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    Summary
    EudraCT Number:2017-004246-20
    Sponsor's Protocol Code Number:LOXO-EXT-17005
    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:2018-02-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-004246-20
    A.3Full title of the trial
    A Phase 1/2 Study of the TRK Inhibitor LOXO-195 in Adult and Pediatric Subjects with Previously Treated NTRK Fusion Cancers
    Estudio en fase I/II del inhibidor de la actividad de la TRK LOXO-195 en pacientes adultos y pediátricos que padezcan un cáncer portador de genes de fusión NTRK tratado previamente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 1/2 study of the investigational treatment LOXO-195 in adults and minors that have a previously treated cancer with a change in a gene called NTRK.
    Un estudio de fase 1/2 del tratamiento de investigación LOXO-195 en adultos y menores que tienen un cáncer previamente tratado con un cambio en un gen llamado NTRK.
    A.4.1Sponsor's protocol code numberLOXO-EXT-17005
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03215511
    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 SponsorLoxo Oncology, 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 supportLoxo Oncology Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace Spain S.L.
    B.5.2Functional name of contact pointMónica Bermejo
    B.5.3 Address:
    B.5.3.1Street AddressAgustín de Foxa 29. 8ª Planta
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28036
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491790056525854
    B.5.5Fax number+34900981853
    B.5.6E-mailSpain.Regulatory@medpace.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 nameLOXO-195
    D.3.2Product code LOXO-195
    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 INNnot available
    D.3.9.1CAS number 2097002-61-2
    D.3.9.2Current sponsor codeLOXO-195
    D.3.9.3Other descriptive nameLOXO-195
    D.3.9.4EV Substance CodeSUB189790
    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: 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 nameLOXO-195
    D.3.2Product code LOXO-195
    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 INNnot available
    D.3.9.1CAS number 2097002-61-2
    D.3.9.2Current sponsor codeLOXO-195
    D.3.9.3Other descriptive nameLOXO-195
    D.3.9.4EV Substance CodeSUB189790
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 nameLOXO-195
    D.3.2Product code LOXO-195
    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 INNnot available
    D.3.9.1CAS number 2097002-61-2
    D.3.9.2Current sponsor codeLOXO-195
    D.3.9.3Other descriptive nameLOXO-195
    D.3.9.4EV Substance CodeSUB189790
    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: 4
    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 nameLOXO-195
    D.3.2Product code LOXO-195
    D.3.4Pharmaceutical form Powder for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNnot available
    D.3.9.1CAS number 2097002-61-2
    D.3.9.2Current sponsor codeLOXO-195
    D.3.9.3Other descriptive nameLOXO-195
    D.3.9.4EV Substance CodeSUB189790
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(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.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
    NTRK fusion cancers previously treated with a TRK inhibitor
    Cánceres con fusión NTRK previamente tratados con un inhibidor de TRK
    E.1.1.1Medical condition in easily understood language
    Solid tumors of all type, including primary CNS tumors
    Tumores sólidos de todo tipo, incluidos tumores primarios del SNC
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10049516
    E.1.2Term Malignant tumor
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10007958
    E.1.2Term Central nervous system neoplasm
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1:
    To determine the recommended dose for further study of oral LOXO-195 in 2 patient groups defined as age 12 and older and age < 12 with previously treated NTRK fusion cancers.
    Phase 2:
    To assess ORR by RECIST v1.1, as determined by independent radiology review in documented NTRK fusion cancer patients previously treated with a TRK inhibitor who have progressed.
    Fase 1:
    Determinar la dosis recomendada para el estudio posterior de LOXO 195 oral en dos grupos de pacientes, definidos como pacientes de 12 años de edad y en adelante y pacientes de menos de 12 años de edad que padezcan un cáncer portador de genes de fusión NTRK tratado previamente.
    Fase 2:
    Evaluar la TRG con los RECIST v. 1.1, determinada por una revisión radiológica independiente, en pacientes que padezcan un cáncer portador de genes de fusión NTRK documentado y tratado previamente con un inhibidor de la TRK que haya progresado.
