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    Summary
    EudraCT Number:2019-003859-11
    Sponsor's Protocol Code Number:MO41552
    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:2021-07-05
    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 number2019-003859-11
    A.3Full title of the trial
    RANDOMIZED, OPEN LABEL, MULTICENTER, PHASE III STUDY OF ENTRECTINIB VERSUS CRIZOTINIB IN PATIENTS WITH LOCALLYADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER HARBORING ROS1 GENE REARRANGEMENTS WITH AND WITHOUT CENTRAL NERVOUS SYSTEM METASTASES
    ESTUDIO FASE III MULTICÉNTRICO, ABIERTO, ALEATORIZADO DE ENTRECTINIB COMPARADO CON CRIZOTINIB EN PACIENTES CON CÁNCER DE PULMÓN NO MICROCÍTICO LOCALMENTE AVANZADO O METASTÁSICO CON REORDENAMIENTOS DEL GEN ROS1, CON O SIN METÁSTASIS EN EL SISTEMA NERVIOSO CENTRAL
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Entrectinib versus Crizotinib in Patients with Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring ROS1 Gene Rearrangements With and Without Central Nervous System Metastases
    Un estudio de entrectinib versus crizotinib en pacientes con cáncer de pulmón de células no pequeñas localmente avanzado o metastásico que alberga reordenamientos del gen ROS1 con y sin metástasis en el sistema nervioso central
    A.4.1Sponsor's protocol code numberMO41552
    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 SponsorRoche Farma S. A. U. que realiza el ensayo en España y que actúa como representante F. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+349132557300
    B.5.5Fax number+34913248196
    B.5.6E-mailspain.start_up_unit@roche.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 nameEntrectinib
    D.3.2Product code RO7102122 - F04/F06/F10/F14/F24
    D.3.4Pharmaceutical form Capsule, hard
    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 INNENTRECTINIB
    D.3.9.2Current sponsor codeRO7102122
    D.3.9.4EV Substance CodeSUB177830
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 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 nameEntrectinib
    D.3.2Product code RO7102122 - F08/F09/F11/F20/F25
    D.3.4Pharmaceutical form Capsule, hard
    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 INNENTRECTINIB
    D.3.9.2Current sponsor codeRO7102122
    D.3.9.4EV Substance CodeSUB177830
    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.IMP: 3
    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 XALKORI
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameCrizotinib
    D.3.4Pharmaceutical form Capsule, hard
    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 INNcrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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: 4
    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 XALKORI
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameCrizotinib
    D.3.4Pharmaceutical form Capsule, hard
    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 INNcrizotinib
    D.3.9.1CAS number 877399-52-5
    D.3.9.3Other descriptive nameCRIZOTINIB
    D.3.9.4EV Substance CodeSUB32267
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Non-small cell lung cancer with ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene rearrangements
    Cáncer de pulmón de células no pequeñas con reordenamientos del gen del protooncogén 1 ROS, receptor de tirosina quinasa (ROS1)
    E.1.1.1Medical condition in easily understood language
    Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung
    El cáncer de pulmón de células no pequeñas es una enfermedad en la que se forman células malignas (cancerosas) en los tejidos del pulmón.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-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 evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline
    • Evaluar la eficacia de entrectinib en comparación con crizotinib en pacientes con CPCNP con reordenamiento de ROS1 positivo y metástasis en el SNC al inicio del estudio.
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC in the whole study population (ITT)
    •To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline
    •To evaluate the safety of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC
    •To evaluate health status utility scores of patients treated with entrectinib to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale (VAS) scores
    • Evaluar la eficacia de entrectinib en comparación con crizotinib en pacientes con CPCNP con reordenamiento de ROS1 positivo en toda la población del estudio (ITT)
    • Evaluar la eficacia de entrectinib en comparación con crizotinib en pacientes con CPCNP con reordenamiento de ROS1 positivo y metástasis en el SNC al inicio del estudio.
