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    Summary
    EudraCT Number:2016-002093-12
    Sponsor's Protocol Code Number:1506-STBSG
    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:2017-05-08
    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 number2016-002093-12
    A.3Full title of the trial
    A Phase II multicenter study comparing the efficacy of the oral angionenesis inhibitor nintedanib with the intravenous cytotoxis compound ifosfamide for treatment of patients with advanced metastatic soft tissue sarcoma after failure of systemic non-oxazaphosporine-based first line chemotherapy for inoperable disease "ANITA"
    Estudio multicéntrico de fase II para comparar la eficacia del inhibidor de la angiogénesis por vía oral nintedanib con el compuesto citotóxico intravenoso ifosfamida en el tratamiento de pacientes con sarcoma de partes blandas metastásico avanzado después del fracaso de una quimioterapia sistémica de primera línea sin oxazafosforinas para la enfermedad inoperable, "ANITA"
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nintedanib vs. ifosfamide in soft tissue sarcoma
    A.4.1Sponsor's protocol code number1506-STBSG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02808247
    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 SponsorEuropean Organisation for Research and Treatment of Cancer (EORTC)
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBoehringer Ingelheim
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportEuropean Organisation for the Research and Treatment of Cancer (EORTC)
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for the Research and Cancer (EORTC)
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street Address83/11 Avenue E. Mounier
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number003227741013
    B.5.5Fax number003227741030
    B.5.6E-mailregulatory@eortc.be
    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 Yes
    D.2.1.1.1Trade name Vargatef
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNintedanib
    D.3.2Product code BIBF1120
    D.3.4Pharmaceutical form Capsule, soft
    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 INNNintedanib 100 mg
    D.3.9.1CAS number 656247-17-5
    D.3.9.3Other descriptive nameNINTEDANIB
    D.3.9.4EV Substance CodeSUB120728
    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: 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 Yes
    D.2.1.1.1Trade name Vargatef
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNintedanib
    D.3.2Product code BIBF1120
    D.3.4Pharmaceutical form Capsule, soft
    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 INNNintedanib 150 mg
    D.3.9.1CAS number 656247-17-5
    D.3.9.3Other descriptive nameNINTEDANIB
    D.3.9.4EV Substance CodeSUB120728
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Yes
    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 nameIfosfamide
    D.3.2Product code Powder for concentrate for solution
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIfosfamide
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit gm/m2 gram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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
    Metastatic soft tissue sarcoma
    E.1.1.1Medical condition in easily understood language
    Metastatic soft tissue sarcoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level HLGT
    E.1.2Classification code 10041299
    E.1.2Term Soft tissue sarcomas
    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 SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the trial is to evaluate whether nintedanib given as second-line therapy for advanced, inoperable and/or metastatic STS prolongs progression-free survival when compared with ifosfamide.
    El objetivo principal del ensayo es evaluar si nintedanib administrado como tratamiento de segunda línea para el SPB avanzado, inoperable o metastásico prolonga la supervivencia sin progresión en comparación con la ifosfamida.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to evaluate the efficacy of nintedanib as compared to ifosfamide in terms of progression-free rate at 12 weeks, overall survival, objective response rate, patient benefit rate, response duration, total duration of treatment with nintedanib safety, Health related Quality of Life and Health Economics.
    Los objetivos secundarios son evaluar la eficacia de nintedanib en comparación con ifosfamida en términos de la tasa de supervivencia sin progresión a las 12 semanas, la supervivencia general, la tasa de respuesta objetiva, la tasa de beneficio para el paciente, la duración de la respuesta, la duración total del tratamiento con nintedanib, la seguridad, la calidad de vida relacionada con la salud y la economía de la salud.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ♦ Histologically proven advanced, inoperable (medical or surgical) and/or metastatic malignant STS of intermediate or high grade
    ♦ Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial.
    ♦ Prior to study enrolment, all patients need to have confirmed RECIST 1.1 disease progression based on local investigator's assessment.
    ♦ Presence of measurable disease according to RECIST 1.1.
    ♦One (and no less or more than one) line of previous systemic chemotherapy for advanced, inoperable and/or metastatic malignant STS.
    ♦ Age 18 years or older
    ♦ WHO performance status (PS) 0-2.
    ♦ Life expectancy of at least 3 months.