    E.2.2Secondary objectives of the trial
    Phase 1:
    To characterize the PK properties of LOXO-195.
    To characterize the safety and tolerability of LOXO-195.
    To assess overall response rate (ORR) according to best response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as determined by independent radiology review, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor.
    To assess the ORR determined by the treating Investigator using Response Assessment in Neuro-Oncology (RANO) in patients with primary CNS malignancies with NTRK fusion.
    Phase 2:
    To characterize the safety and tolerability of LOXO-195 at the RP2D in patients age 12 and older and patients age < 12.
    To assess ORR determined by RECIST v1.1 or RANO as appropriate
    To assess additional parameters including:Duration of response (DOR), Progression-free survival (PFS), Overall survival (OS), Clinical benefit rate (CBR).
    Fase I
    Caracterizar las propiedades FC de LOXO-195
    Caracterizar la seguridad y la tolerabilidad de LOXO-195
    Evaluar la tasa de respuesta global (TRG) de acuerdo con la mejor respuesta, mediante la RECIST v. 1.1, determinada por una revisión radiológica independiente, en pacientes con un cáncer portador de genes de fusión NTRK documentado y tratado previamente con un inhibidor de TRK
    Evaluar la TRG, determinada por el investigador responsable del tratamiento mediante RANO, Response Assessment in Neuro-Oncology en pacientes que padezcan neoplasias malignas primarias del sistema nervioso central (SNC) portadoras de genes de fusión NTRK
    Fase 2
    Caracterizar la seguridad y la tolerabilidad de LOXO-195 de la dosis recomendada para la fase II (DRFII) en pacientes de 12 años de edad y en adelante y en pacientes < 12 años
    Evaluar la TRG, mediante RECIST v. 1.1 o RANO (lo que corresponda)
    Evaluar parámetros adicionales del beneficio clínico para los pacientes incluyendo:DR,SSP,SG, IBC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Advanced solid tumor for which, in the opinion of the Investigator, no other standard therapy offers greater benefit.
    2.A solid tumor diagnosis in the setting of:
    a.a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor
    b.a documented NTRK fusion unresponsive to a prior TRK inhibitor
    c.a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
    3.NTRK (NTRK1, NTRK2, and NTRK3) gene fusions will be identified in a CLIA certified (or equivalent) laboratory.
    4.Performance Status: Eastern Cooperative Oncology Group (ECOG) score 3 (age 16) or Lansky Performance Score (LPS) 40% (age 16). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) (age 16) or LPS (age 16) 50%.
    5.Evaluable and/or measurable disease by RECIST v1.1 or RANO.
    6.Life expectancy 4 weeks.
    7.At least 1 month of age.
    8.Tissue submission. Samples from 2 timepoints are required if available
    9.Adequate hematologic function, for patients without known bone marrow involvement, defined as:
    a.Hemoglobin (Hb) ≥ 8.0 g/dL
    b.Absolute neutrophil count (ANC) ≥ 1.0 × 109 /L
    c.Platelets (Plt) ≥ 100 × 109 /L without need for regular transfusion support
    Patients with known bone marrow involvement will not be evaluable for hematologic DLT and can enroll with:
    a.Hb ≥ 8.0 g/dL (transfusions allowed)
    b.ANC ≥ 0.75 × 109 /L
    c.Plt ≥ 50 × 109 /L (transfusions allowed)
    10.Adequate hepatic function defined as:
    a.AST and ALT ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN if in the setting of liver metastases
    b.Total bilirubin ≤1.5 × ULN or ≤3 × ULN if in the setting of liver metastases or Gilbert's disease; patients with higher total bilirubin levels due to Gilbert's disease or hepatic metastases may be enrolled with Sponsor approval
    11.For patients age 18 and older: Adequate renal function defined as serum creatinine ≤2.0 or estimated glomerular filtration ≥ 30 mL/min using Crockroft-Gault formula.
