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    Summary
    EudraCT Number:2015-000221-37
    Sponsor's Protocol Code Number:Pevonedistat-2001
    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:2015-12-29
    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 number2015-000221-37
    A.3Full title of the trial
    A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia
    Estudio clínico de fase 2, aleatorizado, controlado y abierto para comparar la eficacia y la seguridad de pevonedistat más azacitidina frente a azacitidina en monoterapia en pacientes con síndromes mielodisplásicos de alto riesgo, leucemia mielomonocítica crónica y leucemia mielógena aguda pobre en blastos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study to Compare the Effectiveness and Safety of Azacitidine Versus Pevonedistate Plus Azacitidine in Adults with Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia
    Estudio clínico para comparar la eficacia y la seguridad de azacitidina frente a pevonedistat más azacitidina en pacientes con síndromes mielodisplásicos de alto riesgo, leucemia mielomonocítica crónica y leucemia mielógena aguda pobre en blastos
    A.4.1Sponsor's protocol code numberPevonedistat-2001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02610777
    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 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.3.9.4EV 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)
    Síndrome mielodisplasicos de alto riesgo (SMD),
    Leucemia mielomonocítica crónica (LMMC),
    Leucemia mielógena aguda pobre en blastos (LMA)
    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 síndromes mielodisplásicos se caracterizan por cambios en composición de sangre incluyendo reducciones en glóbulos rojos, blancos y plaquetas. Leucemia es el cáncer de células blancas de sangre.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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 18.1
    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 18.1
    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 18.1
    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 18.1
    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 18.1
    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 18.1
    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 in patients with higher-risk myelodysplastic syndrome (HR MDS), chronic myelomoncytic leukemia (CMML), and low-blast acute myelogenous leukemia (AML) whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared to single-agent azacitidine; for patients with HR MDS or CMML, an event is defined as death or transformation to AML; for patients with low-blast AML, an event is defined as death or disease progression.
    Determinar, en los pacientes con SMD-AR, LMMC, y LMA pobre en blastos, si la combinación de pevonedistat y azacitidina mejora la SLE en comparación con azacitidina en monoterapia; en los casos de SMD-AR o LMMC, se entiende por episodio la transformación en LMA o la muerte; en la LMA pobre en blastos, se entiende por episodio la progresión de la enfermedad o la muerte
    E.2.2Secondary objectives of the trial
    To determine in patients with HR MDS, CMML, and low-blast AML, whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent azacitidine.
    To determine in patients with HR MDS, CMML, and low-blast AML 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 and CMML whether the combination of pevonedistat and azacitidine delays time to AML transformation when compared to single-agent azacitidine.
    To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine, when compared to single-agent azacitidine, improves the rate of complete remission (CR), CR plus partial remission (CR+PR), and/or overall response.
    Determinar, en los pacientes con SMD-AR, LMMC, y LMA pobre en blastos, si la combinación de pevonedistat y azacitidina mejora la SG en comparación con azacitidina en monoterapia. Determinar, en pacientes con SMD-AR, LMMC, y LMA pobre en blastos, si la combinación de pevonedistat y azacitidina mejora las tasas de supervivencia a los 6 meses y al año en comparación con azacitidina en monoterapia. Determinar, en los pacientes con SMD-AR, LMMC, y LMA pobre en blastos, si la combinación de pevonedistat y azacitidina retrasa el tiempo transcurrido hasta la transformación en LMA en comparación con azacitidina en monoterapia. Determinar, en pacientes con SMD-AR, LMMC, y LMA pobre en blastos, si la combinación de pevonedistat y azacitidina, en comparación con azacitidina en monoterapia, mejora la tasa de: RC, RC+RP y respuesta global. La respuesta global en los SMD-AR y en la LMMC se define como RC+ RP+ mejoría hematológica; la respuesta global en la LMA pobre en blastos se define como RC+RP.
    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, nonproliferative CMML (ie, with WBC <20,000/µl), or low-blast AML based on 1 of the following:

    French-American-British (FAB) Classifications:
    - Refractory anemia with excess blasts (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% to 9%
    myeloblasts in the bone marrow).
    - Refractory anemia with excess blasts-2 (RAEB-2 defined as having 10% to
    19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
    - Chronic Myelomonocytic Leukemia-2 (CMML-2 defined as having 10% to
    19% myeloblasts in the bone marrow and/or 5% to 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% to 30% myeloblasts in the bone marrow (defined in this protocol as `Low-Blast AML´) and < 30% myeloblasts in peripheral blood who are considered by investigator to be appropriate for azacitidine-based therapy.

