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    Summary
    EudraCT Number:2013-003713-18
    Sponsor's Protocol Code Number:C14018
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-04-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-003713-18
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, Phase 2 Clinical Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)
    Ensayo clínico aleatorizado, doble ciego, controlado con placebo, de fase 2, de Alisertib (MLN8237) en combinación con paclitaxel frente a placebo en combinación con paclitaxel como tratamiento de segunda línea para el cáncer de pulmón microcítico (CPM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)
    Ensayo de fase 2, de Alisertib (MLN8237) en combinación con paclitaxel frente a placebo en combinación con paclitaxel como tratamiento de segunda línea para el cáncer de pulmón microcítico (CPM)
    A.4.1Sponsor's protocol code numberC14018
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02038647
    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
    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 St
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number001510740-2412
    B.5.5Fax number001800881-6092
    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 nameAlisertib
    D.3.2Product code MLN8237
    D.3.4Pharmaceutical form Gastro-resistant tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlisertib
    D.3.9.1CAS number 1208255-63-3
    D.3.9.2Current sponsor codeMLN8237
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 Paclitaxel 6 mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Limited
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namepaclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGastro-resistant tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or Refractory Small cell lung cancer
    Cancer de pulmón microcítico recidivante o refractorio
    E.1.1.1Medical condition in easily understood language
    Small cell lung cancer
    Cáncer de pulmón microcítico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10041067
    E.1.2Term Small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether the combination of alisertib + paclitaxel improves progression-free survival (PFS) compared with placebo + paclitaxel
    ? Averiguar si la combinación de alisertib + paclitaxel mejora la supervivencia sin progresión (SSP) en comparación con placebo + paclitaxel
    E.2.2Secondary objectives of the trial
    ? To evaluate the safety and tolerability of the combination of alisertib + paclitaxel in small cell lung cancer (SCLC) patients

    ? To determine whether the combination of alisertib + paclitaxel improves overall survival (OS) compared with placebo + paclitaxel

    ? To determine whether the combination of alisertib + paclitaxel improves the overall response rate (ORR) compared with placebo + paclitaxel

    ? To determine whether the combination of alisertib + paclitaxel improves the disease control rate (DCR) compared with placebo + paclitaxel

    ? To determine whether the combination of alisertib + paclitaxel improves the duration of response (DOR) compared with placebo + paclitaxel

    ? To evaluate patient lung cancer associated symptoms of cough, dyspnea, and pain as measured by patient-reported outcome (PRO) instruments

    ? To measure plasma alisertib concentrations to contribute to population pharmacokinetic (PK) analysis
    ? Evaluar la seguridad y la tolerabilidad de la combinación de alisertib + paclitaxel en pacientes con cáncer de pulmón microcítico (CPM)
    ? Averiguar si la combinación de alisertib + paclitaxel mejora la supervivencia general (SG) en comparación con placebo + paclitaxel
    ? Averiguar si la combinación de alisertib + paclitaxel mejora la tasa general de respuesta (TGR) en comparación con placebo + paclitaxel
    ? Averiguar si la combinación de alisertib + paclitaxel mejora la tasa de control de la enfermedad (TCE) en comparación con placebo + paclitaxel
    ? Averiguar si la combinación de alisertib + paclitaxel mejora la duración de la respuesta (DR) en comparación con placebo + paclitaxel
    ? Evaluar los síntomas de tos, disnea y dolor asociados al cáncer de pulmón medidos a través de instrumentos de resultados notificados por los pacientes (PRO)
    ? Medir las concentraciones plasmáticas de alisertib para contribuir al análisis farmacocinético (FC) de la población
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ? 18 years old.

    2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.

    3. Have received and progressed after a platinum based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES). Patients could not have received any prior second-line therapy for relapsed or progressive disease, including re-treatment with original frontline regimen. Patients should have relapsed within < 180 days after their response to first line therapy. At least 3 weeks should have elapsed between the end of first line therapy and the first dose of study drug. No previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression.

    4. Have measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) within ? 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented.

    5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0 1).

    6. Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed, provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed. Radiotherapy must have been completed a minimum of 14 days prior to randomization, and patients must have recovered from AEs related to the radiotherapy to < grade 1 (except alopecia).

    7. Patients requiring full systemic anticoagulation are eligible if they have tolerated treatment with a stable dose and schedule without bleeding complications for more than 1 month.

    8. 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 form (ICF) through 30 days 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.)

    9. The patient or the patient?s legal representative is able to provide written informed consent. 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.

