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    Summary
    EudraCT Number:2016-002307-26
    Sponsor's Protocol Code Number:0216-ASG
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-03-31
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-002307-26
    A.3Full title of the trial
    A phase II single arm clinical trial of a Tailored ImmunoTherapy Approach with Nivolumab in subjects with metastatic or advanced Renal Cell Carcinoma
    Ensayo clínico en fase II y de un solo grupo de un enfoque de inmunoterapia personalizada con nivolumab en sujetos con carcinoma de células renales metastásico o avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of a Tailored ImmunoTherapy Approach with Nivolumab in subjects with metastatic or advanced Renal Cell Carcinoma
    Home Idiomas Ingresar a Epistemonikos Búsqueda avanzada Un ensayo clínico de un enfoque de inmunoterapia a medida con Nivolumab en sujetos con metastásico o avanzado carcinoma de células renales
    A.3.2Name or abbreviated title of the trial where available
    TITAN RCC
    A.4.1Sponsor's protocol code number0216-ASG
    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 SponsorAIO-Studien-gGmbH
    B.1.3.4CountryGermany
    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 supportBristol-Myers Squibb GmbH & Co KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAIO-Studien-gGmbH
    B.5.2Functional name of contact pointClinical trial desk of the sponsor
    B.5.3 Address:
    B.5.3.1Street AddressKuno-Fischer-Straße 8
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code14057
    B.5.3.4CountryGermany
    B.5.4Telephone number+49308145 34431
    B.5.6E-mailinfo@aio-studien-ggmbh.de
    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 nameNivolumab
    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 INNnivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.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) Yes
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIpilimumab
    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 INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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.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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects with previously untreated (1st line) or pretreated (2nd line), intermediate or high risk, advanced or metastatic renal cell carcinoma
    CCR avanzado (no susceptible de cirugía o radioterapia curativas) o metastásico (Estadio IV de la Comisión Conjunta Estadounidense para el Cáncer [AJCC])
    E.1.1.1Medical condition in easily understood language
    Subjects with previously untreated or pretreated, intermediate or high risk, advanced or metastatic renal cell carcinoma
    Los sujetos con carcinoma de células renales avanzado o metastásico previamente no tratado o pretratado, intermedio o de alto riesgo
    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 10038400
    E.1.2Term Renal carcinoma stage IV
    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 10038399
    E.1.2Term Renal carcinoma stage III
    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 10050076
    E.1.2Term Metastatic renal carcinoma
    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 estimate the best ORR based on investigator assessment using RECIST 1.1 of the TITAN regimen in untreated (1st line) and pretreated (2nd line) subjects with IMDC intermediate and high risk, advanced RCC with clear cell component
    Estimar la TRO basada en la valoración del investigador mediante RECIST 1.1 de la pauta TITAN en sujetos no tratados (1.a línea) y tratados previamente (2.a línea) con CCR avanzado de riesgo intermedio y alto según el modelo del consorcio internacional sobre bases de datos de CCRm (IDMC), con componente de células claras
    E.2.2Secondary objectives of the trial
    - PFS (Progression free survival), DOR (Duration of response), Time to Immunotherapy Resistance (TIR) and OS (Overall survival) in untreated (1st line) and pretreated (2nd line) patients, and the overall cohort
    - PFS, DOR, TIR and OS in subgroups of IMDC intermediate and high risk patients (1st line, 2nd line, and the overall cohort)
    - RR (Remission rate), TTR (Time to response) and DOR after nivolumab/ipilimumab combination “boost” for initial SD (Stable disease) and PD (Progressive disease), respectively
    - RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for PD during nivolumab maintenance (including re-treatment)
    - Treatment emergent adverse events according to NCI-CTC version 4 (to assess the overall safety and tolerability of the TITAN regimen)
    -To assess disease related symptoms in each arm based on the NCCN Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (Version 2)
    - immunological analysis
    -SSP, DR, TRI y SG en pacientes no tratados (1.a línea) y tratados previamente (2.a línea) y en el grupo en general
    -SSP, DR, TRI y SG en subgrupos de pacientes con riesgo IMDC intermedio y alto (1.a línea, 2.a línea y el grupo en general)
    -TR, TTR y DR tras el “refuerzo” de la combinación nivolumab/ipilimumab para la EE y la EP, respectivamente
    -TR, TTR y DR tras el “refuerzo” de la combinación de nivolumab/ipilimumab para la EP durante el mantenimiento con nivolumab (incluida la repetición de tratamiento)
    -Acontecimientos adversos surgidos durante el tratamiento según la versión 4 de los Criterios comunes de terminología del Instituto Nacional del Cáncer (CTC del NCI)
    -Evaluar la seguridad y tolerabilidad generales de la pauta TITAN
    -Evaluar los síntomas relacionados con la enfermedad en cada grupo en función del índice 19 de síntomas de cáncer renal de la evaluación funcional del tratamiento del cáncer de la NCCN (Versión 2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Written Informed Consent
    - Subjects or legally acceptable representatives must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
    - Subjects or legally acceptable representatives must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.