    • Evaluar la seguridad de entrectinib en comparación con crizotinib en pacientes con CPCNP con reordenamiento de ROS1 positivo
    • Evaluar las puntuaciones de utilidad del estado de salud de los pacientes tratados con entrectinib para informar el modelado farmacoeconómico mediante el cuestionario EuroQol 5-Dimension Questionnaire (versión de 5 niveles; EQ-5D-5L) puntuaciones basadas en índices y escala analógica visual (VAS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Age ≥ 18 years
    •Histologically- or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C, not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement
    •No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
    •Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment
    •Measurable systemic disease according to RECIST v1.1
    •Patients with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis, are eligible, provided that the patient is neurologically stable for at least 1 week prior to the first dose of study treatment
    •Life expectancy of at least 12 weeks
    •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
    •Adequate hematologic, renal, liver function
    •Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
    •Ability to comply with the study protocol, in the investigator’s judgment
    •Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
    •For women of childbearing potential: agreement to remain abstinent or use contraceptive methods during the treatment period and for up to 5 weeks after the last dose of entrectinib or for at least 90 days after the last dose of crizotinib
    •For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
    •Tener ≥ 18 años
    •Presentar CPNM avanzado o recurrente (estadio IIIB/C no susceptible de tratamiento radical) o metastásico (estadio IV), con diagnóstico confirmado histológica o citológicamente, portador de reordenamientos del gen ROS1 documentados.
    •No haber recibido previamente tratamiento con un inhibidor de la tirosina quinasa ROS1, quimioterapia u otro tratamiento sistémico para CPNM avanzado o recurrente (estadio IIIB/C no susceptible de tratamiento radical) o metastásico (estadio IV).
    •Está permitida la administración previa de radioterapia si han transcurrido más de 14 días desde la terminación del tratamiento y la aleatorización. En los pacientes que han recibido radioterapia cerebral, se deberá haber completado la radioterapia total del cerebro como mínimo 14 días antes y/o la radiocirugía estereotáctica como mínimo 7 días antes de iniciar el tratamiento con entrectinib
    •Enfermedad sistémica medible, de acuerdo con los criterios RECIST v1.1.
    •Los pacientes con lesiones en SNC medibles y no medibles, de acuerdo con los criterios RECIST v1.1, incluida carcinomatosis leptomeníngea, son elegibles, siempre que el paciente esté estable neurológicamente durante al menos 1 semana antes de la administración de la primera dosis del tratamiento del estudio
    •Esperanza de vida de al menos 12 semanas.
    •Estado funcional del Eastern Cooperative Oncology Group (ECOG) 0, 1 o 2

    •Adecuada función hematológica, renal y hepática.
    •Los pacientes se deben haber recuperado de los efectos de cualquier procedimiento de cirugía mayor o de una lesión traumática significativa, como mínimo, 28 días antes de que reciban la primera dosis del tratamiento del estudio.
    •Capacidad para cumplir con los requisitos del protocolo del estudio, de acuerdo con el criterio del investigador
    •Capacidad para tomar las cápsulas de entrectinib y crizotinib enteras, sin masticarlas, triturarlas ni abrirlas.
    •Las mujeres potencialmente fértiles deben comprometerse a practicar la abstinencia sexual de o a usar métodos anticonceptivos, durante el período de tratamiento y hasta 5 semanas después de la última dosis de entrectinib o como mínimo hasta 90 días después de la última dosis de crizotinib
    •Los varones deben comprometerse a practicar la abstinencia sexual o a usar métodos anticonceptivos, así como comprometerse a no donar semen.
    E.4Principal exclusion criteria
    •Current participation in another therapeutic clinical trial
    •Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
    •NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study medication
    •History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
    •History of prolonged QTc interval
    •History of additional risk factors for torsades de pointes
    •Peripheral sensory neuropathy ≥ Grade 2
    •Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
    •Previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
    •Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy
    •Active GI disease or other malabsorption syndrome that would reasonably impact drug absorption
    •History of prior therapy-induced pneumonitis
    •Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of study treatments
    •Known active infections that would interfere with the assessment of safety or efficacy of study treatments (bacterial, fungal or viral, including human immunodeficiency virus positive)
    •History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
    •Pregnant or lactating women
    •Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
    •Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study
    •Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry
    • Participación en otro ensayo clínico terapéutico en la actualidad
    •Tratamiento previo con un inhibidor de tirosina quinasa ROS1, quimioterapia u otro tratamiento sistémico para CPNM avanzado o recurrente (estadio IIIB/C no susceptible de tratamiento radical) o metastásico (estadio IV).
    • Presencia de toxicidades de grado ≥3 (exceptuando alopecia, fatiga, náuseas y pérdida de apetito), de acuerdo con los criterios NCI-CTCAE v5.0, que no hayan mostrado mejoría y se considere estrictamente que vayan a interferir en la medicación actual del estudio
    • Antecedentes recientes (en los 3 últimos meses) de insuficiencia cardíaca congestiva sintomática o fracción de eyección ≤ 50% observada durante el período de selección del estudio
    • Antecedentes de prolongación del intervalo QTc.