    For patients up to age 18: Estimated glomerular filtration rate ≥ 30 mL/minute/1.73 m2 based on local institutional practice for determination OR a serum creatinine based on age/gender
    12.At least 5 half-lives since most recent kinase inhibitor dose OR at least 7 days since last systemic anticancer therapy (whichever is shorter) and recovered to baseline from all toxicity of last cytotoxic chemotherapy dose. Alopecia and other non-acute toxicities are acceptable.
    13.Patients with stable CNS primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of LOXO-195 and there has been no change in steroid dose, if taking steroids to manage CNS symptoms, for 7 days prior to the first dose of LOXO-195. The patient can be receiving any dose of steroids is as long as dosing meets specifications noted above.
    14.Negative serum pregnancy test prior to C1D1 study drug if a woman of child-bearing age. Pregnancy test are not required for pre-pubertal (Tanner 1) girls. A post-menopausal woman will be defined as having no menses for 12 months without an alternative medical cause.
    15.Agreement to adequate contraception in male and female patients with reproductive potential for the duration of treatment and for 6 months following study completion.
    16.Ability to swallow capsules or liquid solution orally or receive liquid enterally via a naso- or gastro-feeding tube, and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
    17.Parent/guardian of child or adolescent subjects has the ability to understand, agree to, and sign the study ICF and applicable Pediatric Assent Form before initiation of any protocol related procedures; subject has the ability to give assent, as applicable, at the time of parental/guardian consent.
    1.Tumor sólido en estadio avanzado para el que, a juicio del investigador, ningún otro tratamiento de referencia ofrece un beneficio mayor.
    2.Diagnóstico de la presencia de un tumor sólido, en las situaciones siguientes:
    a.Presencia documentada de un tumor con gen de fusión NTRK y antecedentes médicos de recidiva después de una respuesta a un inhibidor de la TRK previo.
    b.Presencia documentada de un tumor con gen de fusión NTRK que no respondió a un inhibidor de la TRK previo.
    c.Presencia documentada de un tumor con gen de fusión NTRK y antecedentes médicos de intolerancia a un inhibidor de la TRK previo.
    3.Los genes de fusión NTRK (NTRK1, NTRK2 y NTRK3) se identificarán en un laboratorio con certificación CLIA (o equivalente).
    4.Estado funcional: estado funcional del grupo oncológico cooperativo del este (Eastern Cooperative Oncology Group, ECOG) de 3 (16 años de edad) o estado funcional de Lansky (Lansky Performance Score, LPS) 40 % (16 años). Si se incluye a un paciente con un tumor primario del SNC que deba evaluarse con los criterios RANO, estado funcional de Karnofsky (Karnofsky Performance Score, KPS) (16 años de edad) o LPS (16 años de edad) del 50 %.
    5.Enfermedad evaluable o cuantificable con los criterios RECIST v.1.1 o RANO.
    6.Esperanza de vida de 4 semanas.
    7.Tener al menos 1 mes de edad.
    8.Envío de muestra tumoral. Si se dispone de ellas, son necesarias muestras de dos puntos temporales.
    9.Función hemática adecuada, en el caso de los pacientes de los que se sepa que no existe afectación de la médula ósea, definida como:
    a.Hemoglobina (Hb) ≥ 8,0 g/dl.
    b.Recuento absoluto de neutrófilos (RAN) ≥ 1,0 × 109/l.
    c.Plaquetas (Plt) ≥ 100 × 109/l, que no precise el refuerzo con transfusiones periódicas.