    ♦ Adequate bone marrow, liver and renal function and coagulation parameters
    ♦ Normal cardiac function, 12 lead electrocardiogram without clinically relevant abnormalities. No Class III or IV congestive heart failure, angina pectoris, myocardial infarction within 1 year before registration/randomization, clinically significant cardiac arrhythmia or pericardial effusion.
    ♦Absence of active or uncontrolled infections in particular if requiring systemic antibiotics or antimicrobial therapy.
    ♦ Absence of serious illnesses or medical conditions, including a history of chronic alcohol abuse, active and chronic hepatitis B or C, chronic infection with HIV or clinically relevant liver cirrhosis.
    ♦ Absence of active gastrointestinal disorders or abnormalities that interfere with absorption of the study drug.
    ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration/randomization in the trial.
    ♦ Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to randomization.
    ♦ Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the last study treatment as follows:
    ♦ Nintedanib: for at least 3 months after the last dose
    ♦ Ifosfamide: for at least 1 year after the last dose
    ♦ A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
    ♦ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
    ♦ Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
    ♦ Intrauterine device (IUD)
    ♦ Intrauterine hormone-releasing system (IUS)
    ♦ Bilateral tubal occlusion
    ♦ Vasectomised partner
    ♦ Sexual abstinence
    Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.
    ♦ Female subjects who are breast feeding should discontinue nursing prior to randomization and until 6 months after the last study treatment.
    ♦ Sexually active male participants must use a barrier method of contraception (e.g., condom) during the study treatment period and for at least 3 months (nintedanib) or 6 months (ifosfamide) after the last study treatment.
    ♦ Before patient registration/randomization, written informed consent must be obtained according to international conference on harmonisation/Good clinical practice (ICH/GCP) and national/local regulations.
    •SPB maligno, avanzado, inoperable (por motivos médicos o quirúrgicos) o metastásico de grado intermedio o alto demostrado histológicamente
    •Los cortes de tejido sin tinción o los bloques tumorales representativos fijados en formalina y embebidos en parafina, ya sea del tumor principal o de una lesión metastásica, deben estar disponibles para la revisión histológica central. La revisión histológica central no es necesaria antes del inicio del tratamiento, pero es obligatorio enviar cortes de tumor sin tinción (bloques opcionales) en el momento de entrada en el estudio. Se aceptará el diagnóstico histopatológico local para entrar en este ensayo.
    •Antes de la inscripción en el estudio, todos los pacientes deben presentar progresión de la enfermedad confirmada conforme a los criterios RECIST 1.1, basándose en la evaluación local del investigador.
    •Presencia de enfermedad medible conforme a los criterios RECIST 1.1.
    •Una (y no menos o más de una) línea de quimioterapia sistémica previa para el SPB maligno, avanzado, inoperable o metastásico.
    •Edad de 18 años o más.
    •Estado funcional (EF) 0-2 según la OMS.
    •Esperanza de vida de al menos 3 meses.
    •Función renal, hepática y de la médula ósea, y parámetros de coagulación adecuados
    •Función cardíaca normal (fracción de eyección del ventrículo izquierdo [FEVI] evaluada mediante ventriculografía isotópica o ecografía cardíaca dentro del rango normal de la institución), electrocardiograma de 12 derivaciones (ECG) sin anomalías clínicamente relevantes.
    •Ausencia de infecciones activas o no controladas, en particular si requieren antibióticos sistémicos o tratamiento antimicrobiano.
    •Ausencia de enfermedades o afecciones médicas graves, incluidos antecedentes de alcoholismo crónico, hepatitis B o C crónica y activa, infección crónica con VIH o cirrosis hepática clínicamente relevante.
    •Ausencia de trastornos gastrointestinales activos o anomalías que interfieren con la absorción del fármaco del estudio.
    •Ausencia de antecedentes, en los últimos cinco años, de neoplasias malignas distintas de SPB (excepto: carcinoma de células basales o escamosas de la piel, carcinoma in situ de cuello de útero, cáncer de próstata resecado en estadio pT1-2 con una puntuación de Gleason ≤6 y PSA posoperatorio <0,5 ng/ml). Los pacientes con antecedentes de otras neoplasias malignas que estén libres de enfermedad de esa afección durante más de 5 años son aptos.
    •Las mujeres en edad fértil (MEF) deben tener una prueba de embarazo en suero negativa dentro de las 72 horas previas a la aleatorización.
