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    Summary
    EudraCT Number:2015-005117-72
    Sponsor's Protocol Code Number:AG120-C-005
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-09
    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 number2015-005117-72
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation
    Estudio Fase III, multicéntrico, aleatorizado, doble ciego, controlado con placebo de AG-120 en sujetos previamente tratados con colangiocarcinoma no resecable o metastásico con una mutacion IDH-1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to test for efficacy of an oral investigational drug, AG-120, in patients with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation
    Estudio de fase 3 para evaluar la eficacia de un medicamento experimental por via oral, AG-120, en pacientes con colangiocarcinoma no resecable o metastásico con una mutación IDH1
    A.3.2Name or abbreviated title of the trial where available
    ClarIDHy
    A.4.1Sponsor's protocol code numberAG120-C-005
    A.5.4Other Identifiers
    Name:IND NumberNumber:131191
    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 SponsorAgios Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAgios Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAgios Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDirector, Scientific Communications
    B.5.3 Address:
    B.5.3.1Street Address88 Sidney Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 nameAG-120
    D.3.2Product code AG-120
    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 INNivosidenib
    D.3.9.1CAS number 1448347-49-6
    D.3.9.2Current sponsor codeAG-120
    D.3.9.4EV Substance CodeSUB130391
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nonresectable or Metastatic Cholangiocarcinoma
    Colangiocarcinoma no resecable o metastásico
    E.1.1.1Medical condition in easily understood language
    Cancer of the bile duct that has metastasized or can't be removed with surgery
    Cáncer de las vias biliares que se ha metastatizado o que no puede extirparse con cirugia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10008594
    E.1.2Term Cholangiocarcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10077846
    E.1.2Term Cholangiocarcinoma metastatic
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of AG-120 based on progression-free survival (PFS) per Independent Radiology Center (IRC) assessment compared to placebo in subjects with nonresectable or metastatic cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation.
    Demostrar la eficacia de AG-120 en función de la supervivencia libre de progresión (SLP) conforme a la evaluación del Centro de Radiología Independiente (CRI) en comparación con la del placebo en pacientes con colangiocarcinoma irresecable o metastásico con una mutación de la isocitrato deshidrogenasa 1 (IDH1).
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of AG-120 compared to placebo.
    - To evaluate PFS per Investigator assessment.
    - To compare the efficacy of AG-120 with placebo based on overall survival (OS), objective response rate (ORR), duration of response (DOR), and time to response (TTR), with response assessed per the Investigator and by the IRC.
    - To evaluate quality of life (QOL) with AG-120 compared to placebo as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-BIL21).
    - To evaluate health economic outcomes as assessed by the EQ-5D-5L instrument.
    - To evaluate the pharmacokinetics (PK) of AG-120.
    - To evaluate the PK/pharmacodynamic (PD) relationship of AG-120 and 2-hydroxyglutarate (2-HG) in blood samples.
    - Evaluar la seguridad y la tolerabilidad de AG-120 en comparación con el placebo.
    - Evaluar la SLP conforme a la valoración del investigador.
    - Comparar la eficacia de AG-120 con la del placebo en función de la supervivencia global (SG), la tasa de respuesta objetiva (TRO), la duración de la respuesta (DR) y el tiempo hasta la respuesta (TR). La respuesta la evaluarán el investigador y el CRI.
    - Evaluar la calidad de vida (CV) con AG-120 en comparación con el placebo con los cuestionarios de la calidad de vida desarrollados por la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ-C30 y QLQ-BIL21 de la EORTC).
    - Evaluar los resultados de economía sanitaria determinados con el instrumento EQ-5D-5L.
    - Evaluar la farmacocinética (FC) de AG-120.
    - Evaluar la relación FC/farmacodinámica (FD) de AG-120 y el 2-hidroxiglutarato (2 HG) en las muestras de sangre.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be ≥18 years of age
    2. Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) of nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies.
    3. Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available) based on central laboratory testing (R132C/L/G/H/S mutation variants tested).
    4. Have an ECOG PS score of 0 or 1
    5. Have an expected survival of ≥3 months.
    6. Have at least one evaluable and measurable lesion as defined by RECIST v1.1. Subjects who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥20% growth in size since post-treatment assessment.