    Los pacientes con una afectación conocida de la médula ósea no serán evaluables en la TLD hemática y pueden incluirse con:
    a.Hb ≥ 8,0 g/dl (se permite la transfusión)
    b.RAN ≥ 0,75 × 109/l
    c.Plt ≥ 50 × 109/l (se permite la transfusión)
    10.Función hepática adecuada, definida como:
    a.Concentraciones de aspartato-aminotransferasa (ASAT) y alanina-aminotransferasa (ALAT) ≤ 2,5 × límite superior de la normalidad (LSN) o ≤ 5 × LSN en presencia de metástasis hepáticas.
    b.Bilirrubina total ≤1,5 × LSN o ≤3 × LSN en presencia de metástasis hepáticas o enfermedad de Gilbert; los pacientes con una concentraciones de bilirrubina totales superiores, debidas a la enfermedad de Gilbert o a las metástasis hepáticas, podrían participar en el estudio con la autorización del Promotor.
    11.En el caso de pacientes de 18 años de edad y en adelante: función renal adecuada, definida como creatinina sérica ≤2,0 o una tasa de filtración glomerular estimada de ≥30 ml/min según la fórmula de Crockroft-Gault.
    En el caso de pacientes de hasta 18 años de edad: tasa de filtración glomerular estimada de ≥ 30 ml/minuto/1,73 m2 según la práctica local de la institución en la determinación O una creatinina sérica según sea la razón edad/sexo
    12.Al menos 5 semividas desde la dosis más reciente del inhibidor de la cinasa O al menos 7 días desde el último tratamiento antineoplásico sistémico (lo que sea más breve) y recuperación hasta los valores basales de todas las toxicidades de la última dosis de quimioterapia citotóxica. Se aceptan la alopecia y otras toxicidades no agudas.
    13.Los pacientes con un tumor primario del SNC estable, metástasis cerebrales o compresión espinal tratada son aptos para el estudio si los síntomas neurológicos han permanecido estables durante los 7 días previos a la primera dosis de LOXO-195 y no se ha producido ninguna variación en la dosis de corticoesteroides, si está tomando corticoesteroides para tratar los síntomas del SNC, durante los 7 días previos a la primera dosis de LOXO-195. El paciente puede estar recibiendo cualquier dosis de corticoesteroides, siempre que la pauta posológica cumpla las especificaciones indicadas anteriormente.
    14.Resultado negativo de la prueba de embarazo en suero antes del D1C1 con el fármaco del estudio, en el caso de mujeres en edad fértil.
    15.Los pacientes de los dos sexos en edad fértil deben comprometerse a usar un método anticonceptivo apropiado durante todo el tratamiento y en los 6 meses posteriores a la finalización del estudio.
    16.Poder tragar cápsulas o una solución líquida por vía oral o recibir líquidos por vía enteral a través de una sonda gástrica o nasogástrica y cumplir el tratamiento ambulatorio, la monitorización de las pruebas analíticas y las visitas obligatorias en el centro durante toda la participación en el estudio.
    17.Los padres o los tutores legales de los pacientes pediátricos o adolescentes pueden comprender, aceptar y firmar el documento de consentimiento informado del estudio y el documento de asentimiento pediátrico correspondiente antes del inicio de cualquier procedimiento del protocolo. El paciente puede otorgar su asentimiento, cuando corresponda, en el momento del consentimiento de los padres o el tutor legal.
    E.4Principal exclusion criteria
    1.If received recent therapy, evidence of unstable organ dysfunction due to treatment.
    2.Concurrent treatment with a strong CYP3A4 inhibitor or inducer.
    3.Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of LOXO-195, cardiomyopathy; current or known history within the past 6 months of prolonged QTc interval >480 milliseconds. If there is a known explanation for a limited period of a prolonged QT interval (i.e., a medication known to cause prolonged QT interval was administered and has since been discontinued with clearly documented normal QT interval thereafter), that subject may be enrolled.
    4.Major surgery within 7 days of enrollment. Catheter placement, endoscopic procedures, and dental surgery are not considered major surgery.
    5.Uncontrolled systemic bacterial, fungal or viral infection. Infections treated with a stable dose of antimicrobial therapy for at least 7 days are allowed.
    6.Pregnancy or lactation
    1.Si se ha recibido un tratamiento reciente, indicios de una disfunción orgánica inestable debida al tratamiento.