    3. For MDS and CMML patients, 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. ECOG performance status of 0 to 2

    5. Clinical laboratory values within the following parameters within 3 days before the first dose of study drug:
    - Albumin >2.7 g/dL.
    - Total bilirubin <upper limit of normal (ULN) except in patients with Gilbert´s
    syndrome. Patients with Gilbert´s syndrome may enroll if direct bilirubin <=1.5 x
    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 post-transfusion hemolysis is allowed.

    6. For CMML patients: WBC count <20,000/µl before administration of the first dose of study drug on Cycle 1 Day 1; patients must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

    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 biomarker sampling).

    9. 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 2 effective methods of
    contraception, 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] and withdrawal are not acceptable
    methods of contraception.)

    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    - Agree to practice effective barrier contraception during the entire study treatment period and 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 for the female partner] and withdrawal are not acceptable methods of contraception.)

    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 cualquier sexo de 18 años o más de edad.
    2.Diagnóstico confirmado morfológicamente de SMD, LMMC no proliferativa (es decir, con un recuento de leucocitos < 20.000/µl) o LMA pobre en blastos, basándose en una de las siguientes clasificaciones:
    Clasificación franco americano británica (FAB):
    -Anemia resistente con exceso de blastos (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 resistente con exceso de blastos 1 (AREB 1, definida como la presencia de un 5% 9% de mieloblastos en la médula ósea).
    -Anemia resistente 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 hay >= 5% de blastos en la médula ósea).
    -LMA con 20%-30% de mieloblastos según definición de la OMS (que en este protocolo se define como "LMA pobre en blastos") y < 30% de mieloblastos en sangre periférica en la que, a criterio del investigador, está indicado el tratamiento a base de azacitidina.
    3.En los pacientes con SMD y LMMC, categoría de riesgo pronóstico, basándose en el Sistema internacional de puntuación pronóstica revisado (IPSS R)[1], de:
    -Muy alto (> 6 puntos),
    -Alto (> 4,5 6 puntos) o
    -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.Estado funcional del ECOG de 0 a 2
    5.Valores analíticos dentro de los parámetros siguientes en los 3 días previos a la primera dosis del fármaco del estudio:
    -Albúmina > 2,7 g/dl.
    -Bilirrubina total < límite superior de la normalidad (LSN), salvo en los pacientes con síndrome de Gilbert. Los pacientes con síndrome de Gilbert podrán participar si presentan una bilirrubina directa <= 1,5 veces el LSN de la bilirrubina directa.
    -ALT y AST <=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.
    6.En los pacientes con LMMC: Recuento de leucocitos < 20.000/µl antes de la administración de la primera dosis del fármaco del estudio el día 1 del ciclo 1; los pacientes deberán haber suspendido el tratamiento con hidroxicarbamida durante al menos una semana antes de la evaluación del recuento de leucocitos.
    7.Capacidad de someterse a los procedimientos de obtención de muestras de médula ósea exigidos por el estudio.
    8.Acceso venoso apto para las extracciones de sangre exigidas por el estudio (incluidas las muestras para farmacocinética y biomarcadores).
    9.En las mujeres:
    -Ser posmenopáusica desde al menos un año antes de la visita de selección, o bien
    -Haber sido esterilizada quirúrgicamente, o bien
    -En caso de estar en edad fértil, comprometerse a utilizar simultáneamente dos métodos anticonceptivos eficaces desde el momento de firma del consentimiento informado y hasta 4 meses después de la última dosis del fármaco del estudio.
    -Comprometerse a practicar abstinencia real cuando esté de acuerdo con su modo de vida preferido y habitual. (La abstinencia periódica [por ejemplo, métodos del calendario, ovulación, sintotérmico o postovulatorio] y el coito interrumpido no son métodos anticonceptivos aceptables).
    En los varones, aunque se hayan sometido a esterilización quirúrgica (es decir, se hayan hecho una vasectomía):
    -Comprometerse a utilizar un método anticonceptivo de barrera eficaz durante todo el período de tratamiento del estudio y hasta 4 meses después de la última dosis del fármaco del estudio, o bien
    -Comprometerse a practicar abstinencia real cuando esté de acuerdo con su modo de vida preferido y habitual. (La abstinencia periódica [por ejemplo, métodos del calendario, ovulación, sintotérmico o postovulatorio] y el coito interrumpido no son métodos anticonceptivos aceptables.)
    10.Deberá obtenerse el consentimiento voluntario por escrito antes de llevar a cabo ningún procedimiento relacionado con el estudio que no forme parte de la asistencia médica habitual, entendiendo el paciente que podrá retirar su consentimiento sin perjuicio alguno de la asistencia médica que reciba en el futuro.
    E.4Principal exclusion criteria
    1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

    2. Therapy-related MDS, CMML, or low-blast AML associated with previous cytotoxic chemotherapy (eg, alkylating agents, topoisomerase inhibitors).