    7. Have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic). Subjects must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Subjects who have received systemic adjuvant chemotherapy will be permitted provided there is documented disease progression during or within 6 months of completing the therapy.
    8. Have recovered from toxicities associated with prior anticancer therapy to baseline unless stabilized under medical management.
    9. Have adequate bone marrow function as evidenced by:
    a. Absolute neutrophil count ≥1,500/mm^3 or 1.5 ×109/L
    b. Hemoglobin ≥8 g/dL
    c. Platelets ≥100,000/mm^3 or 100 × 109/L
    10. Have adequate hepatic function as evidenced by:
    a. Serum total bilirubin ≤2 × upper limit of normal (ULN), unless considered due to Gilbert’s disease
    b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN
    11. Have adequate renal 11. function as evidenced by:
    a. Serum creatinine <1.5 × ULN
    OR
    b. Creatinine clearance ≥50 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 − Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine
    12. Be able to understand and willing and able to sign the informed consent and comply with scheduled visits, treatment plans, procedures and laboratory tests including serial peripheral blood sampling and urine sampling, during the study.
    13. Female subjects with reproductive potential must have a negative serum pregnancy test prior to the start of therapy, or a confirmation from an obstetrician in case of equivocal serum pregnancy results. Females of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated) for at least 24 consecutive months (i.e., have not had menses at any time in the preceding 24 consecutive months). Women of reproductive potential, as well as fertile men and their partners who are female with reproductive potential, must agree to abstain from sexual intercourse or to use a highly effective form of contraception from the time of giving informed consent, during the study, and for 90 days (females and males) following the last dose of study drug. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, or male partner sterilization. If not using a highly effective form of contraception, participants must use 2 of the following methods: progestogen-only hormonal contraception; male or female condom with or without spermicide; cap, diaphragm, or sponge with spermicide.
    1. Edad ≥18 años.
    2. Pacientes con diagnóstico histopatológico (muestra de biopsia reciente o de archivo, preferiblemente extraída en los últimos tres años) de colangiocarcinoma irresecable o metastásico y que no sean aptos para resección curativa, trasplante o tratamientos ablativos.
    3. Presentar enfermedad con mutación del gen IDH1 documentada (en una biopsia de tumor reciente o en el tejido tumoral de archivo más reciente disponible) conforme al análisis realizado por el laboratorio central (se analizarán las variantes de la mutación R132C/L/G/H/S).
    4. Presentar un estado funcional del ECOG de 0 o 1.
    5. Tener una previsión de supervivencia >=3 meses.
    6. Presentar como mínimo una lesión mensurable y evaluable según la definición de los criterios RECIST v1.1. Los pacientes que hayan recibido tratamiento local anterior (incluidos, entre otros, la embolización, la quimioembolización, la ablación mediante radiofrecuencia o la radioterapia) son aptos siempre que la enfermedad medible se encuentre fuera del campo de tratamiento o, si está dentro del campo de tratamiento, que presente un aumento de tamaño >=20 % desde la evaluación realizada después del tratamiento.
    7. Presentar progresión documentada de la enfermedad tras haber recibido como mínimo una pauta de tratamiento sistémico anterior, y como máximo dos, para la enfermedad avanzada (irresecable o metastásica). Los pacientes deben haber recibido como mínimo una pauta que contenga gemcitabina o 5-FU para el colangiocarcinoma avanzado. Se permitirá la inclusión de pacientes que hayan recibido tratamiento con quimioterapia sistémica adyuvante siempre que haya progresión documentada de la enfermedad durante el tratamiento o en los 6 siguientes a su finalización.
    8. Se hayan recuperado de toxicidades asociadas al tratamiento antineoplásico anterior hasta la situación basal, a menos que estén estabilizados con tratamiento médico.
    9. Presentar una función adecuada de la médula ósea según los parámetros siguientes:
    a. Recuento absoluto de neutrófilos >=1.500/mm3 o 1,5 ×109/l
    b. Hemoglobina >=8 g/dl
    c. Trombocitos >=100.000/mm3 o 100 × 109/l
    10. Presentar una función hepática adecuada según los parámetros siguientes:
    a. Bilirrubina sérica total <=2 x límite superior de la normalidad (LSN), salvo en sujetos con la enfermedad de Gilbert.
    b. Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) <=5 veces el LSN.
    11. Presentar una función renal adecuada según los parámetros siguientes:
    a. Creatinina sérica < 1,5 × LSN.
    O
    b. Aclaramiento de creatinina >=50 ml/min calculado según la ecuación de filtración glomerular (FG) de Cockcroft-Gault:
    (140-edad) x (peso en kg)x (0,85 si es mujer)/72 x creatinina sérica