    2.Tratamiento simultáneo con un inhibidor o un inductor potentes de la CYP3A4.
    3.Enfermedad cardiovascular activa y clínicamente significativa o antecedentes de un infarto de miocardio en los 3 meses previos al comienzo previsto del tratamiento con LOXO-195, miocardiopatía, antecedentes actuales o conocidos en los últimos 6 meses de una prolongación del intervalo QT corregido para la frecuencia cardíaca (intervalo QTc) >480 milisegundos. Si existe una explicación de un período limitado de un intervalo QT prolongado (es decir, se administró un medicamento del que se sabe que provoca la prolongación del intervalo QT y desde que se interrumpió su administración el intervalo QT documentado es normal), este paciente podría ser incluido en el estudio.
    4.Cirugía mayor en los 7 días previos a la inclusión. La inserción de un catéter, un procedimiento endoscópico y la cirugía odontológica no se consideran cirugías mayores.
    5.Infección bacteriana, fúngica o vírica sistémica no controlada. Se permiten infecciones tratadas con una dosis estable de antibioticoterapia durante al menos 7 días.
    6.Embarazo o lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    Identification of MTD and/or recommended dose for further study of LOXO 195 in patients age 12 and older and age < 12.
    Phase 2:
    Best overall response of confirmed CR or PR as determined by independent radiology review committee using RECIST v1.1 in patients age 12 and older and age < 12 with documented NTRK fusion cancers and demonstration of progression following (or during receipt of) previous treatment with a TRK inhibitor. Confirmed CR or PR is defined as a repeat assessment performed no less than 28 days after the criteria for response is first met.
    Fase 1
    DMT o dosis recomendada para el estudio posterior de LOXO-195 en pacientes de 12 años de edad y en adelante y en pacientes de <12 años de edad.
    Fase 2:
    mejor respuesta global de una RC o una RP confirmadas, determinada por un comité independiente de revisión radiológica con los criterios RECIST v. 1.1 en pacientes de 12 años de edad y en adelante y en pacientes de <12 años de edad que padezcan un cáncer portador de fusiones del gen NTRK documentado y se haya demostrado la progresión después del (o durante la recepción del) tratamiento previo con un inhibidor de la TRK.
    La RC o la RP confirmadas se definen como la repetición de la evaluación realizada a los 28 días como muy pronto de haberse cumplido los criterios de respuesta por primera vez.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1:
    Every cohort from baseline until disease progression,unacceptable toxicity, patient's withdrawal of consent, or death.
    Phase 2:
    Approximately every 8 weeks for the first 12 cycles, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed.
    Fase 1:
    Cada cohorte desde el inicio hasta la progresión de la enfermedad, inaceptable toxicidad , el retiro del consentimiento del paciente o la muerte.
    Fase 2:
    Aproximadamente cada 8 semanas durante los primeros 12 ciclos, luego cada 12 semanas durante el tratamiento, y cada 12 semanas después de la última dosis (hasta 2 años) en pacientes que no han progresado.
    E.5.2Secondary end point(s)
    Phase 1:
    Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related.
    Changes from baseline in clinical safety laboratory values and vital signs.
    Best overall response of confirmed CR or PR assessed by RECIST v1.1, as determined by independent radiology review, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor.
    Best overall response of confirmed CR or PR as determined by the treating Investigator using RANO in patients with primary CNS malignancies.
    Overall survival (OS) defined as the number of months from the initiation of LOXO 195 to the date of death due to any cause.
    To characterize the PK properties of LOXO-195.
    Phase 2:
    Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related in patients age 12 and older and age <12.
    Changes from baseline in clinical safety laboratory values and vital signs.
    Best overall response of confirmed CR or PR using RECIST v1.1 or RANO criteria as appropriate in patients with documented NTRK fusion cancers who discontinued the previous TRK inhibitor due to intolerance.
