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    Summary
    EudraCT Number:2019-000212-28
    Sponsor's Protocol Code Number:LOXO-RET-18036
    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:2019-06-11
    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 number2019-000212-28
    A.3Full title of the trial
    A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors
    Estudio de fase 1/2 del inhibidor de RET oral LOXO 292 en pacientes pediátricos con tumores sólidos avanzados o tumores primarios del sistema nervioso central ambos con alteración de RET
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study on the effects of the LOXO-292 (study drug) in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors
    Estudio de fase 1/2 sobre los efectos de LOXO 292 (fármaco del estudio) en pacientes pediátricos con tumores sólidos avanzados o tumores primarios del sistema nervioso central
    A.4.1Sponsor's protocol code numberLOXO-RET-18036
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03899792
    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
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Addressul. Iłżecka 24
    B.5.3.2Town/ cityWarsaw
    B.5.3.3Post code02-135
    B.5.3.4CountryPoland
    B.5.6E-mailregsubmissions@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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameLOXO-292
    D.3.2Product code LOXO-292
    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 INNLOXO-292
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameLOXO-292
    D.3.2Product code LOXO-292
    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 INNLOXO-292
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameLOXO-292
    D.3.2Product code LOXO-292
    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 INNLOXO-292
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2071
    D.3 Description of the IMP
    D.3.1Product nameLOXO-292
    D.3.2Product code LOXO-292
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNLOXO-292
    D.3.9.1CAS number 2152628-30-1
    D.3.9.2Current sponsor codeLOXO-292
    D.3.9.3Other descriptive nameLOXO-292
    D.3.9.4EV Substance CodeSUB186998
    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
    Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors
    Pacientes pediátricos con tumores sólidos avanzados o tumores primarios del sistema nervioso central (SNC) ambos con alteración de RET
    E.1.1.1Medical condition in easily understood language
    Pediatric patients with an activating RET alteration and an advanced solid or primary Central Nervous System (CNS) Tumors
    Pacientes pediátricos con tumores sólidos avanzados o tumores primarios del sistema nervioso central ambos con alteración activadora de RET
    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 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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10007959
    E.1.2Term Central nervous system neoplasm NOS
    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 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 20.1
    E.1.2Level HLT
    E.1.2Classification code 10007960
    E.1.2Term Central nervous system neoplasms malignant NEC
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    PHASE 1
    The primary objective is to determine the safety, including dose-limiting toxicities (DLTs), of the oral RET inhibitor LOXO-292 in pediatric patients with an advanced solid or primary central nervous system (CNS) tumor harboring an activating RET alteration.

    PHASE 2
    To determine the objective response rate (ORR) as determined by an Independent Review Committee (IRC) and measured by the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors, version 1.1(RECIST 1.1), or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with LOXO-292 in pediatric patients with an advanced cancer harboring an activating RET alteration.
    FASE 1:
    El objetivo principal es determinar la seguridad, incluidas las toxicidades limitantes de la dosis (TLD), del inhibidor oral de RET LOXO-292 en pacientes pediátricos con un tumor sólido avanzado o primario del sistema nervioso central (SNC) que albergue una alteración activadora de RET.
    FASE 2:
    Calcular la tasa de respuesta objetiva (TRO) según lo determinado por un comité de revisión independiente (CEIm) y medida por la proporción de pacientes con mejor respuesta global confirmada de respuesta completa (RC) o respuesta parcial (RP) según los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST 1.1), o los criterios de Evaluación de la respuesta en neurooncología (RANO), según proceda, después del tratamiento con LOXO 292 en pacientes pediátricos con cáncer avanzado que albergue una alteración activadora de RET.
    E.2.2Secondary objectives of the trial
    PHASE 1
    -characterize LOXO-292 PK properties
    -identify MTD and/or the appropriate LOXO-292 dose
    -describe LOXO-292 antitumor activity
    -evaluate changes from baseline in pain and HRQoL measures assessed by Wong-Baker Faces Scale and PedsQL
    PHASE 2
    •determine:
    -ORR using RECIST 1.1 or RANO criteria
    -DOR in patients with best overall response of CR or PR
    -PFS duration following LOXO-292 initiation
    -OS following LOXO-292 initiation
    -evaluate CBR based on proportion of patients with best overall response of CR, PR or stable disease lasting 16 or more weeks
    •assess LOXO-292 safety profile and tolerability
    •characterize LOXO-292 PK properties
    •evaluate concordance of prior molecular profiling that detected an activating RET alteration within the tumor
    •characterize post-operative staging and surgical margin status in patients who have definitive surgery following LOXO-292 treatment
    •describe putative pretreatment surgical plan and capture post treatment actual approach
    FASE 1:Caracterizar FC LOXO-292 ;Identificar DMT y/o dosis adecuada LOXO-292;Describir actividad antitumoral de LOXO-292;Evaluar variaciones respecto a estado basal de mediciones de dolor y CVRS, evaluadas mediante Escala caras Wong-Baker y PedsQL.