    ♦Las pacientes en edad fértil/con capacidad de concebir deben usar medidas de anticoncepción adecuadas, según la definición del investigador, durante el periodo de tratamiento del estudio y después del último tratamiento del estudio, tal como se indica:
    ♦Nintedanib: Por al menos 3 meses después de la última dosis.
    ♦Ifosfamida: Por al menos 1 año después de la ultima dosis
    ♦Un método anticonceptivo altamente eficaz se define como aquel que tiene una baja tasa de fallo (es decir, inferior al 1 % anual) cuando se usa de manera sistemática y correcta. Tales métodos incluyen:
    ♦Contracepción hormonal combinada (que contienen estrógenos y progestererona) asociada a un inhibidor de la ovulación (oral, transdérmico, intravaginal).
    ♦Contracepción basada exclusivamente en progesterona asociada con la inhibición de la ovulación (oral, inyectable, implantable).
    ♦Dispositivo intrauterino (DIU)
    ♦Sistema de liberación de hormonas intrauterino (SIU)
    ♦Oclusión tubárica bilateral.
    ♦Compañero vasectomizado.
    ♦Abstinencia sexual.
    ♦Ya que el efecto de nintedanib sobre el metabolismo y eficacia de los contraceptivos , no se ha investigado, los métodos de barrera deberían ser aplicados como una segunda forma de contracepción con objeto de evitar el embarazo
    ♦Las pacientes de sexo femenino que estén en periodo de lactancia, deben interrumpirla antes de la aleatorización y hasta 6 meses después del último tratamiento del estudio.
    ♦Los participantes varones sexualmente activos deben usar un método anticonceptivo de barrera (p. ej., preservativo) durante el periodo de tratamiento del estudio y durante al menos 3 meses (nintedanib) o 6 meses (ifosfamida) después del último tratamiento del estudio.
    •Antes del registro/la aleatorización de los pacientes, se debe obtener el consentimiento informado por escrito de acuerdo con la Conferencia Internacional sobre la Armonización (ICH)/las buenas prácticas clínicas (BPC) y las normativas nacionales/locales.
    E.4Principal exclusion criteria
    ♦History of central nervous system metastasis or leptomeningeal tumor spread.
    ♦Active brain metastases
    ♦Other anti-cancer therapy within 28 days prior to randomization.
    ♦Treatment with another investigational agent within 28 days prior to randomization.
    ♦Treatment with another investigational agent concomitantly with the trial.
    ♦Known hypersensitivity to or known specific contraindications for the use of nintedanib or ifosfamide.
    ♦Known hypersensitivity to peanut or soy bean.
    ♦Child Pugh B or C hepatic impairment.
    ♦Uncontrolled arterial hypertension defined at baseline as blood pressure ≥ 150/100 mmHg despite adequate medical therapy.
    ♦Use of therapeutic anticoagulation or anti-platelet therapy
    ♦Known inherited predisposition for bleeding or thromboembolism.
    ♦History of clinically significant hemorrhagic or thromboembolic event in the past 6 months.
    ♦previous encephalopathy of any cause or other significant neurological condition.
    ♦acute or chronic, clinically relevant inflammation of urinary bladder.
    ♦major injuries and/or surgery within the past 28 days prior to randomization with incomplete wound healing and/or planned surgery during the on-treatment study period.
    ♦persistence of clinically relevant therapy-related toxicity from previous chemotherapy and/or radiotherapy. Grade 1 or 2 adverse events (AEs) are acceptable.
    ♦history, within the past five years, of malignancies other than STS
    ♦active alcohol or drug abuse.
    •Antecedentes de metástasis en el sistema nervioso central o de diseminación tumoral a las leptomeninges.
    •metástasis cerebral activa
    •otros tratamientos antineoplásicos (tratamiento sistémico, radioterapia (excepto para el cerebro y las extremidades), cirugía, perfusión de extremidades, inmunoterapia) dentro de los 28 días previos a la aleatorización.
    •tratamiento con otro agente en investigación dentro de los 28 días previos a la aleatorización.
    •tratamiento con otro agente en investigación de forma concomitante con el ensayo.
    •hipersensibilidad conocida o contraindicaciones específicas conocidas para el uso de nintedanib o de ifosfamida.
    •hipersensibilidad conocida a los cacahuetes o la soja.
    •insuficiencia hepática de clase B o C según Child Pugh.
    •hipertensión arterial no controlada, definida al inicio como una presión arterial ≥150/100 mmHg a pesar del tratamiento médico adecuado.