    2. Target Population
    - Histological confirmation of RCC with a clear-cell component.
    - Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
    - One (antioangiogenic or temsirolimus) or no prior systemic therapy for RCC with the following exception:
    One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors as well as CTLA-4- or PD-1/PD-L1 immune checkpoint inhibitors, respectively, and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
    - KPS of at least 70% (See Appendix 2)
    - Measurable disease as per RECIST v1.1
    - Tumor tissue (FFPE archival or recent acquisition) must be received by the central pathology (block or unstained slides). (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
    - Patients with risk group intermediate or poor will be eligible for the study.
    To be eligible as intermediate or poor-risk, at least one of the following prognostic factors as per the International Metastatic RCC Database Consortium (IMDC) criteria must be present:
    1. KPS equal to 70%
    2. Less than 1 year from initial diagnosis of RCC (eg, nephrectomy or first diagnostic biopsy) to registration (1st line) or to start of first-line targeted therapy (2nd line), respectively
    3. Hemoglobin less than the lower limit of normal (LLN)
    4. Corrected calcium concentration greater than the upper limit of normal (ULN)
    5. Absolute neutrophil count greater than the ULN
    6. Platelet count greater than the ULN
    If none of the above factors are present, subjects are not eligible (risk group favorable).

    3. Age and Reproductive Status
    - Males and Females, ≥ 18 years of age
    - Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
    - Women must not be breastfeeding
    - Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
    - Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Males who receive nivolumab combined with ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
    Comment: Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in this section
    •Consentimiento informado por escrito firmado
    a)Los sujetos o sus representantes legalmente autorizados deben haber firmado y fechado un formulario de consentimiento informado por escrito aprobado por un CEIC de acuerdo con las directrices normativas e institucionales. Este debe obtenerse antes de la realización de cualquier procedimiento relacionado con el protocolo que no sea parte de la atención médica normal del sujeto.
    b)Los sujetos o sus representantes legalmente autorizados deben estar dispuestos y ser capaces de cumplir con las visitas programadas, la pauta de tratamiento, los análisis y otros requisitos del estudio.

    •Población del estudio
    c)Confirmación histológica del CCR con componente de células claras.
    d)CCR avanzado (no susceptible de cirugía o radioterapia curativas) o metastásico (Estadio IV de la AJCC).
    e)Un tratamiento sistémico (antiangiógeno o temsirolimus) [para optar al grupo de 2.a línea] o ningún tratamiento sistémico para el CCR [para optar al grupo de 1.a línea] con la excepción que sigue:
    •Una terapia previa adyuvante o neoadyuvante para el CCR completamente resecable si dicha terapia no incluyó un fármaco dirigido a VEGF o receptores de VEGF ni a los inhibidores de los controles inmunológicos CTLA-4- o PD-1/PD-L1, respectivamente, y si la recurrencia se dio al menos 6 meses tras la última dosis de terapia adyuvante o neoadyuvante.
    f)Estado funcional de Karnofsky (KPS) de al menos 70 %.
    g)Enfermedad mensurable según RECIST v1.1.
    h)El laboratorio de patología central debe recibir el tejido tumoral (FFPE de archivo o de reciente adquisición; bloques o portaobjetos sin tinción). (Nota: las muestras por aspiración con aguja fina [AAF] y de metástasis óseas no son aceptables para el envío).
    i)Los pacientes con grupo de riesgo intermedio o bajo serán aptos para el estudio.

    Comentario: para ser apto para el grupo de riesgo intermedio o bajo, debe presentar al menos uno de los siguientes factores de pronóstico según los criterios del consorcio internacional sobre bases de datos del CCRm (IMDC):
    1.KPS igual a 70 %
    2.Menos de 1 año desde el diagnóstico inicial de CCR (p. ej., nefrectomía o biopsia de primer diagnóstico) hasta la inclusión (1.a línea) o hasta el inicio de la terapia dirigida de primera línea (2.a línea), respectivamente
    3.Hemoglobina menor al límite inferior de la normalidad (LIN)
    4.Concentración de calcio corregida superior al límite superior de la normalidad (LSN)
    5.Recuento absoluto de neutrófilos superior al LSN
    6.Recuento de plaquetas superior al LSN

    Si ninguno de los factores anteriores están presentes, los sujetos no son aptos (grupo de riesgo favorable).