    Duration or response (DOR) will be determined for patients with best overall response of confirmed CR or PR by 1) an independent radiology review committee and/or 2) the treating Investigator; DOR is defined as the number of months from the start of CR or PR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease is documented, or death.
    Progression-free survival (PFS) defined as the number of months from the initiation of LOXO-195 to the earlier of PD or death due to any cause.
    Overall survival (OS) defined as the number of months from the initiation of LOXO 195 to the date of death due to any cause.
    Clinical benefit rate (CBR) defined by best overall response of confirmed CR, PR, or stable disease lasting 12 or more weeks following the initiation of LOXO-195.
    Fase 1:
    Incidencia, intensidad y duración de los AA, incluidos todos ellos, los graves y los que se considere que están relacionados con el tratamiento.
    Variaciones respecto al periodo basal en los valores analíticos de seguridad y en las constantes vitales.
    Mejor respuesta global de una RC o RP confirmadas, evaluada con los criterios RECIST v. 1.1 y determinada mediante una revisión radiológica independiente, en pacientes que padezcan un cáncer portador de genes de fusión NTRK, tratados previamente con un inhibidor de la TRK.
    Mejor respuesta global de una RC o RP confirmadas, determinada por el investigador responsable del tratamiento con los criterios RANO en pacientes que padezcan neoplasias malignas primarias del SNC.
    SG: número de meses transcurridos desde el inicio del tratamiento con LOXO-195 hasta la fecha de la muerte por cualquier causa.
    Caracterizar las propiedades FC de LOXO-195.
    Fase 2:
    Incidencia, intensidad y duración de los AA, incluidos todos ellos, los graves y los que se consideren que están relacionados con el tratamiento, en pacientes de 12 años de edad y en adelante y en pacientes de <12 años de edad.
    Variaciones respecto al periodo basal en los valores analíticos de seguridad y en las constantes vitales.
    Mejor respuesta global de una RC o RP confirmadas, evaluada con los criterios RECIS v. 1.1 o RANO (cuando corresponda) en pacientes que padezcan un cáncer portador de genes de fusión NTRK, a los que se les haya interrumpido el tratamiento anterior con un inhibidor de la TRK debido a una intolerancia.
    DR: determinada en los pacientes con mejor respuesta global de una RC o una RP confirmadas por: 1) un comité independiente de revisión radiológica y 2) el investigador responsable del tratamiento. La DR se define como el número de meses transcurridos desde el inicio de la RC o la RP (la que se registre en primer lugar) y su posterior confirmación hasta que se documente la primera fecha de recidiva o progresión de la enfermedad o el fallecimiento.
    SSP: número de meses transcurridos desde el inicio del tratamiento con LOXO-195 hasta la fecha de la PE o la muerte por cualquier causa.
    SG: número de meses transcurridos desde el inicio del tratamiento con LOXO-195 hasta la fecha de la muerte por cualquier causa.
    IBC: mejor respuesta global de una RC, una RP o una enfermedad estable confirmadas durante 12 semanas o más después del inicio del tratamiento con LOXO-195.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 1:
    PK properties of LOXO-195 will be determined between C1D6 and C1D8

    Phase 1 and Phase 2: EORTC QLQ-C30 and EQ-5D or PedsQL should be conducted at the same cycle visits as the disease assessment.
    Fase 1
    Las propiedades FC de LOXO-195 se determinarán entre el C1D6 y el C1D8
    Fase 1 y Fase 2: EORTC QLQ-C30 y EQ-5D o PedsQL deben realizarse en las mismas visitas de ciclo que la evaluación de la enfermedad.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    Escalado de dosis
    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.8.3 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Denmark
    France
    Germany
    Italy
    Korea, Republic of
    Singapore
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    F.1.1Number of subjects for this age range: 38
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 16
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors until their legal majority age
    Menores hasta su mayoría de edad legal
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 103
    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)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-18
    P. End of Trial
    P.End of Trial StatusOngoing
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