    3. 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.

    4. Eligible for allogenic stem cell transplantation.

    5. Patients with MDS, CMML, or low-blast AML, whose only site of disease is
    extramedullary, eg, the skin.

    6. Any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the completion of study procedures or could limit patient expected survival to less than 6 months.

    7. Treatment with any investigational products within 14 days before the first dose of any study drug.

    8. Known hypersensitivity to mannitol.

    9. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.

    10. 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.

    11. 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.

    12. Life-threatening illness unrelated to cancer.

    13. Prothrombin time (PT) or aPTT > 1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.

    14. Known human immunodeficiency virus (HIV) seropositive.

    15. 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.

    16. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

    17. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV; see Section 15.3), and/or myocardial infarction within 6 months prior to 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.

    18. Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of pevonedistat.

    19. Systemic antineoplastic therapy or radiotherapy for other conditions within
    12 months before the first dose of any study drug, except for hydroxyurea.

    20. 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.
    1.Tratamiento previo con decitabina, azacitidina u otro fármaco hipometilante.
    2.SMD, LMMC o LMA pobre en blastos relacionados con tratamientos asociado a quimioterapia citotóxica previa (por ejemplo, alquilantes, inhibidores de la topoisomerasa).
    3.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.
    4.Apto para someterse a un alotrasplante de células madre.
    5.Pacientes con SMD, LMMC o LMA pobre en blastos cuyo único foco de enfermedad sea extramedular, por ejemplo, la piel.
    6.Cualquier enfermedad médica o psiquiátrica grave que, en opinión del investigador, podría dificultar la realización de los procedimientos del estudio o limitar la supervivencia prevista de los pacientes a menos de 6 meses.
    7.Tratamiento con cualquier producto en investigación en los 14 días previos a la primera dosis del fármaco del estudio.
    8.Hipersensibilidad conocida al manitol.
    9.Infección o enfermedad infecciosa grave no controlada y activa, como neumonía grave, meningitis o sepsis.
    10.Intervención de cirugía mayor en los 14 días previos a la primera dosis o intervención quirúrgica programada durante el período del estudio; la colocación de un dispositivo de acceso venoso (por ejemplo, catéter o puerto) no se considera cirugía mayor.
    11.Diagnóstico o tratamiento de otra neoplasia maligna en los dos años previos a la aleatorización o diagnóstico previo de otra neoplasia maligna con indicios 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.
    12.Enfermedad potencialmente mortal no relacionada con el cáncer.
    13.Tiempo de protrombina (TP) o TTPa > 1,5 veces el LSN o coagulopatía o trastorno hemorrágico no controlado y activo.
    14.Seropositividad para el virus de la inmunodeficiencia humana (VIH).
    15.Seropositividad para el antígeno de superficie del virus de la hepatitis B o certeza o sospecha de hepatitis C activa. Nota: Los pacientes con anticuerpos aislados contra el antígeno nuclear del virus de la hepatitis B (es decir, en el contexto de un antígeno de superficie del virus de la hepatitis B negativo y anticuerpos negativos contra el antígeno de superficie del virus de la hepatitis B) deberán tener una viremia indetectable de virus de la hepatitis B.
    16.Cirrosis hepática conocida o insuficiencia hepática grave preexistente.
    17.Enfermedades cardiorrespiratorias conocidas, definidas como angina de pecho inestable, arritmias clínicamente importantes, insuficiencia cardíaca congestiva (clase III o IV según la New York Heart Association [NYHA]), infarto de miocardio en los 6 meses previos a la primera dosis o hipertensión pulmonar grave. Por ejemplo, una fibrilación auricular bien controlada no sería un criterio de exclusión, mientras que sí lo sería una fibrilación auricular no controlada.
    18.Tratamiento con inhibidores o inductores potentes de la enzima CYP3A en los 14 días previos a la primera dosis de pevonedistat.
    19.Tratamiento antineoplásico sistémico o radioterapia por otras enfermedades en los 12 meses previos a la primera dosis del fármaco del estudio, excepto hidroxicarbamida.
    20.Mujeres que estén dando el pecho o tengan una prueba de embarazo en suero positiva durante el período de selección o una prueba de embarazo en orina positiva el día 1 antes de la primera dosis del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    EFS;
    for patients with HR MDS or CMML, an event is defined as death or transformation to AML; whichever come earlier.
    for patients with low-blast AML, an event is defined as death or disease progression; whichever come earlier.
    SLE; en los casos de SMD-AR o LMMC, se entiende por episodio la transformación en LMA o la muerte; en la LMA pobre en blastos, se entiende por episodio la progresión de la enfermedad o la muerte