    •Edad y estado reproductivo
    j)Hombres o mujeres, 18 años de edad.
    k)Las mujeres con capacidad de concebir (MCC) deben haber obtenido una prueba de embarazo en suero u orina negativa (sensibilidad mínima de 25 UI/l o unidades equivalentes de HCG) en el plazo de 24 horas antes del inicio del estudio.
    l)Las mujeres no pueden estar en periodo de lactancia.
    M)Las mujeres con capacidad de concebir (MCC) debe aceptar seguir las instrucciones sobre métodos anticonceptivos durante un periodo de 30 días (duración del ciclo ovulatorio) más el tiempo necesario para que el fármaco en investigación supere las cinco semividas. Las semividas terminales de nivolumab e ipilimumab son de hasta 25 días y 18 días, respectivamente. Las MCC deben usar un método adecuado para evitar el embarazo durante 23 semanas (30 días más el tiempo necesario para que nivolumab supere las cinco semividas) tras la última dosis del fármaco en investigación.
    n)Los hombres que sea sexualmente activos con MCC deben aceptar seguir las instrucciones sobre métodos anticonceptivos durante un periodo de 90 días (duración del ciclo ovulatorio) más el tiempo necesario para que el fármaco en investigación supere las cinco semividas. Las semividas terminales de nivolumab e ipilimumab son de hasta 25 días y 18 días, respectivamente. Los hombres que reciben nivolumab combinado con ipilimumab que sean sexualmente activos con MCC deben continuar con el método anticonceptivo durante 31 semanas (90 días más el tiempo necesario para que nivolumab supere las cinco semividas) tras la última dosis de fármaco en investigación.
    Comentario: los hombres azoospérmicos y las MCC que no sean heterosexualmente activos de forma continuada están exentos de los requisitos sobre anticonceptivos. No obstante, las MCC aún deben someterse a las pruebas de embarazo descritas en esta sección.
    E.4Principal exclusion criteria
    1.Target Disease Exceptions
    - Any history of or current CNS metastases. Baseline imaging of the brain by MRI (preferred) or CT scan is required within 28 days prior to registration.
    2. Medical History and Concurrent Diseases
    - Prior systemic treatment with more than one of the following drugs: mTOR, VEGF or VEGF receptor targeted therapy (including, but not limited to, temsirolimus, everolinus, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab).
    - Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA 4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
    - Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
    - Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
    - Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
    - Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
    Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
    - Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
    - Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
    - Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
    3. Physical and Laboratory Test Findings
    - Any of the following laboratory test findings:
    i) WBC < 2,000/mm3
    ii) Neutrophils < 1,500/mm3
    iii) Platelets < 100,000/mm3
    iv) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
    v) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
    vi) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
    Female: CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL
    Male: CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL
    4. Allergies and Adverse Drug Reaction
    - History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product
    5. Other Exclusion Criteria
    -Subjects who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts and who don’t have a legally acceptable representative.
    - Subject who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
    - Participation in another clinical intervention trial 30 days prior to registration
    •Excepciones de enfermedad diana
    a)Todo antecedente o presencia actual de metástasis del SNC. Las imágenes diagnósticas iniciales del cerebro mediante RM (preferida) o TAC son necesarias en el plazo de 28 días antes de la inclusión.