    12. Entender y estar dispuesto a firmar un consentimiento informado y cumplir con las visitas programadas, los planes de tratamiento, los procedimientos y los análisis clínicos, que incluyen toma de muestras de sangre periférica seriadas y toma de muestras de orina, durante el estudio.
    13. Las mujeres con capacidad reproductiva deben tener una prueba de embarazo en suero negativa antes de iniciar el tratamiento o la confirmación de un obstetra en caso de resultados dudosos de la prueba de embarazo en suero. Se define a las mujeres con capacidad reproductiva como mujeres sexualmente maduras que no se hayan sometido a histerectomía, ooforectomía bilateral o ligadura de trompas o que no sean posmenopáusicas de forma natural (es decir, que no hayan tenido la menstruación) durante al menos 24 meses consecutivos (es decir con amenorrea en cualquier momento durante los 24 meses consecutivos anteriores). Las mujeres con capacidad reproductiva, así como los varones fértiles y sus parejas femeninas con capacidad reproductiva, deben comprometerse a abstenerse de mantener relaciones sexuales o a utilizar un método anticonceptivo altamente eficaz desde el momento de otorgar el consentimiento informado, durante el estudio y durante los 90 días (mujeres y varones) tras la última dosis del fármaco del estudio. Se consideran métodos anticonceptivos altamente eficaces los anticonceptivos hormonales orales, inyectables, parches, dispositivo intrauterino, sistemas intrauterinos de liberación de hormonas, ligadura de trompas bilateral o esterilización de la pareja masculina. Si no se utiliza un método anticonceptivo altamente eficaz, los participantes deberán utilizar dos de los métodos siguientes: anticonceptivo hormonal con sólo gestágenos; preservativo masculino o femenino con o sin espermicida; capuchón, diafragma o esponja con espermicida.
    E.4Principal exclusion criteria
    1. Received a prior IDH inhibitor.
    2. Received systemic anticancer therapy or investigational agent <2 weeks prior to Day 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the first dose of study treatment should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
    3. Received radiotherapy to metastatic sites of disease <2 weeks prior to Day 1.
    4. Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to Day 1.
    5. Have known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, havediscontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.
    6. Have a history of another primary cancer, with the exception 6. of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid or liquid tumor with no known active disease present that, in the opinion of the Investigator, will not affect subject outcome in the setting of current cholangiocarcinoma diagnosis.
    7. Underwent major surgery within 4 weeks of Day 1 or have not recovered from postsurgery toxicities.
    8. Are pregnant or breastfeeding.
    9. Are taking known strong CYP3A4 inducers or inhibitors, or sensitive CYP3A4 substrate medications, unless they can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the medications can be properly monitored during the study.
    10. Are taking P-gp transporter-sensitive substrate medications or inhibitors unless they can be transferred to other medications within ≥5 half-lives prior to administration of study treatment, or unless the medications can be properly monitored during the study.
    11. Have an active infection requiring systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days of Day 1 (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
    12. Have any known hypersensitivity to any of the components of AG-120 or the matched placebo.
    13. Have significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke.
    14. Have LVEF <40% by ECHO and/or MUGA scan obtained within 28 days prior to the start of study treatment.
    15. Have a heart-rate corrected QT interval (using Fredericia’s formula) (QTcF) ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTcF interval are permitted with approval of the Medical Monitor.
    16. Are taking medications that are known to prolong the QT interval, unless they can be transferred to other medications within ≥5 half-lives prior to dosing or unless the medications can be properly monitored during the study. (If equivalent medication is not available, QTcF should be closely monitored.)
    17. Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness. Subjects with a sustained viral response to HCV or immunity to prior HBV infection will be permitted.
    18. Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of Day 1) or active suicidal ideation or behavior, or a 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 subject inappropriate for entry into this study.
    19. Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).
    1. Haber recibido anteriormente un inhibidor de IDH.
    2. Haber recibido tratamiento antineoplásico sistémico o un fármaco en fase de investigación en las dos semanas anteriores al día 1 (el período de reposo farmacológico del tratamiento antineoplásico inmunitario anterior es de 4 semanas). Además, no se debería administrar la 1ª dosis del tratamiento del estudio antes de transcurridas >=5 semividas desde que se administró el medicamento en fase de investigación.