    FASE 2:
    -Determinar:TRO con criterios RECIST 1.1 o RANO;DR en pacientes con mejor respuesta global RC o RP;SSP tras inicio LOXO-292;*SG tras inicio del tratamiento LOXO-292;Evaluar TBC basándose en proporción pacientes con mejor respuesta global RC, RP o enferm. estable durante 16 semanas o más.
    -Evaluar perfil seguridad y tolerabilidad LOXO-292.
    -Caracterizar propiedades farmacocinéticas LOXO-292.
    -Evaluar concordancia perfil molecular previo que detectó una alteración activadora de RET en tumor.
    -Caracterizar estadif. posoperatoria y estado margen quirúrgico en pacientes sometidos a cirugía definitiva tras tratamiento LOXO-292.
    -Describir plan quirúrgico propuesto previo al tratamiento y captar enfoque real posterior al tratamiento
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pediatric patients ≥ 6 months of age and ≤ 21 years of age at Cycle 1 Day 1 (C1D1) with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and/or for which no standard or available systemic curative therapy exists.
    a) Patients with locally advanced disease who would require, in the option of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection are also eligible.
    2. Evidence of an activating RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation.
    3. Patients with primary CNS tumors or cerebral metastasis:
    a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment
    b) Must have not required increasing doses of steroids within the 7 days prior to study entry to manage CNS symptoms
    4. Imaging study must be performed within 28 days of C1D1 while on stable dose steroid medication (if needed) for at least 7 days immediately before the imaging study.
    5. Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebral spinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG).
    6. Patients must have measurable or evaluable disease.
    7. Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) performance score of at least 50.
    8. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy to CTCAE (v5.0) Grade ≤ 2.
    9. An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to Section 7.5 of the protocol).
    10. Adequate hematologic status, defined as:
    a) Absolute neutrophil count (ANC) ≥ 0.75× 10^9/L not requiring growth factor support for at least 7 days prior to treatment unless evidence of disease involvement in the bone marrow.
    b) Platelet count ≥ 75 × 10^9/L not requiring transfusion support for at least 7 days prior to treatment unless evidence of disease involvement in the bone marrow.
    c) Hemoglobin (Hb) ≥ 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment unless evidence of disease involvement in the bone marrow.
    11. Adequate hepatic function, defined as:
    a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) or ≤ 5 × ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor) and
    b) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement (patients with Gilbert’s Disease may be enrolled with prior Sponsor approval).
    12. Adequate renal function, defined as:
    a) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional practice for determination, or a minimum serum creatinine by age and gender as presented in Synopsis Table 3.
    13. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
    14. Willingness of male and female patients with reproductive potential to utilize double effective birth control methods
    15. Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube.
    16. Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study Informed Consent Form (ICF) and applicable Pediatric Assent Form before initiation of any protocol-related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.
    1.Pacientes pediátricos 6 meses y 21 años el día 1 del ciclo 1 (D1C1) con un tumor sólido localmente avanzado o metastásico o primario del SNC que haya recidivado, progresado o no haya respondido a los tratamientos disponibles o para el que no exista un tratamiento curativo sistémico convencional o disponible.
    a)También podrán participar los pacientes con la enfermedad localmente avanzada que precisen, en opinión del investigador, una cirugía desfigurante o la amputación de una extremidad para lograr una resección quirúrgica completa.
    2)Se requieren pruebas de una alteración activadora del gen RET en el tumor o la sangre identificadas mediante análisis moleculares, tal como se realizaron en la evaluación clínica.
    3)Pacientes con tumores primarios del SNC o metástasis cerebrales:
    a)Deben ser neurológicamente estables según una exploración neurológica estable durante 7 días antes de la inclusión.
    b)No deben haber necesitado dosis crecientes de esteroides en los 7 días previos a la incorporación en el estudio para tratar los síntomas del SNC.
