante examen morfológico de médula ósea, mediante hibridación in situ con fluorescencia o citogenética de sangre periférica o médula ósea o mediante otro análisis aceptado.
    3. Paciente apto para recibir quimioterapia intensiva o alotrasplante de células madre. Entre los motivos para que un paciente no sea apto para recibir quimioterapia intensiva o alotrasplante de células madre figuran uno o más de los siguientes:
    - Edad > 75 años.
    - Enfermedades concomitantes.
    - Incapacidad para tolerar la quimioterapia intensiva (p. ej., pacientes con LMA con 20%-30% de blastos y TRM >= 4).
    - Decisión del médico (p. ej., ausencia de un donante de células madre disponible).
    El motivo por el cual un paciente no es elegible debe documentarse en el cuaderno de recogida de datos (eCRD).
    4. Pacientes con signos clínicos o antecedentes de afectación del sistema nervioso central por la LMA.
    5. Cualquier enfermedad médica o psiquiátrica grave que, en opinión del investigador, podría interferir con la finalización de los procedimientos del estudio o podría limitar la supervivencia esperada del paciente a menos de 6 meses.
    6. Tratamiento con cualquier fármaco con actividad antileucémica o contra los SMD (p. ej., citarabina, antraciclinas o análogos de las purinas) o con cualquier producto en investigación en los 14 días previos a la primera dosis de cualquier fármaco del estudio.
    7. Hipersensibilidad conocida al manitol.
    8. Infección activa no controlada o enfermedad infecciosa grave, como neumonía grave, meningitis o septicemia.
    9. Cirugía mayor dentro de los 14 días anteriores a la primera dosis o una cirugía programada durante el período de estudio; la inserción de un dispositivo de acceso venoso no se considera cirugía mayor.
    10. Paciente diagnosticado o tratado por otra neoplasia maligna en los dos años previos a la aleatorización o diagnosticado previamente de otra neoplasia maligna y con datos de enfermedad residual. No se excluirá a los pacientes con un cáncer de piel distinto del melanoma o un carcinoma in situ de cualquier tipo si se ha practicado una extirpación del mismo.
    11. Enfermedad potencialmente mortal no relacionada con el cáncer.
    12. Tiempo de protrombina o tiempo de tromboplastina parcial activado > 1,5 veces el LSN o coagulopatía o trastorno hemorrágico no controlado activo. Quedarán excluidos de participar los pacientes que reciban tratamiento anticoagulante con warfarina, inhibidores directos de la trombina, inhibidores directos del factor Xa o heparina.
    13. Seropositivo conocido del virus de inmunodeficiencia humana (VIH) .
    14. Antígeno de superficie de hepatitis B conocido seropositivo, o infección conocida o sospechada de hepatitis C activa. Nota: Los pacientes que tienen anticuerpos contra la hepatitis B positivos aislados deben tener una carga viral de hepatitis B indetectable.
    15. Cirrosis hepática conocida o insuficiencia hepática preexistente severa.
    16. Enfermedad cardiopulmonar conocida definida como angina inestable, arritmia clínicamente significativa, insuficiencia cardíaca congestiva (Asociación de corazón de Nueva York clase III o IV) y / o infarto de miocardio dentro de los 6 meses previos a la primera dosis o hipertensión pulmonar severa. Como ejemplo, la fibrilación auricular bien controlada no sería una exclusión, mientras que la fibrilación auricular no controlada sería una exclusión.
    17. Tratamiento con inductores potentes del citocromo P450 3A en los 14 días previos a la primera dosis de pevonedistat
    18. Pacientes femeninas que están lactando y amamantando o que tienen una prueba positiva de embarazo en suero durante el período de evaluación o una prueba de embarazo positiva en orina el día 1 antes de la primera dosis del fármaco del estudio.
    19. Pacientes mujeres que desean donar óvulos (óvulos) durante el transcurso de este estudio o 4 meses después de recibir su última dosis del medicamento (s) del estudio.
    20. Pacientes masculinos que desean donar esperma durante el transcurso de este estudio o 4 meses después de recibir su última dosis de medicamento (s) del estudio
    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).
    - TRG en el ciclo 6 (la respuesta global en los pacientes con SMD-AR o LMMC se define como RC+RP y en los pacientes con LMA pobre en blastos, como RC+RCi+RP).
    - SSE: tiempo transcurrido desde la aleatorización hasta la fecha de un episodio de SSE (definido como la muerte o transformación en LMA en los pacientes con SMD o LMMC, lo que antes ocurra, y como la muerte en los pacientes con LMA pobre en blastos).
