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    Summary
    EudraCT Number:2013-002620-17
    Sponsor's Protocol Code Number:B7461001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2013-12-05
    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 number2013-002620-17
    A.3Full title of the trial
    Phase 1/2 study of PF-06463922 (an ALK/ROS1 tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer harboring specific molecular alterations.
    Estudio de fase 1/2 de PF-06463922 (un inhibidor de tirosina quinasa ALK/ROS1) en pacientes con cáncer de pulmón de células no pequeñas avanzado con ciertas alteraciones moleculares
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study with investigational drug PF-06463922 in patients with a specific type of advanced lung cancer
    Estudio con fármaco en investigación PF-06463922 en pacientes con un tipo específico de cáncer de pulmón
    A.4.1Sponsor's protocol code numberB7461001
    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 SponsorPfizer Inc, 235 East 42nd Street, New York, NY 10017
    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 supportPfizer Inc, 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York, NY
    B.5.3.3Post code10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 namePF-06463922
    D.3.2Product code PF-06463922
    D.3.4Pharmaceutical form 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 INNPF-06463922
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 namePF-06463922
    D.3.2Product code PF-06463922
    D.3.4Pharmaceutical form 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 INNPF-06463922
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 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 namePF-06463922
    D.3.2Product code PF-06463922
    D.3.4Pharmaceutical form 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 INNPF-06463922
    D.3.9.3Other descriptive namePF-06463922 Form 3 (acetic acid solvate)
    D.3.9.4EV Substance CodeSUB126819
    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
    Anaplastic Lymphoma Kinase (ALK)-positive (ALK+) or ROS oncogene 1 (ROS1)-positive (ROS1+) advanced non-small cell lung cancer (NSCLC).
    Cáncer de pulmón de células no pequeñas avanzado (NSCLC) quinasa de linfoma anaplásico (ALK)-positivo (ALK+) u oncogén 1 de ROS (ROS1)-positivo(ROS1+).
    E.1.1.1Medical condition in easily understood language
    a specific type of advanced lung cancer
    un tipo específico de cáncer de pulmón avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10066490
    E.1.2Term Progression of non-small cell lung cancer
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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
    This study has separate primary objectives for the two study portions: Phase 1 and Phase 2.
    Phase 1 study portion:
    To assess safety and tolerability of PF-06463922 as a single agent at increasing dose levels in patients with advanced ALK+ or advanced ROS1+ NSCLC in order to estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
    Phase 2 study portion:
    To evaluate overall (intra- and extra-cranial) and intracranial anti-tumor activity of single-agent PF-06463922 at RP2D in patients with advanced ALK+ NSCLC and advanced ROS1+ NSCLC.
    Este estudio tiene objetivos primarios diferentes para las dos partes del estudio: Fase 1 y Fase 2.
    Parte Fase 1 del estudio:
    Valorar la seguridad y la tolerabilidad del PF-06463922 como agente único a mayores niveles de dosis en pacientes con NSCLC ALK+ avanzado o ROS1+ avanzado con el fin de estimar la Dosis Máxima
    tolerada (MTD) y seleccionar la Dosis Recomendada para la Fase 2 (RP2D).
    Parte Fase 2 del estudio:
    Evaluar la actividad antitumoral general (intra y extracraneal) e intracraneal del PF-06463922 como agente único a la RP2D en pacientes con NSCLC ALK+ avanzado y NSCLC ROS1+ avanzado.
    E.2.2Secondary objectives of the trial
    Please refer to study protocol to ckeck separate secondary objectives for the two study portions Phase 1 and Phase 2.
    Por favor, consulte el protocolo del estudio para revisar los objetivos secundarios, diferentes para las dos partes Fase 1 y Fase 2 del estudio.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - During the Phase 1 portion of the study, a midazolam (MDZ) drug-drug interaction (DDI) substudy will be conducted at 3 to 4 PF-06463922 dose levels to evaluate the effect of PF-06463922 on CYP3A inhibition/ induction.
    - During the Phase 2 portion of the study, a MDZ DDI substudy and a food effect substudy will be conducted at the Recommended Phase 2 Dose (RP2D) in advanced ALK+ NSCLC patients.
    - Durante la Fase 1 del estudio, se realizará un subestudio de interacción fármaco-fármaco (IFF) del midazolam (MDZ) en 3 a 4 niveles de dosis de PF-06463922 para evaluar el efecto del PF-06463922 en la inhibición/inducción de CYP3A.