    4.El estudio de imagen se deberá realizar en los 28 días previos al D1C1 mientras se reciba tratamiento estable con esteroides (en caso necesario) durante al menos 7 días inmediatamente antes del estudio de imagen.
    5.Verificación histológica del tumor maligno en el momento del diagnóstico original o de la recidiva, excepto en pacientes con tumores del tronco encefálico intrínsecos, gliomas de la vía óptica, o pacientes con tumores pineales y elevaciones del líquido cefalorraquídeo (LCR) o marcadores tumorales séricos, incluyendo alfafetoproteína o gonadotropina coriónica humana beta (HCG).
    6.Los pacientes deben presentar una enfermedad medible o evaluable.
    7.Puntuación funcional de Karnofsky (pacientes con 16 años o más) o de Lansky (pacientes menores de 16 años) de al menos 50.
    8.Los pacientes se deberán haber recuperado por completo de los efectos tóxicos agudos de toda quimioterapia antineoplásica previa hasta un grado ≤ 2 de los CTCAE (v5.0).
    9.Se deberá disponer de una muestra de tejido tumoral de archivo (IPFF o congelada en fresco) o reciente (véase la Sección 7.5.).
    10.Estado hematológico adecuado, definido como:
    a)Recuento absoluto de neutrófilos (RAN) ≥ 0,75x10^9/l sin necesidad de apoyo con factores de crecimiento durante al menos 7 días antes del tratamiento, a no ser que haya indicios de afectación de la enfermedad en la médula ósea.
    b)Recuento de plaquetas ≥ 75x10^9/l sin necesidad de apoyo con transfusiones durante al menos 7 días antes del tratamiento, a no ser que haya indicios de afectación de la enfermedad en la médula ósea.
    c)Hemoglobina (Hb) ≥ 8 mg/dl que no precise apoyo con transfusiones ni eritropoyetina durante al menos 7 días antes del tratamiento, a no ser que haya indicios de afectación de la enfermedad en la médula ósea.
    11.Función hepática adecuada, definida como:
    a)Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) ≤ 2,5 el límite superior de la normalidad (LSN) o ≤ 5 LSN con afectación hepática documentada (como metástasis hepáticas o un tumor biliar primario), y b)Bilirrubina total ≤ 1,5 LSN o ≤ 3 LSN con afectación hepática documentada (los pacientes con la enfermedad de Gilbert podrán participar con la aprobación previa del promotor).
    12.Función renal adecuada, definida como:a)Tasa estimada de filtración glomerular ≥ 30 ml/min/1,73 m2 según la práctica del centro local para la determinación o un valor mínimo de creatinina sérica por edad y género como se indica en la Tabla 3 de la sinopsis.
    13.Capacidad de cumplir el tratamiento ambulatorio, los controles analíticos y las visitas al centro necesarias mientras dure la participación en el estudio.
    14.Disposición de los pacientes masculinos y femeninos en edad fértil a utilizar métodos anticonceptivos de doble eficacia.
    15.Capacidad de ingerir cápsulas o suspensión líquida, o acceso gástrico por sonda nasogástrica o gástrica.
    16.El progenitor/tutor del menor o adolescente tiene capacidad para comprender, aceptar y firmar el documento de consentimiento informado (DCI) del estudio y el documento de asentimiento pediátrico correspondiente antes del inicio de cualquier procedimiento relacionado con el protocolo; el paciente es capaz de facilitar su asentimiento, si procede, en el momento del consentimiento del progenitor/tutor.
    E.4Principal exclusion criteria
    1. Major surgery within 14 days (2 weeks) prior to C1D1.
    2. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval corrected for heart rate (QTc) interval > 470 milliseconds.
    3. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes the risk: benefit ratio for the patient to participate in the trial unfavorable.
    4. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
    5. Pregnancy or lactation.
    6. Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the patient required a modification to current thyroid medication in the 7 days prior to first dose of study treatment).
    7. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
    8. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Appendix D of the main protocol for examples).
    9. Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for patients who will receive LOXO-292 suspension.
    10. Current treatment with proton pump inhibitors (PPIs).
    1) Intervención quirúrgica importante en los 14 días (2 semanas) previos al D1C1.
    2) Enfermedad cardiovascular activa clínicamente significativa o antecedentes de infarto de miocardio en los 6 meses previos al D1C1; miocardiopatía en curso; o intervalo QT prolongado actual corregido por la frecuencia cardíaca (QTc) > 470 milisegundos.