    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.
    SLE se define como el tiempo desde la aleatorización a la ocurrencia de un evento.
    E.5.2Secondary end point(s)
    - OS.
    - Six-month and 1-year survival rates.
    - Time to AML transformation in HR MDS and CMML patients.
    - CR, CR+PR, overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML).
    - CR, CR+PR, overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML) by Cycle 4.
    - Duration of CR, duration of CR+PR, duration of overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML).
    - Time to first CR or PR.
    - Time to subsequent therapy.
    - RBCs and platelet-transfusion independence.
    - Percent of patients with at least one inpatient hospital admissions related to HR MDS or CMML (collected through transformation to AML or until initiation of subsequent therapy, whichever occurs first) or low-blast AML (collected through AML progression or until initiation of subsequent therapy, whichever occurs first).
    - Time to PD, relapse after CR or PR, or death.
    - AEs and serious adverse events (SAEs), abnormal clinical laboratory values, Eastern Cooperative Oncology Group (ECOG) performance status, ECGs, and vital sign measurements.
    -SG
    -Tasas de supervivencia a los 6 meses y al año
    -Tiempo transcurrido hasta transformación en LMA en pacientes con SMD-AR y LMMC
    -RC/RC+RP/respuesta global (RC+RP+MH en los pacientes con SMD-AR y LMMC; RC+RP en los pacientes con LMA pobre en blastos)
    -RC+RP y respuesta global en el ciclo 4
    -Duración de la RC, duración de la RC+RP, duración de la respuesta global
    -Tiempo transcurrido hasta la primera RC o RP
    -Tiempo transcurrido hasta el tratamiento posterior
    -Independencia de transfusiones de eritrocitos y plaquetas
    -% pacientes con al menos un ingreso hospitalario relacionado con el SMD AR o LMMC (recopilados hasta la transformación en LMA o comienzo de un tratamiento posterior, lo que ocurra antes), o con LMA pobre en blastos (recopilados hasta la progresión de la LMA o comienzo de tratamiento posterior, lo que ocurra antes)
    -Tiempo transcurrido hasta progresión de enfermedad, recidiva tras RC o RP o muerte
    -AA y AAG, valores analíticos anómalos, ECOG, ECG y constantes vitales.
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS will be calculated from date of randomization to the date of patient death.
    Six-month survival rate is defined as the percentage of patients who are still alive six months after randomization.
    One-year survival rate is defined as the percentage of patients who are still alive one year after randomization.
    Time to AML transformation is defined as time from randomization to documented AML transformation.
    Time to first CR or PR is defined as time from randomization to first documented CR or PR, whichever occurs first.
    Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy.
    Time to PD, relapse after CR or PR, or death is defined as the time from randomization until disease progression, or relapse after CR or PR, or death.
    SG se mide desde fecha de aleatorización hasta fecha de muerte del paciente.
    Tasa de supervivencia 6meses: porcentaje de pacientes que siguen vivos seis meses después de aleatorización.
    Tasa de supervivencia a un año: porcentaje de pacientes que siguen vivos un año después de aleatorización.
    Tiempo de transformación AML: tiempo desde aleatorización hasta transformación AML documentada.
    Tiempo a primera RC o RP: tiempo desde aleatorización hasta primera documentada RC o RP, lo que pase primero.
    Tiempo posterior a terapia: tiempo desde aleatorización hasta fecha de la primera terapia subsiguiente.
    Tiempo para la PE, recaída después de RC o RP, o muerte: tiempo desde aleatorización hasta progresión de enfermedad, o recaída después de RC o RP, o muerte.
    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) 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 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 No
    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 EEA43
    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
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Spain
    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
    LPLV - Patients will be considered to have completed the study if they are followed until death or until the sponsor terminates the study.
    UVUP- Se considerará que los pacientes han completado el estudio si son seguidos hasta la muerte o hasta que el promotor termine 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 months9
    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 months9
    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: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 101
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 117
    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)
    After subjects have ended participation in the study, they will be treated as per local standard of care.
    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 Decision2016-02-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-09
    P. End of Trial
    P.End of Trial StatusOngoing
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