    - Durante la Fase 2 del estudio, se llevará a cabo un subestudio de interacción fármaco-fármaco (IFF) del midazolam (MDZ) y un subestudio de la interacción de la comida a la RP2D en pacientes con NSCLC ALK+ avanzado.
    E.3Principal inclusion criteria
    1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA)-approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT-PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). A central laboratory confirmation by a Sponsor-selected, validated test will retrospectively determine final ROS1 status. All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
    2. ALK+ NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after 1 or 2 previous ALK inhibitor therapy(ies), as the last therapy given. ROS1+ NSCLC patients must either be treatment naïve in the advanced setting or have had disease progression after 1 or 2 previous ROS1 inhibitor therapy(ies), as the last therapy given.
    3. Tumor Requirements:
    Phase 1: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are not eligible to entry in the Phase 1.
    Phase 2: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients controlled with stable or decreasing steroid use within the last 2 weeks prior to study entry) will be eligible. The brain metastases may be newly diagnosed or be present as progressive disease after surgery, whole brain radiotherapy or stereotactic radiosurgery (see Exclusion Criterion #3 for the lapsed time period required between the end of radiotherapy and study entry). Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on MRI or if documented baseline cerebral spinal fluid (CSF) positive cytology is available.
    4. Age ?18 years.
    5. ECOG Performance Status (PS):
    - Phase 1: 0 or 1;
    - Phase 2: 0, 1, or 2.
    6. Adequate Bone Marrow Function, including:
    - Absolute Neutrophil Count (ANC) ?1.5 x 109/L;
    - Platelets ?100 x 109/L;
    - Hemoglobin ?9 g/dL.
    7. Adequate Pancreatic Function, including:
    - Serum amylase (pancreatic isoenzyme) ?1.5 upper limit of normal (ULN);
    - Serum lipase ?1.5 ULN.
    8. Adequate Renal Function, including:
    - Serum creatinine ?1.5 x ULN or estimated creatinine clearance ?60 mL/min as calculated using the method standard for the institution.
    9. Adequate Liver Function, including:
    - Total serum bilirubin ?1.5 x ULN;
    - Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ?2.5 x ULN; ?5.0 x ULN if there is liver metastases involvement;
    - Alkaline phosphatase ?2.5 x ULN (?5 x ULN in case of bone metastasis).
    10. Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade ?1 except for AEs that in the investigator? judgment do not constitute a safety risk for the patient.
    11. Serum pregnancy test (for females of childbearing potential) negative at screening and at the baseline visit (before the patient may receive the investigational product). A patient is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active.
    12. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
    13. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

    For more inclusion criteria refer to the protocol.
    1. Evidencia de diagnóstico histológica o citológicamente confirmado de
    NSCLC localmente avanzado o metastásico (Etapa IV, AJCC v7.0) que
    incorpora un reordenamiento de ALK, según lo determinado por el
    ensayo FISH aprobado por la FDA (Abbott Molecular Inc) o por
    Inmunohistoquímica (IHC) (Ventana Inc), o un reordenamiento de ROS1
    según lo determinado por FISH o RT-PCR o Secuenciación de última
    generación (NGS) mediante una prueba de diagnóstico local (LDT). La
    confirmación de un laboratorio central mediante una prueba validada
    seleccionada por el Patrocinador determinará retrospectivamente el
    estado ROS1 final. Se debe recoger una muestra disponible de tejido de
    todos los pacientes (ALK positivo y ROS1 positivo) para archivo antes de
    la inscripción
    2. Pacientes con NSCLC ALK+ deben o bien no haber recibido tratamiento previo en el entorno avanzado o haber tenido un avance de la enfermedad después de 1 o 2 terapias anteriores con un inhibidor de ALK como la última terapia administrada. Pacientes con NSCLC ROS1+ deben o bien no haber recibido tratamiento previo en el entorno avanzado o haber tenido un avance de la enfermedad después de 1 ó 2 terapias anteriores con un inhibidor de ROS1 como la última terapia administrada
    3. Requisitos tumorales:
    Fase 1: todos los pacientes deben tener al menos una lesión extracraneal
    objetivo mesurable según RECIST v1.1. También serán elegibles los
    pacientes con metástasis asintomáticas en el SNC (incluyendo pacientes
    asintomáticos por medio de dosis estables o decrecientes de esteroides
    en las últimas 2 semanas anteriores a la entrada en el estudio). Las
    metástasis en el cerebro pueden ser recientemente diagnosticadas o
    estar presentes como enfermedad progresiva después de cirugía,
    radioterapia cerebral completa o radiocirugía estereotáctica (véase el
    Criterio de exclusión nº 3 respecto al tiempo transcurrido requerido
    entre el final de la radioterapia y la entrada en el estudio). Los pacientes
    con enfermedad leptomeníngea (LM) o meningitis carcinomatosa (MC)
    no son elegibles para entrar en la Fase 1
    Fase 2: todos los pacientes deben tener al menos una lesión extracraneal
    objetivo mesurable según RECIST v1.1. También serán elegibles los
    pacientes con metástasis asintomáticas en el SNC (incluyendo pacientes
    controlados con uso estable o decreciente de esteroides en las últimas 2
    semanas anteriores a la entrada en el estudio). Las metástasis en el
    cerebro pueden ser recientemente diagnosticadas o estar presentes
    como enfermedad progresiva después de cirugía, radioterapia cerebral
    completa o radiocirugía estereotáctica (véase el Criterio de exclusión nº
    3 respecto al tiempo transcurrido requerido entre el final de la
    radioterapia y la entrada en el estudio). Los pacientes que tienen
    enfermedad leptomeníngea (LM) o meningitis carcinomatosa (MC) serán
    elegibles si la LM/MC se visualiza en una RM o si hay disponible una
    citología positiva documentada de líquido cefalorraquídeo (LCR) como
    línea de base.
