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    EudraCT Number:2012-003524-21
    Sponsor's Protocol Code Number:D4880C00003
    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:2013-07-12
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-003524-21
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Second- or Third-line Treatment of Subjects with Unresectable Pleural or Peritoneal Malignant Mesothelioma
    Ensayo de fase 2, aleatorizado y con doble enmascaramiento, de comparación entre tremelimumab y placebo en el tratamiento de segunda o tercera línea de pacientes con mesotelioma pleural o peritoneal maligno e irresecable
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Subjects with Unresectable Malignant Mesothelioma
    Ensayo aleatorizado y con doble enmascaramiento, de comparación entre tremelimumab y placebo en pacientes con mesotelioma pleural o peritoneal maligno e irresecable
    A.4.1Sponsor's protocol code numberD4880C00003
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01843374
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1143-4798
    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 SponsorMedImmune, LLC
    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 supportMedImmune, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedImmune, LLC
    B.5.2Functional name of contact pointClinical Trial Enquiries
    B.5.3 Address:
    B.5.3.1Street AddressOne MedImmune Way
    B.5.3.2Town/ cityGaithersburg
    B.5.3.3Post codeMD 20878
    B.5.3.4CountryUnited States
    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 nameTremelimumab
    D.3.2Product code MEDI1123
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNTremelimumab
    D.3.9.1CAS number 745013-59-6
    D.3.9.2Current sponsor codeMEDI1123
    D.3.9.3Other descriptive nameHuman cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody
    D.3.9.4EV Substance CodeSUB37101
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    unresectable pleural or peritoneal malignant mesothelioma
    mesotelioma pleural o peritoneal maligno irresecable
    E.1.1.1Medical condition in easily understood language
    malignant mesothelioma that is not surgically resectable and that has previously been treated
    mesotelioma maligno que no es resecable y que ha sido tratado previamente
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10034670
    E.1.2Term Peritoneal mesothelioma malignant localised
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10035606
    E.1.2Term Pleural mesothelioma malignant localised
    E.1.2System Organ Class 100000004864
    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 is to compare the overall survival (OS) between the 2 treatment arms (tremelimumab and placebo) in subjects with unresectable malignant mesothelioma.
    El objetivo principal es comparar la supervivencia global (SG) en los 2 grupos de tratamiento (tremelimumab y placebo) en pacientes con mesotelioma maligno irresecable.
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    - to estimate and compare durable disease-control rate (DCR), progression-free survival (PFS), overall response rate (ORR) and duration of response,
    - to evaluate the effect of tremelimumab on patient-reported outcomes (PROs),
    - to describe the safety and tolerability of tremelimumab in treated subjects,
    - to evaluate the immunogenicity of tremelimumab
    - and to describe the pharmacokinetics (PK) of tremelimumab in treated subjects.
    Los objetivos secundarios son:
    -Calcular y comparar la tasa de control de la enfermedad (TCE) duradero, supervivencia sin progresión (SSP) en los pacientes tratados, tasa de respuesta global (TRG) y duración de la respuesta.
    -Evaluar el efecto de tremelimumab en los resultados comunicados por los pacientes (CRP).
    -Describir la seguridad y la tolerabilidad de tremelimumab en los pacientes tratados;
    -Evaluar la inmunogenia de tremelimumab en los pacientes tratados;
    -Describir la farmacocinética (FC) de tremelimumab en los pacientes tratados.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following criteria:
    - Histologically and/or cytologically confirmed pleural or peritoneal malignant mesothelioma. Disease not amenable to curative surgery;

    - Age 18 and over at the time of consent;

    - ECOG Performance status 0-1;

    - Previous receipt of 1-2 prior systemic chemotherapies that included first-line pemetrexed (or anti-folate)-based regimen in combination with platinum agent;

    - Recovered from all toxicities associated with prior treatment

    - Measurable disease

    - Adequate bone marrow, hepatic, and renal function

    - Negative screening test results for human immunodeficiency virus (HIV), hepatitis A, B and C.

    - Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive authorization in the EU) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations;

    - Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product;

    - Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Day 1 through 90 post last dose.
    Los pacientes deberán cumplir todos los criterios siguientes:

    -Mesotelioma maligno pleural o peritoneal confirmado por histología o por citología; Enfermedad que no se puede curar por cirugía;

    -Edad de 18 años o más en el momento del consentimiento;

    -Estado funcional ECOG de 0 a 1;

    -Tratamiento previo con 1 o 2 pautas de quimioterapia sistémica, a base de permetrexed (o un antifolato) combinado con platino en primera línea.

    -Haberse recuperado de todos los efectos tóxicos asociados al tratamiento previo,

    -Enfermedad mensurable

    -Funciones medular, hepática y renal satisfactorias

    -Resultado negativo en las pruebas de detección de los virus de la inmunodeficiencia humana (VIH) y de las hepatitis A, B y C.

    -El paciente o su representante legal deberán otorgar su consentimiento informado por escrito y cualquier autorización local que sea necesaria (p.ej., la HIPAA en los Estados Unidos, la autorización de la Directiva sobre protección de datos en la UE) antes de someterse a cualquier actuación relacionada con el protocolo, incluidas las evaluaciones de selección;

    -Las mujeres en edad fértil que mantengan relaciones sexuales con un varón no esterilizado deberán comprometerse a utilizar un anticonceptivo de gran eficacia desde 28 días antes de recibir la primera dosis del producto en investigación hasta 6 meses después de la última;

    -Los varones no esterilizados que mantengan relaciones sexuales con mujeres en edad fértil deberán utilizar un anticonceptivo de gran eficacia desde el día 1 hasta el día 90 después de la última administración.
    E.4Principal exclusion criteria
    Any of the following would exclude the subject from participation in the study:

    - Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1);

    - History of chronic inflammatory or autoimmune disease;

    - Active, untreated central nervous system (CNS) metastasis;

    - History of other malignancy unless the subject has been disease-free for at least 3 years. Non-invasive cancer history (such as carcinoma in situ [CIS] that has been resected) is allowed;

    - Pregnant or breast feeding at time of consent;

    - Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol;

    - Active or history of diverticulitis. Note that diverticulosis is permitted;

    - Active or history of inflammatory bowel disease (eg, colitis,
    Crohn's), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosis or Wegener's granulomatosis;

    - History of sarcoidosis syndrome;

    - Currently receiving systemic corticosteroids or other
    immunosuppressive medications;

    - Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment;

    - The last dose of prior chemotherapy or radiation therapy (with the exception of palliative radiotherapy) was received less than 2 weeks prior to randomization;

    - Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;

    - Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks (participation in the survival follow-up period of a study is not an exclusion criterion);

    - Employees of the study site directly involved with the conduct of the study, or immediate family members of any such individuals.
    No podrán participar en el estudio los pacientes que cumplan cualquiera de las siguientes condiciones:

    -Pacientes que hayan recibido tratamiento con un anticuerpo monoclonal anti-CTLA-4, con proteína de muerte celular programada 1 (PD1) o con ligando 1 de la proteína de muerte celular programada 1 (PD-L1);

    -Antecedentes de enfermedad inflamatoria crónica o autoinmunitaria;

    -Metástasis activa y no tratada en el sistema nervioso central (SNC);

    -Antecedentes de otros trastornos malignos, salvo que el paciente esté libre de la enfermedad desde al menos 3 años antes; Se permiten los antecedentes de cáncer no invasivo (como carcinoma in situ [CIS] resecado);

    -Paciente embarazada o en periodo de lactancia en el momento del consentimiento;

    -Cualquier trastorno que le impida al paciente entender o facilitar información y aceptar y cumplir los requisitos de este protocolo;

    -Diverticulitis, activa o en el pasado. Obsérvese que se acepta la diverticulosis.

    -Enfermedad inflamatoria intestinal (p. ej., colitis, enfermedad de Crohn) activa o en el pasado, enfermedad del intestino irritable, enfermedad celíaca u otras enfermedades digestivas crónicas graves que se asocien a diarrea; Lupus eritematoso sistémico o granulomatosis de Wegener, activas o en el pasado;

    -Antecedentes de síndrome de sarcoidosis;

    -Pacientes que reciban tratamiento en la actualidad con corticosteroides sistémicos o con otros inmunosupresores;

    -Los pacientes no podrán recibir vacunas atenuadas vivas en el mes previo al inicio del tratamiento con tremelimumab;