    •uso de anticoagulación o tratamiento antiplaquetario
    •predisposición heredada para el sangrado o tromboembolismo.
    •antecedentes de hemorragia clínicamente significativa o acontecimiento tromboembólico en los últimos 6 meses.
    •encefalopatía previa por cualquier causa u otra afección neurológica significativa.
    •inflamación aguda o crónica, clínicamente relevante de la vejiga urinaria.
    •lesiones o cirugía durante los últimos 28 días previos a la aleatorización con curación incompleta de la herida o cirugía programada durante el periodo de tratamiento en el estudio.
    •persistencia de toxicidad clínicamente relevante relacionada con la quimioterapia o radioterapia previas. Los acontecimientos adversos (AA) de grado 1 o 2 son aceptables.
    •abuso activo de alcohol o fármacos.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end-point is progression-free survival defined according to RECIST 1.1.
    Criterio de valoración principal: Supervivencia sin progresión (RECIST 1.1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor evaluations for the assessment of PFS will be done every 6 weeks during the first 48 weeks and every 12 weeks thereafter
    La evaluación de los tumores afin de avaluar la supervivencia sin progresión se realizarán cada 6 semanas durante las primeras 48 semanas y cada 12 semanas después
    E.5.2Secondary end point(s)
    Secondary end-points include:
    ♦ Progression-free rate at 12 weeks (binary)
    ♦ Overall survival
    ♦ Objective response rate
    ♦ Clinical benefit rate
    ♦ Response duration
    ♦ Total duration of treatment with nintedanib (including treatment beyond RECIST progression)
    ♦ Safety (Common Toxicity Criteria CTCAE 4.0)
    ♦ Health related quality of life (QLQ-C30)
    ♦ Health economics (EQ-5D-5L, health care resource utilities)
    Criterios de valoración secundarios:
    • Tasa de supervivencia sin progresión a las 12 semanas (binaria)
    • Supervivencia general
    • Tasa de respuesta objetiva
    • Tasa de beneficio clínico
    • Duración de la respuesta
    • Duración total del tratamiento con nintedanib (incluido el tratamiento después de la progresión según RECIST)
    E.5.2.1Timepoint(s) of evaluation of this end point
    ♦ Progression-free rate at 12 weeks
    ♦ OS every 3 weeks during treatment, every 12 weeks thereafter until death
    ♦ ORR Tumor evaluations for the assessment of ORR will be done every 6 weeks during the first 48 weeks and every 12 weeks thereafter
    ♦ Total duration of treatment with nintedanib: every 3 weeks until end of treatment
    ♦ Safety every 3 weeks during treatment + 30 days after the last dose of study treatment
    ♦ Health related quality of life: within 7 days before randomization; every 3 weeks during the treatment period only for limited period, it changes to link to tumor assessments
    ♦ Health economics: within 7 days before randomization; every 3 weeks during the treatment period only for limited period, it changes to link to tumor assessments
    ♦ Tasa de supervivencia sin progresión a las 12 semanas (binaria)
    ♦ Supervivencia general cada 3 semanas durante el tratamiento, cada 12 semanas después hasta la muerte
    ♦ Tasa de respuesta objetiva cada 6 semanas durante las primeras 48 semanas, cada 12 semanas después
    ♦ Duración total del tratamiento con nintedanib cada 3 semanas hasta fin del tratamiento
    ♦ Seguridad cada 3 semanas durante el tratamiento + 30 días después de la última dosis de tratamiento del estudio
    ♦ Calidad de vida relacionada con la salud: en los 7 días antes de la aleatorización; cada 3 semanas durante el período de tratamiento sólo por un período limitado
    ♦ Economía de la salud: en los 7 días antes de la aleatorización; cada 3 semanas durante el período de tratamiento sólo por un período limitado
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 Yes
    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 EEA17
    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
    Belgium
    France
    Israel
    Lithuania
    Netherlands
    Poland
    Spain
    Switzerland
    United Kingdom
    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
    End of study occurs when all of the following criteria have been satisfied:
    1. Thirty days after all patients have stopped protocol treatment
    2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
    3. The database has been fully cleaned and frozen for this analysis
    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 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: 103
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 143
    F.4.2.2In the whole clinical trial 158
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The treatment will be left to the discretion of the treating physician.
    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 Decision2017-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-05-13
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