    4. Edad ?18 años
    5. Estado según ECOG (PS):
    ? Fase 1: 0 o 1
    ? Fase 2: 0, 1 o 2
    6. Función adecuada de la médula ósea, incluyendo:
    ? Recuento absoluto de neutrófilos (RAN) ?1.5 x 109/L
    ? Plaquetas ?100 x 109/L
    ? Hemoglobina ?9 g/dl
    7. Función pancreática adecuada, incluyendo:
    ? Amilasa sérica (isoenzima pancreática) ?1,5 límite superior de la
    normalidad (LSN)
    ? Lipasa sérica ?1,5 LSN
    8. Función renal adecuada, incluyendo:
    ? Creatinina sérica ?1,5 veces LSN o depuración estimada de creatinina
    ?60 ml/min según lo calculado usando el método estándar para la
    institución
    9. Función hepática adecuada, incluyendo:
    ? Bilirrubina sérica total ?1,5 veces LSN
    ? Aspartato-aminotransferasa (ASAT) y alanina-aminotransferasa
    (ALAT) ?2,5 veces LSN; ?5,0 veces LSN si existe compromiso por
    metástasis hepáticas
    ? Fosfatasa alcalina ?2,5 veces LSN (?5 veces LSN en caso de
    metástasis ósea)
    10. Efectos agudos de cualquier terapia anterior resueltos según la
    gravedad inicial o según el Grado ?1 de la clasificación CTCAE salvo AE
    que a juicio del investigador no constituyan un riesgo de seguridad para
    el paciente
    11. Prueba de embarazo en suero (para mujeres fértiles) negativa en la selección y en la visita inicial (antes de que la paciente pueda recibir el
    producto bajo investigación). Una paciente tiene el potencial de ser fértil si, en opinión del investigador, es biológicamente capaz de tener hijos y mantiene relaciones sexuales
    12. Evidencia de un documento de consentimiento personalmente
    firmado y fechado que indique que el paciente ha sido informado de
    todos los aspectos pertinentes del estudio
    13. Voluntad y capacidad de cumplir con las visitas, planes de
    tratamiento, pruebas de laboratorio y otros procedimientos programados del estudio

    Por favor, consulte el protocolo del estudio para comprobar más criterios
    de inclusión
    E.4Principal exclusion criteria
    1.Spinal cord compression is excluded unless the patient demonstrates good pain control attained through therapy and there is stabilization or recovery of neurological function for the 4 weeks prior to study entry
    2.Major surgery within 4 weeks of study entry.Minor surgical procedures are not excluded but sufficient time should have passed for wound healing
    3.Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry.Palliative radiation (?10 fractions) must have been completed at least 48 hours prior to study entry.Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry.Whole brain radiation must have completed at least 4 weeks prior to study entry
    4.Systemic anti-cancer therapy completed within 2 weeks or 5 half-lives of study entry
    5.Previous high-dose chemotherapy requiring stem cell rescue
    6.Prior irradiation to >25% of the bone marrow
    7.Active and clinically significant bacterial, fungal, or viral infection including HBV, HCV, known HIV or AIDS-related illness
    8.Any one of the following currently or in the previous 3 months: myocardial infarction,congenital long QT syndrome,Torsades de Pointes,arrhythmias,right bundle branch block and left anterior hemiblock (bifascicular block),unstable angina,coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident,transient ischemic attack or symptomatic pulmonary embolism not adequately medically managed with anticoagulants;as well as bradycardia defined as <50 bpms.Ongoing cardiac dysrhythmias of NCI CTCAE Grade ?2,symptomatic atrial fibrillation of any grade,or QTc interval ?481 msec at screening.Right bundle branch block
    9.Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (see protocol for more details).