    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).
    - SSE se define como tiempo transcurrido desde la aleatorización hasta la fecha de un episodio
    - TRG en el ciclo 6 (ciclos de 28 días).
    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.
    - SG
    - Tasas de supervivencia a los seis meses y al año.
    - Tasas de supervivencia a los 30 y 60 días.
    - Tiempo transcurrido hasta la transformación en LMA en los pacientes con SMD-AR o LMMC.
    - Tasa de RC (RC en los pacientes con SMD-AR o LMMC, RC+RCi en los pacientes con LMA pobre en blastos), RC+RC en médula ósea (en los pacientes con SMD-AR o LMMC), RC+RP+mejoría hematológica (MH) (en los pacientes con SMD-AR o LMMC), RC+RC en médula ósea+RP (en los pacientes con SMD-AR o LMMC), RC+RC en médula ósea+RP+MH (en los pacientes con SMD-AR o LMMC), respuesta global y respuesta global 2. La respuesta global en los pacientes con SMD-AR o LMMC se define como RC+RP y en los pacientes con LMA pobre en blastos, como RC+RCi+RP. La respuesta global 2 en los pacientes con SMD-AR o LMMC se define como RC+RP+MH y en los pacientes con LMA pobre en blastos, como RC+RCi+RP.
    - Duración de la RC (RC en los pacientes con SMD-AR o LMMC, RC+RCp en los pacientes con LMA pobre en blastos), la respuesta global (RC+RP en los pacientes con SMD-AR o LMMC, RC+RCi+RP en los pacientes con LMA pobre en blastos) y la respuesta global 2 (RC+RP+MH en los pacientes con SMD-AR o LMMC, RC+RCi+RP en los pacientes con LMA pobre en blastos).
    - Tasas de independencia de transfusiones de eritrocitos y plaquetas.
    - Duración de la independencia de transfusiones de eritrocitos, independencia de transfusiones de plaquetas e independencia de transfusiones de plaquetas y eritrocitos.
    - Tiempo transcurrido hasta la primera RC o RP.
    - Tasas de MH en los pacientes con SMD-AR o LMMC.
    - Pacientes con ingresos hospitalarios relacionados con el SMD-AR, la LMMC (recopilados hasta la transformación en LMA o el comienzo de un tratamiento posterior, lo que antes ocurra) o la LMA pobre en blastos (recopilados hasta el comienzo de un tratamiento posterior).
    - Tiempo transcurrido hasta la PE, la recidiva a partir de RC o RP o la muerte.
    - CVRS evaluada mediante el cuestionario QLQ-C30 de la EORTC.
    - Datos de concentración plasmática-tiempo de pevonedistat.
    - TRG, SSE y SG en los pacientes con mutaciones de TP53 o deleciones 17p o en los que se determine que pertenecen a un grupo de riesgo citogenético adverso en ambos grupos de tratamiento.
    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:
    - TRG para ciclo 6: el número y porcentaje de pacientes que lograron una respuesta objetiva (RC + RP para pacientes con SMD-AR o LMMC, RC + RCi + RP para pacientes con LMAde baja explosión) en el ciclo 6. Hasta 6 años
    - SSE: el tiempo desde la aleatorización hasta la ocurrencia de un evento. Para pacientes con SMD-AR / LMMC, un evento se define como muerte o transformación a LMA; para pacientes con LMA de baja explosión, un evento se define como muerte. Hasta 6 años
    Secundario:
    - SG: el tiempo desde la aleatorización hasta la muerte por cualquier causa. Hasta 6 años
    (Por favor refiérase al protocolo para la lista completa)
    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
    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 concerned9
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Brazil
    Canada
    Czech Republic
    France
    Germany
    Greece
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Sweden
    Turkey
    United Kingdom
    United States
    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.
    El estudio se considerará completo una vez que se haya completado el análisis final de la SG o el Promotor haya finalizado el estudio.
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    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 state31
    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.
    Después de las visitas de seguimiento de la SSE y la respuesta, los pacientes con SMD-AR o LMMC que suspendan el tratamiento del estudio por transformación en LMA, así como aquellos con LMA pobre en blastos que suspendan el tratamiento del estudio por PE, se incorporarán a un seguimiento de la supervivencia global (SG) y se contactará con ellos cada tres meses hasta su muerte para documentar los tratamientos posteriores y el estado de supervivencia.
    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 Decision2018-01-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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