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    Summary
    EudraCT Number:2012-005201-48
    Sponsor's Protocol Code Number:1199.93
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-11-23
    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 number2012-005201-48
    A.3Full title of the trial
    Double blind, randomised, multicentre, phase II/III study of nintedanib in combination with pemetrexed / cisplatin followed by continuing nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin followed by continuing placebo monotherapy for the treatment of patients with unresectable malignant pleural mesothelioma
    Estudio de fase II/III doble ciego, aleatorizado y multicéntrico de nintedanib en combinación con pemetrexed/cisplatino seguido de nintedanib en monoterapia frente a placebo en combinación con pemetrexed/cisplatino seguido de placebo en monoterapia para el tratamiento de pacientes con mesotelioma pleural maligno irresecable
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nintedanib (BIBF 1120) in Mesothelioma
    Nintedanib (BIBF 1120) en Mesotelioma
    A.4.1Sponsor's protocol code number1199.93
    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 SponsorBoehringer Ingelheim España, S.A.
    B.1.3.4CountrySpain
    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 supportBoehringer Ingelheim España, S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number+34 (93) 404-5100
    B.5.5Fax number+34 (93) 404-5580
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.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 Yes
    D.2.1.1.1Trade name Vargatef
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    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 100 mg capsules
    D.3.2Product code BIBF 1120
    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
    D.3.9.2Current sponsor codeBIBF 1120
    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 International GmbH
    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 150 mg capsules
    D.3.2Product code BIBF 1120
    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
    D.3.9.2Current sponsor codeBIBF 1120
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    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
    Unresectable Malignant Pleural Mesothelioma
    Mesotelioma pleural maligno irresecable
    E.1.1.1Medical condition in easily understood language
    Cancer of the pleura (the lining covering the lungs) which cannot be treated by surgery
    Cáncer de la pleura (revestimiento de los pulmones) que no puede ser tratado con cirugía
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10059518
    E.1.2Term Pleural mesothelioma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the randomised, parallel-controlled Phase II/III study is to evaluate the safety and efficacy in terms of progression-free survival of nintedanib + pemetrexed / cisplatin followed by nintedanib (arm A) versus placebo + pemetrexed / cisplatin followed by placebo (arm B), as first line treatment for patients with unresectable MPM.
    El objetivo principal del estudio de fase II/III aleatorizado, paralelo-controlado es evaluar la seguridad y eficacia en términos de supervivencia libre de progresión de nintedanib + pemetrexed/cisplatino seguido de nintedanib (brazo A) frente a placebo + pemetrexed/cisplatino seguido de placebo (brazo B), como primera línea tratamiento para los pacientes con MPM irresecable.
    E.2.2Secondary objectives of the trial
    The key secondary objective is to evaluate OS in patients treated with the nintedanib regimen (arm A) versus the placebo regimen (arm B). Further secondary objectives are to evaluate the objective tumour response rate and to evaluate the disease control rate. Further objectives in this trial are to evaluate related measures of tumour response, to assess the percentage changes from baseline in forced vital capacity (FVC), to obtain information on quality of life (QoL), and to examine exposure to nintedanib in patients with unresectable MPM. In addition, biological specimens will be collected for the evaluation of molecular markers and possible correlation with treatment outcome
    El objetivo secundario clave es evaluar la SG en pacientes tratados con la pauta posológica de nintedanib (brazo A) frente a la pauta posológica de placebo (brazo B).
    Otros objetivos secundarios son evaluar la tasa de respuesta tumoral objetiva y la tasa de control de la enfermedad. Otros objetivos en este estudio son evaluar medidas relativas a la respuesta tumoral, evaluar el porcentaje de variación de la capacidad vital forzada (CVF) en comparación con el estado basal, obtener información sobre la calidad de vida (CdV), y analizar la exposición de nintedanib en pacientes con MPM irresecable. Además, se recogerán muestras biológicas para la evaluación de marcadores moleculares y la posible correlación con el resultado del tratamiento.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    No individual trial protocols will be used for substudies. The following investigations are integrated in the protocol of the main study:

    - Optional analysis of archived tumour tissue and serum derived biomarkers: the set of planned biomarkers is exploratory in nature and will be used as hypothesis-generating studies
    - Optional pharmacogenomic analysis: Genotyping of promoter variants in the mesothelin gene, analysis of polymorphisms in the genes encoding for VEGFR1 and VEGFR3 and DNA-banking
    No se utilizarán protocolos individuales del estudio para sub-estudios. Las siguientes investigaciones están integradas en el protocolo del estudio principal:
    - Análisis opcional del tejido tumoral de archivo y biomarcadores derivados de sérum: el conjunto de biomarcadores previstos es de carácter exploratorio y se utilizará como estudios generadores de hipótesis
    - Análisis opcional farmacogenómico: Genotipado de las variantes promotoras en el gen mesotelina, análisis de polimorfismos en los genes codificadores de VEGFR1 y VEGFR3 y banco de ADN.
    E.3Principal inclusion criteria
    - Histologically confirmed MPM (subtype: epithelioid or biphasic)
    - Life expectancy of at least 3 months in the opinion of the investigator
    - ECOG score of 0 or 1
    - Measurable disease according to modified RECIST criteria
    - MPM confirmado histológicamente (subtipo: epitelioide o bifásico)
    - Esperanza de vida de mínimo 3 meses en la opinión del investigador
    - Estado funcional de 0 o 1 según el Eastern Cooperative Oncology Group (ECOG).
    - Enfermedad medible según los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) modificados
    E.4Principal exclusion criteria
    - Previous systemic chemotherapy for MPM
    - Prior treatment with nintedanib or any other prior line of therapy
    - Patients with sarcomatoid subtype MPM
    - Radiotherapy (except extremities) within 3 months prior to baseline imaging
    - Patients that may be eligible for or being considered for radical resection or elective surgery during the course of the study.
    - Radical surgery within 4 weeks prior to randomisation
    - Active brain metastases (e.g. stable for < 4 weeks)
    - Therapeutic anticoagulation or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day)
    - Major injuries within the past 4 weeks prior to randomisation with incomplete wound healing
    - Other malignancies within 3 years prior to screening other than basal cell skin cancer or carcinoma in situ of the cervix
    - Quimioterapia sistémica previa para MPM
    - Tratamiento previo con nintedanib u otra línea de terapia previa
    - Pacientes con subtipo MPM sarcomatoide
    - Radioterapia (excepto extremidades) en los 3 meses previos a la imagen en el estado basal
    - Pacientes que pueden ser elegibles o ser considerados para resección radical o cirugía electiva durante el curso del estudio.
    - Cirugía radical en las 4 semanas previas a la aleatorización
    - Metástasis cerebral activa (e.g. estable durante < 4 semanas)
    - Anticoagulación terapéutica o terapia anti-plaquetas (excepto terapia dosis baja con ácido acetilsalicílico < 325 mg por día)
    - Lesiones mayores en las últimas 4 semanas previas a la aleatorización con curación de la herida incompleta
    - Otras malignidades dentro de los 3 años previos a la exploración diferentes al cáncer de piel celular basal o carcinoma de cuello uterino in situ
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival measured from the time of randomisation to the time of disease progression or death of any cause, whichever occurs earlier
    Supervivencia libre de progresión medida desde el momento de aleatorización hasta que se produzca progresión de la enfermedad o muerte por cualquier causa, cualquiera que ocurra antes
    E.5.1.1Timepoint(s) of evaluation of this end point
    The observation period for PFS will continue until approximately 237 OS events have occurred for Phase III patients or until approximately 44 months has elapsed since the first Phase III patient was randomised

    Planned timepoint: November 2018
    El periodo de observación para SLP continuará hasta que hayan ocurrido aproximadamente 237 acontecimientos de supervivencia global (OS) para pacientes en fase III o hasta que hayan transcurrido 44 meses desde que el primer paciente en fase III fue aleatorizado.

    Criterio de valoración programado: noviembre 2018
    E.5.2Secondary end point(s)
    - Overall survival measured from the time of randomisation to the time of death of any cause (key secondary endpoint)
    - Objective response according to modified RECIST analysed by objective response rate
    - Disease control according to modified RECIST analysed by disease control rate
    - Supervivencia global medida desde el momento de aleatorización hasta que se produzca la muerte por cualquier causa (criterio secundario de valoración clave)
    - Respuesta objetiva según los criterios RECIST modificados analizada por tasa de respuesta objetiva
    - Control de la enfermedad según los criterios RECIST modificados analizado por tasa de control de la enfermedad
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the time of PFS analysis (November 2018) and if patients are still ongoing or in follow-up at the time of the clinical trial report for PFS, the clinical trial database will be kept open to collect the additional data.

    Final evaluation: November 2018
    En el momento del análisis de la SLP (noviembre 2018) y si los pacientes están todavía en tratamiento o en seguimiento en el momento del informe del estudio clínico para SLP, la base de datos del estudio clínico se mantendrá abierta para recoger datos adicionales.

    Evaluación final: noviembre 2018
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker
    Biomarcador
    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) 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) No
    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 EEA64
    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
    Argentina
    Australia
    Austria
    Belgium
    Canada
    Chile
    Czech Republic
    Denmark
    Egypt
    France
    Germany
    Israel
    Italy
    Mexico
    Netherlands
    Norway
    Poland
    Portugal
    Russian Federation
    South Africa
    Spain
    Sweden
    Switzerland
    Turkey
    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
    The trial will be considered completed 18 months after the last patient was randomised. The primary analysis of PFS will be conducted and reported when approximately 237 patients have progressed or died. However, it may also be performed with fewer events within approximately 44 months total trial duration. If patients are still ongoing or in follow-up at the time of the clinical trial report for PFS, the clinical trial database will be kept open to collect the additional data.
    El estudio se considerará finalizado 18 meses tras la aleatorización del último paciente.
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 262
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 214
    F.4.2.2In the whole clinical trial 397
    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 will be treated in the trial until cancer progression or undue toxicity. Follow-up treatment after disease progression is at the discretion of the treating physician according to local standard of care.
    If the trial is ended by the sponsor for any reason, patients still being treated with a clinical benefit will be offered treatment in a follow-up trial. In case the trial is terminated by the sponsor for safety reasons, patients will not continue treatment with the trial drug.
    Los pacientes serán tratados en el ensayo hasta progresión del cáncer o toxicidad indebida. Tratamiento de seguimiento tras la progresión de la enfermedad es a criterio del médico que le trata según las normas locales.
    Si el el promotor finaliza el estudio por cualquier razón, a los pacientes todavía tratados con un beneficio clínico se les ofrecerá tratamiento en un estudio de seguimiento. En el caso de que se finalice por razones de seguridad, los pacientes no continuarán el tratamiento.
    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 Decision2016-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-08-28
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