    10.History of extensive,disseminated,bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersentivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis. Patients with history of prior radiation pneumonitis are not excluded
    11.Participation in other studies within 2 weeks prior to study entry
    12.Other severe acute or chronic medical or psychiatric condition,including recent (within the past year) or active suicidal ideation or behavior,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 entry into this study
    13.Patients who are investigational site staff members directly involved in the conduct of the trial and their family members,site staff members otherwise supervised by the Investigator,or patients who are Pfizer employees directly involved in the conduct of the trial
    14.Evidence of active malignancy within the last 3 years. See protocol for more details
    15.Active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease or previous gastric resection or lap band. Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed

    For more exclusion criteria refer to the protocol.
    1. La compresión de médula espinal está excluida a no ser que el
    paciente demuestre que se ha logrado un buen control del dolor
    mediante terapia y que existe estabilización o recuperación de la función neurológica durante las 4 semanas anteriores a la entrada en el estudio
    2. Cirugía importante en un plazo de 4 semanas de la entrada en el
    estudio. Los procedimientos quirúrgicos de importancia menor (como la
    inserción de un catéter) no están excluidos, pero debería haber
    transcurrido suficiente tiempo (es decir, hasta dos semanas) para la
    curación de las heridas
    3. Terapia de radiación (salvo terapia paliativa para aliviar el dolor óseo) en un plazo de 2 semanas de la entrada en el estudio. La radiación paliativa (?10 fracciones) debe haberse completado al menos 48 horas antes de la entrada en el estudio. La radiación cerebral estereotáctica o de campo pequeño debe haberse completado en un plazo de como mínimo 2 semanas antes de la entrada en el estudio. La radiación cerebral completa debe haberse completado como mínimo 4 semanas antes de la entrada en el estudio
    4. Terapia sistémica anticáncer completada en un plazo de 2 semanas o
    5 semividas (lo que dure más) de la entrada en el estudio
    5. Quimioterapia anterior de alta dosis que requiera rescate de células
    madre
    6. Radiación anterior hasta >25% de la médula ósea (véase el Anexo 5
    Reserva de médula ósea en adultos)
    7. Infección activa y clínicamente significativa por bacterias, hongos o
    virus, incluyendo hepatitis B (VHB), hepatitis C (VHC), virus conocido de
    la inmunodeficiencia humana (VIH) o enfermedad relacionada con el
    síndrome de la inmunodeficiencia adquirida (SIDA)
    8. Cualquiera de los siguientes en la actualidad o en los 3 meses
    anteriores: infarto de miocardio, síndrome de QT prolongado congénito, Torsades de Pointes, arritmias (incluyendo taquicardia ventricular y fibrilación ventricular sostenidas), bloqueo de rama derecha de haz y hemibloqueo anterior izquierdo (bloqueo bifascicular), angina inestable, injerto de derivación de arteria coronaria/periférica, insuficiencia cardíaca congestiva sintomática (ICC Clase III o IV según la NY Heart Association), accidente cerebrovascular, ataque isquémico transitorio o embolismo pulmonar sintomático no gestionado médicamente de manera adecuada con anticoagulantes; así como bradicardia definida como <50 bpms. Trastornos continuos del ritmo cardíaco según la clasificación
    CTCAE Grado ?2 del NCI, fibrilación atrial sintomática de cualquier grado o intervalo QTc ?481 mseg durante la selección. Bloqueo de rama derecha de haz
    9. Pacientes con predisposición a pancreatitis aguda a juicio del
    investigador (como hiperglicemia no controlada, enfermedad actual de
    cálculos biliares, alcoholismo [más de 4 bebidas en cualquier día o 14
    bebidas a la semana donde una bebida se define como una bebida
    alcohólica que contiene aproximadamente 14 gramos de alcohol puro, p. ej. 12 fl oz/360 ml de cerveza regular o 5 fl oz/150 ml de vino] en el
    último mes
    10. Historial de fibrosis intersticial o enfermedad intersticial de los
    pulmones extensa, diseminada, bilateral o de Grado 3 o 4 incluyendo