    3) Infección bacteriana, vírica o micótica sistémica no controlada y activa que, en opinión del investigador, de lugar a una relación desfavorable entre los riesgos y beneficios del paciente por participar en el ensayo.
    4) Síndrome de malabsorción activa clínicamente importante u otra afección que pueda influir en la absorción gastrointestinal del fármaco del estudio.
    5) Embarazo o lactancia.
    6) Hipertiroidismo o hipotiroidismo sintomático no controlado (el paciente necesitó una modificación de la medicación tiroidea actual en los 7 días previos a la primera dosis del tratamiento del estudio).
    7) Hipercalcemia o hipocalcemia no controlada y sintomática.
    8) Tratamiento actual con inhibidores o inductores potentes del citocromo P450 3A4 (CYP3A4) (se pueden consultar ejemplos en el Apéndice D del protocolo principal).
    9) Hipersensibilidad conocida a cualquiera de los componentes del fármaco en investigación, LOXO-292, o a Ora Sweet® SF y OraPlus® en el caso de los pacientes a los que se administre la suspensión de LOXO-292.
    10) Tratamiento actual con inhibidores de la bomba de protones (IBP).
    E.5 End points
    E.5.1Primary end point(s)
    PHASE 1
    1. Frequency, severity and relatedness of TEAEs and SAEs, including DLTs in pediatric patients receiving LOXO-292

    PHASE 2
    1. ORR based on RECIST 1.1 or RANO as appropriate to tumor type as determined by an IRC
    FASE 1:
    Frecuencia, intensidad y relación causal de los AAAT y AAG, incluidas las TLD, en pacientes pediátricos tratados con LOXO-29.
    FASE 2:
    TRO conforme a los criterios RECIST 1.1 o RANO, dependiendo del tipo de tumor, según lo determinado por un CEIm.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PHASE 1:
    1. From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose). DLTs during the first 28-day cycle of LOXO-292 treatment

    PHASE 2:
    1. approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed.
    FASE 1:
    1.Desde el momento del consentimiento informado, durante aproximadamente 24 meses (o antes si el paciente interrumpe su particioacion en el estudio), hasta el seguimiento de seguridad (28 días tras la última dosis).
    FASE 2:
    1.Aproximadamente cada 8 semanas durante un año, a partir de entonces cada 12 semanas, 7 días tras la última dosis (hasta durante 2 años) en pacientes que no hayan progresado.
    E.5.2Secondary end point(s)
    PHASE 1:
    1. Plasma concentrations of LOXO-292 and PK parameters, including, but not limited to area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), degree of accumulation, and other characterizations
    2. To identify the MTD and/or the RP2D of LOXO-292 in pediatric patients
    3. To describe the antitumor activity of LOXO-292 in pediatric patients with tumors harboring an activating RET alteration
    4. Changes from baseline in pain scales and PedsQL-Core scores

    PHASE 2
    1. To determine the following in patients with advanced cancer harboring an activating RET alteration o ORR based on RECIST 1.1 or RANO as appropriate to tumor type per the treating Investigator’s response assessment
    o DOR (IRC and treating Investigator)
    o PFS
    o OS
    o CBR (IRC and treating Investigator)
    2. Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, and assessments of physical examinations, vital signs, and ECGs
    3. Concordance rate of prior molecular profiling that detected a RET alteration within the patient’s tumor with diagnostic tests being evaluated by the Sponsor
    4. Post-operative staging and surgical margin status in patients who have definitive surgery following treatment with LOXO-292
    5. Number of patients with putative pretreatment surgical plan and the actual post treatment approach with an emphasis on the functional and cosmetic outcome
    FASE 1:
    1.Concentraciones plasmáticas de LOXO-292 y parámetros FC, entre ellos, área bajo la curva de concentración-tiempo desde el momento 0 hasta las 24 horas (AUC0-24), concentración máxima del fármaco (Cmáx), tiempo hasta la concentración plasmática máxima (Tmáx), grado de acumulación y otras caracterizaciones
    2.Identificar la DMT o la DRF2 de LOXO-292 en pacientes pediátricos
    3.Describir la actividad antitumoral de LOXO-292 en pacientes pediátricos con tumores que alberguen una alteración activadora de RET
    4.Variaciones con respecto al momento estado basal de las puntuaciones en las escalas de dolor y PedsQL-Core
    FASE 2:
    1.Determinar lo siguiente en pacientes con cáncer avanzado que alberguen una alteración activadora de RET o TRO conforme a los criterios RECIST 1.1 o RANO según proceda en función del tipo de tumor basándose en la evaluación de la respuesta por parte del investigador responsable del tratamiento