    •Antecedentes médicos y enfermedades concomitantes
    b)Tratamiento sistémico anterior con más de uno de los fármacos que siguen: tratamiento dirigido a mTOR, VEGF o receptor de VEGF (incluyendo, entre otros, temsirolimus, everolimús, sunitinib, pazopanib, axitinib, tivozanib y bevacizumab).
    c)Tratamiento previo con cualquier anticuerpo anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4, o cualquier otro anticuerpo o fármaco dirigido específicamente a la coestimulación de los linfocitos T o las vías de control.
    d)Todo antecedente reciente o presencia activa de enfermedad autoinmunitaria sospechada o conocida o antecedentes recientes de un síndrome que requiriera corticosteroides sistémicos (>10 mg diarios de equivalente de prednisona) o medicamentos inmunosupresores excepto los síndromes que no se esperaría que regresaran en ausencia de un desencadenante externo. Se permite la inclusión de sujetos con vitíligo o diabetes mellitus de tipo I o hipotiroidismo residual debido a tiroiditis autoinmunitaria que solo requiere tratamiento de sustitución hormonal.
    e)Toda afección que necesite tratamiento sistémico con corticosteroides (>10 mg diarios de equivalentes de prednisona) u otras medicaciones inmunosupresoras en los 14 días previos a la primera dosis del fármaco del estudio. Dosis de corticosteroides inhalados y de corticosteroides de sustitución suprarrenal >10 mg diarios de equivalentes de prednisona se permiten en ausencia de enfermedad autoinmunitaria.
    f)Neoplasia maligna previa activa en los 3 años previos excepto cánceres curables de forma localizada que se han curado aparentemente, como carcinoma basocelular o espinocelular de piel, cáncer superficial de vejiga, o carcinoma in situ de la próstata, de cuello de útero o de mama.
    g)Infección por el virus de la inmunodeficiencia humana (VIH) o síndrome de inmunodeficiencia adquirida (SIDA) conocidos.
    h)Cualquier prueba positiva del virus de la hepatitis B o hepatitis C que indique una infección aguda o crónica.
    i)Afección médica conocida (p. ej., dolencia asociada a diarrea o diverticulitis aguda) que, en opinión del investigador, incrementaría el riesgo asociado con la participación en el estudio o la administración del fármaco del estudio o interferiría en la interpretación de los resultados de seguridad.
    j)Cirugía mayor (p. ej., nefrectomía) menos de 28 días antes de la primera dosis del fármaco del estudio.
    k)Tratamiento anticancerígeno menos de 28 días antes de la primera dosis del fármaco del estudio o radioterapia paliativa focal menos de 14 días antes de la primera dosis del fármaco del estudio.
    l)Presencia de cualquier toxicidad atribuida un tratamiento anticancerígeno previo, aparte de alopecia, que no se haya resuelto hasta grado 1 (CTCAE del NCI v. 4) o el valor inicial antes de la administración del fármaco del estudio.
    •Hallazgos físicos y analíticos
    m)Cualquiera de los siguientes hallazgos de pruebas analíticas:
    i)LEU <2000/mm3
    ii)Neutrófilos <1500/mm3
    iii)Plaquetas <100 000/mm3
    iv)AST o ALT >3 x LSN (>5 x LSN si presenta metástasis de hígado)
    v)Bilirrubina total >1,5 x LSN (excepto en sujetos con síndrome de Gilbert, que pueden tener una bilirrubina total <3,0 mg/dl)
    vi)Creatinina sérica >1,5 x límite superior de la normalidad (LSN) o aclaramiento de creatinina <40 ml/min (medido o calculado según la fórmula de Cockroft-Gault)
    •Alergias y reacción adversa al fármaco
    n)Antecedentes de reacción de hipersensibilidad grave a cualquier anticuerpo monoclonal o a cualquier componente del producto.
    •Otros criterios de exclusión
    o)Sujetos que no pueden dar su consentimiento porque no comprenden la naturaleza, significado e implicaciones del ensayo clínico y por tanto no pueden formarse una intención racional a la vista de los hechos y que no tienen un representante legalmente autorizado.
    p)Un sujeto que haya sido encarcelado o institucionalizado de forma no voluntaria por orden judicial o por las autoridades.
    q)Participación en otro ensayo clínico de intervención 30 días antes a la inclusión.
    E.5 End points
    E.5.1Primary end point(s)
    ORR based on investigator assessment using RECIST 1.1 of the TITAN regimen in untreated (1st line) and pretreated (2nd line) subjects with IMDC intermediate and high risk, advanced RCC with clear cell component or metastatic RCC 30 weeks after last patient first treatment
    ORR basado en la evaluación del investigador usando RECIST 1.1 del régimen de TITAN en sujetos no tratados (1ª línea) y pretratados (2ª línea) con IMDC de riesgo intermedio y alto, RCC avanzado con componente celular claro o RCC metastásico 30 semanas después del primer tratamiento del paciente
    E.5.1.1Timepoint(s) of evaluation of this end point
    30 weeks after all subjects have been treated (30 weeks after last patient first treatment)
    30 semanas después de que todos los sujetos hayan sido tratados (30 semanas después del primer tratamiento del paciente)
    E.5.2Secondary end point(s)
    Remission Rate, Time to response, Duration of Response, Progresion free Survival, Time to Immunotherapy Resistance and Overall survival all as assessed by investigators among all treated subjects, first line subjects, and second line subjects.
    Patients with IMDC intermediate and high risk will be analysed separately.
    Tasa de remisión, tiempo de respuesta, duración de la respuesta, supervivencia libre de Progresión, tiempo hasta la resistencia a la inmunoterapia y supervivencia general según lo evaluado por los investigadores entre todos los sujetos tratados, sujetos de primera línea y sujetos de segunda línea. Los pacientes con IMDC de riesgo intermedio y alto serán analizados por separado
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 42 months
    Después de 42 meses
    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 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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 100
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the end of the study, subjects who continue to demonstrate clinical benefit will be eligible to receive BMS supplied study drug in agreement with the sponsor. Study drug will be provided through another mechanism at the discretion of BMS and in alignment with the sponsor.
    Después del final del estudio, los sujetos que continúen demostrando beneficio clínico serán elegibles para recibir el medicamento del estudio suministrado por BMS de acuerdo con el patrocinador. El medicamento para el estudio se proporcionará a través de otro mecanismo a discreción de BMS y en alineación con el patrocinador.
    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 Opinion2017-05-08
    P. End of Trial
    P.End of Trial StatusOngoing
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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