    10. Screening clinical laboratory values as specified below:
    ? Absolute neutrophil count (ANC) ? 1500/mm3, platelet count ? 100,000/mm3, and hemoglobin ? 9 g/dL
    ? Total bilirubin ? 1.5 x the institutional upper limit of normal (ULN)
    ? Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ? 2.5 x the institutional ULN (< 5 x if liver function test elevations are due to liver metastases)
    ? Serum albumin ? the lower limit of normal (LLN)
    ? Creatinine < 1.5 x institutional ULN or estimated creatinine clearance using the Cockcroft-Gault formula ? 30 mL/minute for patients with creatinine levels above institutional limits

    11. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before randomization, and otherwise noted in other inclusion/exclusion criteria.

    12. Suitable venous access for the conduct of blood sampling and intravenous administration of study treatments.

    13. Recovered (ie, ? Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
    1. Pacientes de sexo masculino o femenino ? 18 años.
    2. Diagnóstico de CPM confirmado mediante estudios de anatomía patológica (histología o citología).
    3. Haber recibido y progresado después de un tratamiento con quimioterapia estándar a base de platino como tratamiento de primera línea para el CPM, ya sea en un estadio localizado (EL) o extendido (EE). Los pacientes no pueden haber recibido ningún tratamiento de segunda línea previo para la enfermedad recidivante o progresiva, ni siquiera un segundo tratamiento con el régimen de primera línea original. Los pacientes deben haber recaído en un plazo < 180 días después de su respuesta al tratamiento de primera línea. Deben haber transcurrido al menos 3 semanas entre el final del tratamiento de primera línea y la primera dosis del fármaco del estudio. No pueden haber recibido irradiación previa en la única localización de la enfermedad mensurable o evaluable, a menos que dicha localización haya mostrado posteriormente indicios de progresión.
    4. Presentar enfermedad medible según los Criterios de Evaluación de la Respuesta en Tumores Sólidos versión 1.1 (RECIST 1.1) en las ? 2 semanas previas a la aleatorización. Deben haberse documentado indicios radiográficos claros de progresión de la enfermedad tras el tratamiento inicial.
    5. Estado general (EG) según la escala del Grupo Oncológico Cooperativo del Este (ECOG) de 0 o 1 (EG 0 1)
    6. Se pueden inscribir pacientes con metástasis cerebrales tratadas (mediante cirugía o radioterapia cerebral completa o estereotáctica), siempre y cuando las lesiones se hayan mantenido estables durante al menos 2 semanas y el paciente haya dejado los corticoesteroides o los siga tomando con una dosis estable. Los pacientes no deben presentar trastornos neurológicos que hagan confundir la evaluación de AA neurológicos o de otros tipos. Los pacientes con metástasis cerebrales no deben requerir el uso de antiepilépticos inductores enzimáticos (como carbamacepina, fenitoína o fenobarbital) en los 14 días previos a la primera dosis y durante el estudio. Se permite el uso de antiepilépticos más recientes que no produzcan interacciones farmacológicas (IF) de inducción enzimática. La radioterapia debe haber concluido al menos 14 días antes de la aleatorización, y los pacientes deben haberse recuperado de los AA relacionados con la radioterapia hasta < grado 1 (excepto la alopecia).
    7. Se podrá inscribir a pacientes que requieran anticoagulación sistémica completa si han tolerado el tratamiento con una dosis y una pauta estables sin complicaciones hemorrágicas durante más de 1 mes.
    8. Pacientes de sexo femenino que:
    ? lleven siendo posmenopáusicas al menos desde 1 año antes de la visita de selección;
    ? hayan sido esterilizadas quirúrgicamente;
    ? si tienen capacidad reproductiva, que acepten el uso de 2 métodos anticonceptivos eficaces al mismo tiempo desde el momento de firmar el formulario de consentimiento informado (FCI) y hasta 30 días después de la administración de la última dosis del fármaco del estudio; o
    ? acepten la práctica de una abstinencia verdadera, si ello es compatible con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p.e., los métodos del calendario, de la ovulación, los sintotérmicos o los de postovulación] y la interrupción del coito no se consideran métodos anticonceptivos aceptables).
    Pacientes varones, aunque hayan sido esterilizados quirúrgicamente (es decir, después de someterse a una vasectomía) que:
    ? acepten utilizar métodos anticonceptivos eficaces de barrera durante todo el periodo de tratamiento del estudio y durante los 4 meses posteriores a la última dosis del fármaco del estudio; o
    ? acepten la práctica de una abstinencia verdadera, si ello es compatible con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p. e., los métodos del calendario, de la ovulación, los sintotérmicos o los de postovulación para la pareja de sexo femenino] y la interrupción del coito no se consideran métodos anticonceptivos aceptables).
    9. Paciente o representante legal de este que sea capaz de otorgar su consentimiento informado por escrito. El consentimiento voluntario por escrito debe otorgarse antes de realizar cualquier procedimiento relacionado con el estudio distinto de la atención médica estándar, siendo consciente de que el paciente puede retirar su consentimiento en cualquier momento sin perjuicio de su atención médica futura.
    (para más información véase sección 5.1 del protocolo)
    E.4Principal exclusion criteria
    1. Any prior therapy for second-line treatment of SCLC.