    3. Haber recibido radioterapia en las localizaciones metastásicas de la enfermedad en las dos semanas anteriores al día 1.
    4. Haber recibido radioterapia hepática, quimioembolización y ablación mediante radiofrecuencia en las 4 semanas anteriores al día 1.
    5. Pacientes con metástasis cerebrales sintomáticas conocidas que precisen corticosteroides. Los sujetos con metástasis cerebrales diagnosticadas previamente son aptos si han finalizado el tratamiento y se han recuperado de los efectos agudos de la radioterapia o la cirugía antes de ser incluidos en el estudio, han interrumpido el tratamiento con corticosteroides para dichas metástasis durante como mínimo cuatro semanas y la enfermedad ha permanecido estable desde el punto de vista radiográfico durante como mínimo los tres meses anteriores a la inclusión en el estudio. 6.Presenten antecedentes de otro cáncer primario, con la excepción de: a) cáncer de piel distinto del melanoma con resección curativa; b) carcinoma cervical in situ con tratamiento curativo; o c) otros tumores primarios sólidos o líquidos sin enfermedad activa conocida que, a discreción del investigador, no afectará al desenlace del paciente en el contexto del diagnóstico actual de colangiocarcinoma.
    7. Se hayan sometido a cirugía mayor en las 4 semanas anteriores al día 1 o no se hayan recuperado de los efectos secundarios posquirúrgicos.
    8. Pacientes embarazas o en período de lactancia.
    9. Tomen potentes inductores o inhibidores del citocromo P450 (CYP)3A4, o medicamentos sensibles al sustrato de CYP3A4, a menos que puedan pasarse a otra medicación en el plazo de >=5 semividas antes de la administración del fármaco o a menos que se pueda realizar la vigilancia de los medicamentos durante el estudio.
    10. Tomen medicamentos de sustrato sensibles al transportador de la glucoproteína P (P-gp) o inhibidores de esta, a menos que puedan pasarse a otra medicación en el plazo de >=5 semividas antes de la administración del tratamiento del estudio o a menos que se pueda realizar la vigilancia de los medicamentos durante el estudio.
    11. Presenten una infección activa que precise tratamiento sistémico antiinfeccioso o con fiebre sin explicación superior a 38,5 ºC en los 7 días previos al día 1 (a discreción del investigador, pueden incluirse los pacientes con fiebre tumoral).
    12. Presenten una hipersensibilidad conocida a cualquier componente de AG-120 o del placebo equivalente.
    13. Presenten cardiopatía activa importante en los 6 meses anteriores al inicio del tratamiento del estudio, entre otras, la insuficiencia cardíaca congestiva de clase III o IV según la New York Heart Association (NYHA); infarto de miocardio; angina inestable o ictus.
    14. Presenten FEVI < 40% en ECO o ventriculografía isotópica obtenida en los 28 días previos al inicio del tratamiento del estudio.
    15. Presenten un intervalo QT corregido para la frecuencia cardiaca (con la fórmula de Fredericia [QTcF]) >=450 ms u otros factores que aumentan el riesgo de prolongación del intervalo QT, o episodios arrítmicos. Están permitidos con la aprobación del monitor médico los bloqueos de rama y el intervalo QTcF prolongado.
    16. Tomen medicamentos que se sepa que prolongan el intervalo QT, a menos que puedan pasarse a otra medicación en el plazo de >=5 semividas antes de la administración del fármaco o a menos que se pueda realizar la vigilancia de los medicamentos durante el estudio.
    17. Presentar infecciones activas conocidas por el virus de la hepatitis B (VHB)o la hepatitis C (VHC), resultados positivos conocidos de anticuerpos contra el virus de la inmunodeficiencia humana (VIH) o enfermedad relacionada con el síndrome de inmunodeficiencia adquirida (SIDA). Se permitirán los pacientes con una respuesta vírica sostenida al tratamiento para el VHC o inmunidad a infección previa por VHB.
    18. Presenten otro trastorno médico o psiquiátrico agudo o crónico.
    19. Presenten enfermedad gastrointestinal inflamatoria activa, diarrea crónica, resección gástrica anterior o disfagia por banda gástrica, síndrome de intestino corto, gastroparesia u otras enfermedades que limiten la ingesta o la absorción gastrointestinal de fármacos administrados por vía oral. Se permite la enfermedad de reflujo gastroesofágico en tratamiento médico (suponiendo que no haya posibilidad de interacción farmacológica).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS, the time from date of randomization to date of first documented disease progression (as assessed by the IRC per RECIST v1.1), or date of death due to any cause.
    La variable principal es la supervivencia libre de progresión (SLP), el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la primera progresión documentada de la enfermedad (según la evaluación del CRI conforme a los criterios RECIST v1.1), o la fecha de la muerte por cualquier causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ongoing basis from randomization until progression of disease or death
    De forma continua, desde la aleatorización hasta la progresión de la enfermedad o la muerte
    E.5.2Secondary end point(s)
    AEs, SAEs, AEs leading to discontinuation or death.