    •Antecedentes de factores de riesgo adicionales para torsades de pointes
    • Neuropatía periférica sensorial de grado ≥ 2.
    • Enfermedad pulmonar intersticial documentada, fibrosis intersticial o antecedentes de neumonitis inducida por inhibidores de tirosina quinasa.
    •Neoplasias malignas en los 3 últimos años (exceptuando carcinoma de piel basocelular tratado con intención curativa, carcinoma gastrointestinal (GI) precoz tratado con resección endoscópica, carcinoma in situ de cérvix o cualquier otro cáncer curado que se considere que no va a influir en la SLP y en la SG del CPNM actual.
    •Recuperación incompleta de cualquier intervención quirúrgica antes de iniciar el tratamiento del estudio que pudiera interferir en la evaluación de la seguridad o la eficacia.
    •Enfermedad GI activa u otros síndromes de malabsorción que pudieran afectar razonablemente a la absorción del fármaco.
    •Antecedentes de neumonitis inducida por una terapia previa.
    •Cualquier condición médica (en los 3 últimos meses) que pudiera interferir en la evaluación de la seguridad o la eficacia de los tratamientos del estudio.
    •Infecciones activas conocidas (bacterianas, micóticas o virales, incluyendo serología positiva para virus de inmunodeficiencia humana) que pudieran interferir en la evaluación de la seguridad o la eficacia de los tratamientos del estudio
    •Antecedentes de hipersensibilidad a cualquiera de los excipientes de la formulación de entrectinib y/o crizotinib

    •Mujeres embarazadas o en período de lactancia
    •Serología positiva confirmada para virus de inmunodeficiencia humana (VIH) o enfermedades
    relacionadas con el síndrome de inmunodeficiencia adquirida (SIDA).
    •Cualquier enfermedad o trastorno concomitante clínicamente significativo que pudiera interferir en el tratamiento, o viceversa, en el desarrollo del estudio o en la absorción de medicaciones orales o que, de acuerdo con la opinión del investigador principal, suponga un riesgo inaceptable para el paciente en este estudio
    •Cualquier situación psicológica, familiar, sociológica o geográfica que pudiera impedir el cumplimiento de los requisitos del protocolo del estudio y/o los procedimientos de seguimiento; estas situaciones se deben considerar con el paciente antes de su inclusión en el estudio
    E.5 End points
    E.5.1Primary end point(s)
    1.Progression-free survival (PFS) in patients with CNS metastases at baseline, defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by a blinded independent review committee (BIRC) using RECIST v1.1
    1) Supervivencia libre de progresión (SLP) en pacientes con metástasis en el SNC al inicio del estudio, definida como el tiempo desde la aleatorización hasta la primera progresión documentada de la enfermedad (extracraneal o intracraneal) o la muerte por cualquier causa, lo que ocurra primero, según lo determinado por un estudio independiente cegado. comité de revisión (BIRC) usando RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.Up to 7 years
    1.Hasta 7 años
    E.5.2Secondary end point(s)
    1.Progression-free survival in the CNS (CNS-PFS), defined as the time from randomization to the first documented disease progression in the CNS or death from any cause, whichever occurs first, as determined by the BIRC using RECIST v1.1
    2.Overall response rate (ORR), defined as the percentage of patients who attain CR or PR, as assessed by the BIRC and the investigator per RECIST v1.1
    3.Duration of response (DOR), defined as the time from when response (CR or PR) is first documented to disease progression or death, whichever occurs first, as assessed by the BIRC and the investigator per RECIST v1.1
    4.Progression-free survival (PFS), defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by the BICR and investigator using RECIST v1.1
    5.Overall survival (OS), defined as the time from randomization to death from any cause
    6.Impact on functioning, including health-related quality of life, using the Global Health Status/Quality of Life (GHS/QoL), the Physical Functioning (PF) and Role Function (RF) scores, as assessed by the EORTC QLQ-C30 and analyzed as a time to first and confirmed clinically meaningful deterioration
    7.Impact on lung cancer-specific symptoms, as assessed by the EORTC QLQ-LC13
    8.Objective response rate in the CNS (CNS-ORR), defined as the percentage of patients who attain CR or PR for lesions in the CNS, as determined by the BIRC per RECIST v1.1
    9.Duration of response in the CNS (CNS-DOR), defined as the time from when a CNS response (CR or PR) is first documented to disease progression in the CNS, as determined by the BIRC per RECIST v1.1
    10.Incidence, type, timing, relatedness and severity of AEs, including SAEs and AEs leading to dose modifications/interruptions, study drug withdrawal or death, as assessed by the investigator according to the NCI CTCAE v5.0