    2. Patients who relapsed ? 180 days after their response to first-line treatment.

    3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib in any setting or any other investigational agent in the relapsed setting.

    4. Prior treatment with paclitaxel or any other taxane agent.

    5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.

    6. Any comorbid condition or unresolved toxicity that would preclude administration of alisertib or weekly paclitaxel.

    7. Prior history of ? Grade 2 neurotoxicity that is not resolved to ? Grade 1.

    8. Patients with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.

    9. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during study conduct. Major prohibited enzyme inducers include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John?s wort.

    10. Inability to swallow alisertib or other orally administered medications.

    11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or pancreatic enzymes. Use of any PPI in either continued or intermittent use will be prohibited during the conduct of the study and patients must discontinue any use of PPI within 4 days prior to the first dose of alisertib.

    12. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.

    13. Other severe acute or chronic medical or psychiatric condition(s), including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.

    14. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of Grade > 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. Patients with a pacemaker may be enrolled in the study upon discussion with the project clinician.

    15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. Patients with prior allogeneic bone marrow or organ transplantation or with an active condition of chronic immune suppression are not eligible.

    16. Infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

    17. Patients who are lactating or have a positive serum pregnancy test.

    18. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status. Insertion of a vascular device is allowed.

    19. Unwilling or unable to comply with the protocol or
    cooperate fully with the investigator and site personnel.
    1. Cualquier tratamiento previo de segunda línea para el CPM.
    2. Pacientes que hayan recaído ? 180 días después de su respuesta al tratamiento de primera línea.
    3. Tratamiento previo con un agente dirigido específicamente a la proteína-cinasa Aurora A o a todas las proteínas-cinasas Aurora, incluido el alisertib en cualquier entorno o cualquier otro fármaco en investigación para las recaídas.
    4. Tratamiento previo con paclitaxel o con cualquier otro taxano.
    5. Hipersensibilidad conocida al Cremophor® EL, al paclitaxel o a sus componentes.
    6. Cualquier comorbilidad o toxicidad sin resolver que impida la administración del alisertib o del paclitaxel semanalmente.
    7. Antecedentes de neurotoxicidad ? grado 2 sin resolver hasta ? grado 1.
    8. Pacientes con metástasis cerebral sintomática o progresiva o con meningitis carcinomatosa.
    9. Tratamiento con inductores enzimáticos clínicamente significativos en los 14 días previos a la primera dosis de alisertib y durante la realización del estudio. Entre los principales inductores enzimáticos prohibidos se encuentran la fenitoína, la carbamacepina, el fenobarbital, la rifampicina, la rifabutina, la rifapentina y el hipérico o hierba de san Juan.
    10. Incapacidad para tragar el alisertib u otros medicamentos administrados por vía oral.
    11. Necesidad de administración de inhibidores de la bomba de protones (proton pump inhibitors, PPI), de antagonistas de los receptores H2 o de enzimas pancreáticas. Queda prohibido el uso de cualquier PPI de forma continua o intermitente durante la realización del estudio, y los pacientes deben interrumpir el consumo de cualquier PPI en los 4 días previos a la primera dosis de alisertib.
    12. Diagnóstico o tratamiento para otra neoplasia maligna en los 3 años previos a la primera dosis del fármaco del estudio, o diagnóstico previo de otra neoplasia maligna con algún indicio de enfermedad residual. Los pacientes con cáncer de piel distinto del melanoma o con carcinoma in situ de cualquier tipo pueden participar en el estudio si se han sometido a una resección completa y no presentan indicios de enfermedad activa.
    13. Presencia de otras afecciones graves médicas o psiquiátricas, ya sean agudas o crónicas, como diabetes incontrolada, malabsorción, resección pancreática o de la porción superior del intestino delgado, necesidad de recibir enzimas pancreáticas, cualquier afección que modifique la absorción en el intestino delgado de medicamentos por vía oral o anomalías analíticas que puedan incrementar el riesgo asociado a la participación en este estudio o la administración del producto en investigación o que puedan interferir con la interpretación de los resultados del estudio y que, a juicio del investigador, haga que el paciente sea inadecuado para su inscripción en este estudio.
    14. Antecedentes de infarto de miocardio, isquemia cardíaca sintomática inestable, hipertensión incontrolada a pesar de recibir un tratamiento médico adecuado, cualquier otra arritmia cardíaca en curso de grado > 2, episodios tromboembólicos (p. ej., trombosis venosa profunda, embolia pulmonar o episodios cerebrovasculares sintomáticos), o bien cualquier otra afección cardíaca (p. ej., derrame pericárdico o miocardiopatía restrictiva) en los 6 meses previos a la recepción de la primera dosis del fármaco del estudio. Se admite la fibrilación auricular crónica estable con tratamiento anticoagulante. Los pacientes con marcapasos podrán ser inscritos en este estudio tras consultar con el médico del proyecto.
    15. Antecedentes conocidos de infección por virus de la inmunodeficiencia humana (VIH), de la hepatitis B o de la hepatitis C. No es necesario realizar las pruebas en ausencia de hallazgos clínicos o de sospecha. Los pacientes sometidos previamente a trasplante alógeno de médula ósea o de algún órgano, o que presenten alguna afección activa de inmunosupresión crónica no serán aptos.
    16. Infección que requiera tratamiento antibiótico IV u otra infección grave en los 14 días previos a la primera dosis del fármaco del estudio.
    17. Pacientes que estén amamantando o que hayan dado positivo en una prueba de embarazo en suero.
    18. Intervención quirúrgica en las 3 semanas anteriores (o 2 semanas si se trata de cirugía menor) a la inscripción en el estudio y que no hayan recuperado plenamente su estado inicial o cuyo estado clínico no sea estable. Se permite la inserción de dispositivos vasculares.
    19. Rechazo o incapacidad para cumplir el protocolo o para colaborar plenamente con el investigador y el personal del centro.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS
    El criterio de valoración principal es la SSP.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS will be assessed every cycle of therapy for the first 6 months, and then every 2 cycles between Days 21 and 28