    -DR (CEIm e investigador responsable del tratamiento)
    -SSP
    -SG
    -TBC (CEIm e investigador responsable del tratamiento)
    2.Frecuencia, intensidad y relación de AAAT y AAG, variaciones de los valores de hematología y bioquímica sanguínea, y evaluaciones de exploraciones físicas, constantes vitales y ECG
    3.Tasa de concordancia del perfil molecular previo que detectó una alteración de RET en el tumor del paciente con pruebas diagnósticas evaluadas por el promotor
    4.Estadificación posoperatoria y estado del margen quirúrgico en pacientes sometidos a una cirugía definitiva después del tratamiento con LOXO-292
    5.Número de pacientes con un plan quirúrgico propuesto previo al tratamiento y enfoque real posterior al tratamiento, haciendo hincapié en el resultado funcional y estético
    E.5.2.1Timepoint(s) of evaluation of this end point
    PHASE 1:
    1.Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation
    2.MTD: Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation
    2.RP2D: first 28 days of treatment (Cycle 1) and every cycle for approx.12 months
    3.Approx.every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed
    4.Up to 24 months

    PHASE 2:
    1.Approx. every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed.
    2.From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose)
    3. 6months
    4. 6months
    5. 6months
    FASE 1:
    1.Dia 1 y 8 ciclo 1, dia 1 ciclo 3 y dia 8 tras dosis aumento intra-paciente.
    2.DMT: Dia 1 y 8 ciclo 1, dia 1 ciclo 3 y dia 8 tras dosis aumento intra-paciente.
    2.DRP2: primeros 28 días de tratamiento (Ciclo 1) y cada ciclo durante aprox. 12meses.
    3.Aprox. cada 8 semanas durante 1año, luego cada 12semanas, 7días tras última dosis (hasta durante 2 años) en pacientes no hayan progresado.
    4.Hasta 24 meses.
    FASE 2:
    1.Aprox. cada 8 semanas durante in año, luego cada 12 semanas, 7días tras última dosis (hasta durante 2 años) en pacientes no hayan progresado.
    2.Desde momento consentimiento informado, durante aprox 24 meses (o antes si el paciente interrumpe participación en el estudio), hasta seguimiento de seguridad (28 días tras última dosis).
    3. 6meses
    4. 6meses
    5. 6meses
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) 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
    Aumento 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.8.2.4Number 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 EEA5
    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
    Canada
    Denmark
    France
    Germany
    Italy
    Japan
    Spain
    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
    Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. It is anticipated that a patient on this study will receive treatment with open-label LOXO-292 until the patient is able to obtain commercially available LOXO-292 in their respective country, the patient does not meet criteria requiring discontinuation of treatment, and the patient’s participation in the study has not ended.
    Cada paciente continuará con la administración hasta PE, toxicidad inaceptable u otro motivo de suspensión del tratamiento. Se prevé que los pacientes de este estudio reciban LOXO-292 en abierto hasta que el paciente pueda disponer de LOXO-292 comercializado en su pais, si no cumple criterios que requieran la interrupción del tratamiento, y la participación del paciente en el studio no ha finalizado.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 73
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 42
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    F.1.3Elderly (>=65 years) No
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 90
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After treatment discontinuation, Long-Term Follow-up (LTFU) assessments and procedures will be conducted in accordance with the Schedule of Assessments (Protocol, Table 11-1). LTFU will occur approximately every 3 months (±1 month) until the patient experiences PD, withdraws consent for further participation, is lost to follow-up, has died, or close of the study.
    Tras la interrupción del tratamiento, se llevarán a cabo evaluaciones y procedimientos de Seguimiento a Largo Plazo (SLP) de acuerdo al Calendario de evaluaciones (Protocolo, Tabla 11-1). el SLP tendrá lugar aproximadamente cada 3 meses (más/menos un mes) hasta la PE del paciente, o si retira su consentimiento para su participación, se pierde el contacto durante el seguimiento, fallece o se cierra el estudio.
    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 Decision2020-04-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-19
    P. End of Trial
    P.End of Trial StatusOngoing
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