    -Los pacientes no podrán haber recibido quimioterapia ni radioterapia (salvo radioterapia paliativa) en las 2 semanas previas a la aleatorización;

    -Cualquier trastorno que, en opinión del investigador, pueda interferir en la evaluación del producto en investigación o en la interpretación de la seguridad del paciente o de los resultados del estudio;

    -Reclutamiento concurrente en otro estudio clínico, o haber recibido un producto en investigación en las 4 últimas semanas (la participación en el período de seguimiento de la supervivencia de un estudio no será motivo de exclusión);

    -Empleados del centro de estudio que intervengan directamente en el estudio, o sus familiares directos.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is OS which is defined as the time from randomization until death due to any cause.
    El criterio de valoración principal es la SG, que se define como el tiempo que transcurre desde la aleatorización hasta la muerte por cualquier causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of OS will be performed after a number of deaths have occurred among the approximately 180 participants randomized. For participants who are alive at the time of the primary analysis or lost to follow-up, OS will be censored on the last date when participants are known to be alive.
    El análisis principal de este criterio de valoración se llevará a cabo cuando se hayan producido un número de fallecimientos en los aproximadamente 180 pacientes aleatorizados. En el caso de los pacientes que sigan vivos en el momento del análisis principal o que se pierdan en el seguimiento, la SG se censará en la última fecha en la que se tenga conocimiento de que aún estaban con vida
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints include PRO as well as durable DCR, PFS, ORR, and duration of response, based on modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural mesothelioma and RECIST criteria v1.1 for peritoneal mesothelioma.

    The safety endpoints include adverse events (AEs) and serious adverse events (SAEs) from the time that written informed consent is obtained through 90 days after the last dose of investigational product, changes from baseline in clinical laboratory evaluations, electrocardiograms (ECGs), and vital signs. Adverse events and SAEs will be assessed for severity and relationship to investigational product.

    The immunogenic potential of tremelimumab will be analyzed and the pharmacokinetics of tremelimumab will be assessed.
    Los criterios secundarios de valoración de la eficacia son la TCE duradero, la SSP, la puntuación LCSS-Meso, la TRG y la duración de la respuesta, basada en los RECIST modificados para el mesotelioma pleural y en la versión 1.1 de dichos criterios para el mesotelioma peritoneal.

    Los criterios de valoración de la seguridad son los acontecimientos adversos (AA) y los acontecimientos adversos graves (AAG) desde el momento de la firma del consentimiento informado por el paciente hasta 90 días después de la administración de la última dosis del producto en investigación, las variaciones desde el inicio en la evaluaciones analíticas, los electrocardiogramas (ECG) y las constantes vitales. Se evaluarán la intensidad de los AA y los AAG y su relación con el producto en investigación.

    Se llevará a cabo un análisis del potencial inmunógeno de tremelimumab y se evaluará la farmacocinética de tremelimumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analysis of these secondary endpoints will be based on investigator-determined response data
    El análisis de estas variables secundarias se basará en datos de respuesta determinados por el investigador.
    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 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. 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 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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA76
    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
    Korea, Republic of
    Russian Federation
    South Africa
    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 end of the study (?study completion?) is defined as the date when the prespecified number of death events has been reached for the primary endpoint or the date the sponsor stops the study.
    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 months3
    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 months3
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 180
    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)
    An individual subject will be considered to have completed the study if the subject was followed up through the end of the study as defined in Section 4.9 of Protocol or met the primary endpoint of the study.

    Subjects will be considered not to have completed the study if consent was withdrawn or the subject was lost to follow-up.
    After the end of study, subjects who are still receiving treatment and considered to be gaining benefit will be provided with an option for continued treatment.
    Un paciente ha completado el estudio si ha recibido seguimiento hasta el final del estudio como se define en el apartado 4.9 o si cumple el crit. de valoración principal del estudio. Un paciente no ha completado el estudio si retira su consentimiento o si se pierde el contacto con él durante el seguimiento. Una vez concluido el estudio, los pacientes que sigan recibiendo tratamiento y se considere que se benefician de él tendrán la opción de seguir recibiéndolo (i.e.estudio de continuación).
    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 Decision2013-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-12
    P. End of Trial
    P.End of Trial StatusCompleted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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