    It is expected that the study will last approximately 22 months to reach the final analysis of the PFS endpoint for the maximum sample size (16 months of enrollment and 6 months of additional follow-up for PFS)
    La SSP se evaluará en cada ciclo de tratamiento durante los 6 primeros meses, y posteriormente cada 2 ciclos entre los días 21 y 28.
    Se espera que el estudio dure aproximadamente 22 meses hasta llegar al análisis final del criterio de valoración de SSP con el tamaño muestral máximo (16 meses de inscripción y 6 meses de seguimiento adicional para la SSP).
    E.5.2Secondary end point(s)
    ? Safety and tolerability
    ? OS
    ? ORR, including complete response rate (CRR)
    ? Disease control rate (DCR)
    ? Duration of response (DOR)
    ? Symptom score, time to symptom relief, percentage of patients experiencing symptom relief, and time to symptom progression (cough, dyspnea, and pain)
    ? Plasma alisertib concentration (ie, PK)
    ? Seguridad y tolerabilidad
    ? SG
    ? TGR, incluida la tasa de respuesta completa (TRC)
    ? Tasa de control de la enfermedad (TCE)
    ? Duración de la respuesta (DR)
    ? Puntuación de síntomas, período transcurrido hasta el alivio de los síntomas, porcentaje de pacientes que experimentan alivio sintomático y periodo transcurrido hasta la progresión de los síntomas (tos, disnea y dolor)
    ? Concentración plasmática de alisertib (es decir, la FC)
    E.5.2.1Timepoint(s) of evaluation of this end point
    safety- ongoing
    Patients will be followed for OS every 2 months (± 2 weeks) until death events are obtained from approximately 80% of all patients in the ITT population or 14 months after last patient is randomized, whichever occurs first
    Seguridad en curso
    Se hará un seguimiento de SG de los pacientes cada 2 meses (± 2 semanas) hasta que se obtengan eventos de muerte aproximadamente del 80 % de todos los pacientes de la población ITT o hasta 14 meses después de aleatorizar al último paciente, lo que suceda primero.
    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 Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    Calidad de vida
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Poland
    Spain
    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
    last patient last visit
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months22
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months22
    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: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 89
    F.4.2.2In the whole clinical trial 166
    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)
    not applicable
    No aplica
    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 Decision2014-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-07-10
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