    historial de neumonitis, neumonitis con hipersensibilidad, neumonía
    intersticial, enfermedad pulmonar intersticial, bronquiolitis obliterante y fibrosis pulmonar. Pacientes con historial de neumonitis anterior
    con radiación no están excluidos
    11. Participación en otros estudios en un plazo de 2 semanas antes de la
    entrada en el estudio
    12. Otra condición médica o psiquiátrica aguda o crónica severa,
    incluyendo pensamientos o conducta suicida reciente (en el último año)
    o activa, o anormalidad de laboratorio que pueda aumentar el riesgo
    asociado con la participación en el estudio o la administración del
    producto bajo investigación o pueda interferir con la interpretación de
    los resultados del estudio y, a juicio del investigador, haría que el
    paciente fuera inapropiado para entrar en este estudio
    13. Los pacientes que son miembros del personal del centro de
    investigación directamente involucrados en la realización del ensayo y
    sus familiares, los miembros del personal del centro que estén de otro
    modo bajo la supervisión del Investigador o los pacientes que sean
    empleados de Pfizer y que estén directamente involucrados en la
    realización del ensayo
    14. Evidencia de malignidad activa (salvo NSCLC actual, cáncer de piel
    sin melanoma, cáncer cervical in situ, cáncer tiroidal papilar, CDIS de
    mama o localizado y cáncer de próstata supuestamente curado) en los
    últimos 3 años
    15. Enfermedad gastrointestinal inflamatoria activa, diarrea crónica,
    enfermedad diverticular sintomática o resección gástrica o banda
    gástrica previas. La enfermedad por reflujo gastroesofágico bajo
    tratamiento con inhibidores de la bomba de protones está permitida
    (asumiendo que no exista potencial de interacción de fármacos)

    Por favor, consulte el protocolo del estudio para comprobar más criterios de exclusión
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1 Primary Endpoint:
    - Cycle 1 Dose-Limiting Toxicities (DLTs).
    Phase 2 Primary Endpoint:
    - Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. In patients with asymptomatic CNS metastases, up to five (5) intracranial target lesions in addition to the five (5) extracranial target lesions will be assessed.
    Criterio de valoración principal en la Fase 1:
    - Toxicidades limitadoras de la dosis (DLT)
    Criterio de valoración principal en la Fase 2:
    Respuesta objetiva a los tumores, según lo valorado por los Criterios de evaluación de respuesta en tumores sólidos (RECIST), versión 1.1. En pacientes con metástasis asintomáticas en el SNC, se evaluarán hasta cinco (5) lesiones intracraneales objetivo además de las cinco (5) lesiones extracraneales objetivo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 Primary Endpoint:
    - Cycle 1 Dose-Limiting Toxicities (DLTs): cycle 1.
    Phase 2 Primary Endpoint:
    - Objective tumor response: at baseline and at the stipulated intervals during treatment.
    Please refer to Schedule of Activities of the protocol.
    Criterio de valoración principal en la Fase 1:
    - Toxicidades limitadoras de la dosis (DLT): Ciclo 1.
    Criterio de valoración principal en la Fase 2:
    - Respuesta objetiva a los tumores: al inicio del estudio y a los intervalos estipulados durante el tratamiento.
    Por favor refiérase al Cronograma de Actividades del protocolo.
    E.5.2Secondary end point(s)
    Secondary Endpoints [all patients unless otherwise indicated]:
    - MTD and RP2D [Phase 1 only].
    - Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing.
    - Vital Signs (heart rate, blood pressure).
    - Total Mini Mental State Examination Score.
    - Pharmacokinetic parameters of PF-06463922: Single Dose - Cmax, Tmax, AUClast,AUC t, CL/F, and Vz/F and t1/2, AUCinf as data permit. Multiple Dose (assuming steady-state is achieved) - Css,max, Tss,max, AUCss,t, t1/2, Css,min, Css,av, CL/F, Vss/F, Rac (AUCss,t/AUCsd,t) and Rss (AUCss,t/AUCsd,inf) as data permit. Urine PK parameters (Ae%, and CLR) of PF-06463922 from MDZ and food effect substudy.
    - Pharmacokinetic parameters of midazolam: Cmax, Tmax, AUClast, CL/F, and Vz/F and t1/2, AUCinf as data permit.
    - Patient reported functioning and impact on disease/treatment-related symptoms of lung cancer and global QOL.