    Safety laboratory parameters, vital signs, 12-lead ECGs, evaluation of left ventricular ejection fraction (LVEF), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and concomitant medications.

    Secondary efficacy endpoints include:
    - OS, defined as the time from date of randomization to date of death.
    - ORR, defined as the proportion of subjects with a best overall response defined as CR or PR
    - DOR, defined as the time from date of first documented complete response (CR) or partial response (PR) to date of first documented disease progression or death due to any cause
    - PFS as determined by the Investigator.
    - TR, defined as the time from date of randomization to date of first documented
    - CR or PR for responders, as assessed by the Investigator and by the IRC per RECIST v1.1.

    Quality of Life as assessed by validated instruments.

    Health economic outcomes as assessed by the EQ-5D-5L instrument.

    Serial or sparse blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters of AG-120.

    Blood sampling at specified time points for determination of 2-HG levels to characterize the PD effects of AG-120.
    AA, AAG, AA que provoquen la retirada o la muerte.

    Parámetros analíticos de seguridad; constantes vitales; ECG de 12 derivaciones; fracción de eyección del ventrículo izquierdo (FEVI), estado funcional (EF) del Eastern Cooperative Oncology Group (ECOG) y medicaciones concomitantes.

    Los criterios de valoración secundarios de la eficacia son:
    - SG, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la muerte
    - TRO, definida como la proporción de sujetos con una mejor respuesta global definida como RC o RP
    - DR, definida como el tiempo transcurrido desde la fecha de la primera respuesta completa (RC) o respuesta parcial (RP) documentada hasta la fecha de la primera progresion de la enfermedad documentada o la muerte debida a cualquier causa.
    - SLP según determine el investigador
    - TR, definido como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la primera respuesta completa (RC) o respuesta parcial (RP) documentada, según valoración del investigador y del CRI conforme a los criterios RECIST v1.1.

    Calidad de vida evaluada mediante herramientas validadas.

    Resultados de economía sanitaria evaluados mediante el instrumento EQ-5D-5L.

    Toma de muestras de sangre seriada o dispersa en momentos especificos para la determinación de los perfiles de concentración plasmática-tiempo y parámetros farmacocinéticos (FC) de AG-120.

    Toma de muestras de sangre en momentos específicos para la determinación de los niveles de 2-HG para caracterizar los efectos farmacodinámicos (FD) de AG-120.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening
    D1, D15 and D28 of each cycle
    end of treatment
    safety follow-up
    Selección
    D1, D15 y D28 de cada ciclo
    Fin de tratamiento
    Seguimiento de seguridad
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    France
    Germany
    Italy
    Korea, Republic of
    Spain
    United Kingdom
    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
    LVLS
    UVUS (última visita del último sujeto)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 86
    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 state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 103
    F.4.2.2In the whole clinical trial 186
    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 are released into Standard of Care
    Los pacientes seguirán tratados segun práctica clinica habitual.
    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 Decision2017-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-30
    P. End of Trial
    P.End of Trial StatusCompleted
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