    11.Health utility from the EQ-5D-5L and pharmacoeconomic model
    1) Supervivencia libre de progresión en el SNC (SNC-SLP), definida como el tiempo desde la aleatorización hasta la primera progresión documentada de la enfermedad en el SNC o la muerte por cualquier causa, lo que ocurra primero, según lo determinado por el BIRC utilizando RECIST v1.1
    2.Tasa de respuesta general (ORR), definida como el porcentaje de pacientes que logran RC o PR, según la evaluación del BIRC y el investigador según RECIST v1.1
    3.Duración de la respuesta (DOR), definida como el tiempo desde que se documenta por primera vez la respuesta (RC o RP) hasta la progresión de la enfermedad o la muerte, lo que ocurra primero, según la evaluación del BIRC y el investigador según RECIST v1.1
    4) Supervivencia libre de progresión (SSP), definida como el tiempo desde la aleatorización hasta la primera progresión documentada de la enfermedad (extracraneal o intracraneal) o la muerte por cualquier causa, lo que ocurra primero, según lo determinado por el BICR y el investigador utilizando RECIST v1.1
    5. Supervivencia general (SG), definida como el tiempo desde la aleatorización hasta la muerte por cualquier causa
    Impacto en el funcionamiento, incluida la calidad de vida relacionada con la salud, utilizando las puntuaciones de Estado de salud global / Calidad de vida (GHS / QoL), Funcionamiento físico (PF) y Función de rol (RF), según la evaluación de EORTC QLQ- C30 y analizado como un tiempo hasta el primer y confirmado deterioro clínicamente significativo
    Impacto sobre los síntomas específicos del cáncer de pulmón, según la evaluación de la EORTC QLQ-LC13
    8. Tasa de respuesta objetiva en el SNC (SNC-ORR), definida como el porcentaje de pacientes que logran RC o RP por lesiones en el SNC, según lo determinado por el BIRC según RECIST v1.1
    9.Duración de la respuesta en el SNC (CNS-DOR), definida como el tiempo desde que se documenta por primera vez una respuesta del SNC (RC o PR) hasta la progresión de la enfermedad en el SNC, según lo determinado por el BIRC según RECIST v1.1
    Incidencia, tipo, momento, relación y gravedad de los EA, incluidos los EA y los EA que conducen a modificaciones / interrupciones de la dosis, retirada del fármaco del estudio o muerte, según la evaluación del investigador de acuerdo con NCI CTCAE v5.0
    11.Utilidad para la salud del modelo EQ-5D-5L y farmacoeconómico
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-10.Up to 7 years
    11.Baseline (Day 1), Week 4, Week 8, all subsequent visits (every 8 weeks), Post-progression visits on treatment in case of isolated CNS progression (every 8 weeks), Post-Treatment Visit / Safety Follow Up Visit (4 weeks after permanent treatment discontinuation)
    1-10 hasta 7 años
    11.Línea de base (día 1), semana 4, semana 8, todas las visitas posteriores (cada 8 semanas), visitas posteriores a la progresión en el tratamiento en caso de progresión aislada del SNC (cada 8 semanas), visita posterior al tratamiento / visita de seguimiento de seguridad (4 semanas después de la interrupción permanente del tratamiento)
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    CRIZOTINIB
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA47
    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
    China
    Guatemala
    Jordan
    Lebanon
    Russian Federation
    Turkey
    Croatia
    France
    Germany
    Greece
    Italy
    Netherlands
    Romania
    Slovakia
    Spain
    Sweden
    Switzerland
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur approximately 24 months after the last patient is enrolled.
    The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 7 years.
    final de este estudio es la fecha en que se produce el último paciente, la última visita (LPLV) o la fecha que se recibe el último punto de datos requerido para el análisis estadístico o el seguimiento de seguridad del último paciente,lo que ocurra más tarde.El final del estudio ocurrirá aproximadamente 24 meses después de que se inscriba al último paciente.Se espera que la duración total del estudio,desde la selección del primer paciente hasta el final del estudio,sea de aproximadamente7años.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    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: 176
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 44
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 220
    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)
    The Sponsor will offer continued access to entrectinib free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    El Promotor ofrecerá acceso continuo a entrectinib sin cargo a los pacientes elegibles de acuerdo con la Política Global de Roche sobre Acceso Continuo a Medicamentos en Investigación.
    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 Decision2021-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
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