    - QTc interval.
    - Time-to-event endpoints: eg, Duration of Response (DR), Progression-Free Survival (PFS), Overall Survival (OS).
    - CTC enumeration and molecular characterization.
    - Selected molecular profiling of tumor tissue, eg, ALK kinase domain mutations.
    - Selected molecular profiling of Circulating Nucleic Acid (CNA), eg, ALK kinase domain mutations.
    - CSF concentration of PF-06463922.
    Criterios de valoración secundarios [todos los pacientes salvo que se indique lo contrario]:
    - MTD y RP2D [solo Fase 1].
    - Eventos adversos caracterizados por tipo, frecuencia, severidad (según la clasificación CTCAE v.4.03 del NCI), momento, gravedad y relación con la terapia del estudio.
    - Anormalidades de laboratorio por tipo, frecuencia, severidad (según la clasificación CTCAE v.4.03 del NCI) y momento.
    - Fracción de eyección del ventrículo izquierdo (FEVI).
    - Signos vitales (frecuencia cardíaca, presión arterial).
    - Puntuación total del Miniexamen de estado mental.
    - Parámetros farmacocinéticos del PF-06463922: Dosis única - Cmáx, Tmáx, AUCult, AUCt, CL/F y Vz/F y t1/2, AUCinf según lo permitan los datos. Dosis múltiple (asumiendo que se logre un estado estable) - Css,máx, Tss,máx, AUCss,t, t1/2, Css,mín, Css,prom, CL/F, Vss/F, Rac
    (AUCss,t/AUCsd,t) y Rss (AUCss,t/AUCsd,inf) según lo permitan los datos. Parámetros PK de orina (%AE y CLR) del PF-06463922 del subestudio de MDZ y sobre el efecto de la comida.
    - Parámetros farmacocinéticos del midazolam: Cmáx, Tmáx, AUCult, CL/F y Vz/F y t1/2, AUCinf según lo permitan los datos.
    - Funcionamiento notificado de los pacientes e impacto de los síntomas relacionados con la enfermedad/el tratamiento del cáncer de pulmón y QOL global.
    - Intervalo QTc.
    - Tasa de control de la enfermedad (DCR) a las 6 y 12 semanas definida como el porcentaje de pacientes con una respuesta completa (CR), una respuesta parcial (PR) o una enfermedad estable (SD) confirmadas según RECIST 1.1, a las 6 y 12 semanas respectivamente [solo Fase 2].
    - Criterios de valoración de tiempo transcurrido hasta el evento: p. ej. duración de la respuesta (DR), supervivencia libre de avance (PS), supervivencia general (OS).
    - Enumeración de CTC y caracterización molecular.
    - Ciertos perfiles moleculares de tejido tumoral, p. ej. mutaciones del dominio quinasa ALK.
    - Ciertos perfiles moleculares de ácido nucleico circulante (ANC) p. ej. mutaciones del dominio quinasa ALK.
    - Concentración de líquido cefalorraquídeo (LCR) del PF-06463922.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to Schedule of Activities of the protocol.
    Por favor refiérase al Cronograma de Actividades del protocolo.
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To characterize the effect of food on single-agent PF-06463922 at the RP2D (ALK+NSCLC patients only) in the Phase 2 Portion of the Study.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Poland
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    United Kingdom
    United States
    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
    In a Member State of the European Union: time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory and ethics applications (ie, CTA) in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
    End of Trial in all other participating countries: 18 months after Last Patient First Visit (LPFV)
    En un estado miembro de la Unión Europea: momento en que se considera que suficientes pacientes se han reclutado y han completado el estudio según lo indicado en las solicitudes regulatorias y de ética (como CTA) en el estado miembro. Un bajo reclutamiento en un estado miembro no es motivo de terminación prematura sino una conclusión normal del estudio en dicho estado miembro
    En todos los demás países participantes: 18 meses después de la Primera visita del último paciente (LPFV)
    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 months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 78
    F.4.2.2In the whole clinical trial 200
    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)
    Patients may continue PF-06463922 treatment after objective progression of disease is determined if the patient is continuing to experience clinical benefit, in the opinion of the investigator, and after discussion with the Sponsor.
    Los pacientes pueden continuar el tratamiento con PF-06463922 después de que se determine un avance objetivo de la enfermedad si el paciente continúa experimentando un beneficio clínico, en la opinión del investigador, y tras discusión con el Patrocinador.
    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 Decision2014-03-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-24
    P. End of Trial
    P.End of Trial StatusRestarted
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