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    Summary
    EudraCT Number:2018-004372-36
    Sponsor's Protocol Code Number:BL-8040.PAC.201
    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:2019-05-27
    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 number2018-004372-36
    A.3Full title of the trial
    A phase IIa, multicenter, Open-Label Study to Assess the Safety and Efficacy of the Combination of BL-8040 and Pembrolizumab in Patients with Metastatic Pancreatic Cancer, the COMBAT study
    Estudio en fase IIa, sin enmascaramiento y multicéntrico para analizar la seguridad
    y eficacia de la combinación de BL-8040 y pembrolizumab en pacientes con cáncer
    pancreático metastásico, el estudio COMBAT.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and effect of BL-8040 with pembrolizumab in patients with pancreatic cancer
    Eficacia y seguridad de BL-8040 en combinación con pembrolizumab en pacientes con cáncer pancreático
    A.3.2Name or abbreviated title of the trial where available
    BL-8040 with pembrolizumab for treatment of pancreatic cancer - The COMBAT Study
    BL-8040 en combinación con pembrolizumab para el tratamiento del cáncer pancreático - Estudio COMBAT
    A.4.1Sponsor's protocol code numberBL-8040.PAC.201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02826486
    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 SponsorBioLineRx Ltd.
    B.1.3.4CountryIsrael
    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 supportBioLineRx Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital de la Vall d’Hebron
    B.5.2Functional name of contact pointHead of CRS Unit
    B.5.3 Address:
    B.5.3.1Street AddressP.º Vall d’Hebron 119-129
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08035
    B.5.3.4CountrySpain
    B.5.4Telephone number+34934893000
    B.5.6E-mailsmunoz@vhio.net
    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 nameBL-8040
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmotixafortide
    D.3.9.1CAS number 664334-36-5
    D.3.9.2Current sponsor codeBL-8040
    D.3.9.3Other descriptive nameBKT140; 4F-benzoyl-TN14003
    D.3.9.4EV Substance CodeSUB187495
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number36.5
    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 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 nameKeytruda
    D.3.2Product code MK-3475
    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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK3475
    D.3.9.4EV Substance CodeSUB167136
    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 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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pancreatic cancer
    Cáncer pancreático
    E.1.1.1Medical condition in easily understood language
    Pancreatic cancer
    Cáncer pancreático
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to assess the efficacy and safety of BL-8040 in combination with pembrolizumab and BL8040/ Pembrolizumab in combination with liposomal irinotecan (Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) in subjects with metastatic pancreatic adenocarcinoma.
    analizar la eficacia y seguridad de BL-8040 en combinación con pembrolizumab y BL-8040/pembrolizumab en combinación con irinotecán liposomal (Onivyde®)/5-fluorouracilo/ácido folínico (5-FU/AF) en personas con adenocarcinoma pancreático metastásico
    E.2.2Secondary objectives of the trial
    to determine T-cell responses and NK cells in peripheral blood and during cohort-1 in tumor tissue (before and after treatment if possible); change in tumor marker (CA19-9), and tumor tissue analysis
    determinar las respuestas de los linfocitos T y de linfocitos citolíticos naturales (NK) en la sangre periférica (SP) y durante la cohorte 1 en el tejido tumoral (a ser posible, antes y después del tratamiento); cambios en el marcador tumoral (CA19-9), y analisis del tejido tumoral.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.18 years and older
    2.Patients must sign a written informed consent prior to entering the study.
    3.Histologically confirmed (either previously or newly biopsied) metastatic unresectable pancreatic adenocarcinoma, including intraductal papillary mucinous neoplasm.
    4.Have measurable disease (≥ 1 measurable lesion) based on RECIST v1.1 as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
    5.Previous treatment lines
    a.Cohort 1: Have documented objective radiographic progression after stopping treatment with first-line or further therapy, i.e. chemotherapy and or radiotherapy. Surgery not followed with neoadjuvant therapy will not be considered as first-line therapy.
    b.Cohort 2: Have documented objective radiographic progression after stopping treatment with first-line, gemcitabine-based chemotherapy. Only primary metastatic patients will be allowed to participate. Patients with previous surgery for their pancreatic cancer will not be allowed to participate.
    6.Willing to submit an evaluable tumor tissue sample, preferably from a liver metastasis, unless tumor is considered inaccessible or biopsy is otherwise considered not in the subject’s best interest
    7.Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If the subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
    8.ECOG status ≤1.
    9.Life expectancy of at least 3 months.
    10.Adequate organ function at Baseline as defined below. All laboratory assessments should be performed within 10 days of treatment initiation
    a.Hematological:
    •White blood cell (WBC) ≥ 2,500/mm^3
    •Absolute neutrophil count
    oCohort 1: ≥ 1000 /mm^3
    oCohort 2: ≥ 1500 /mm^3
    •Platelet count ≥ 100,000/mm^3
    •Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
    •Hematocrit ≥30%
    b.Renal function:
    •Creatinine ≤1.5x Upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR]) can also be used in place of creatinine or (CrCl) > 60 mL/min for subject with creatinine levels > 1.5x institutional ULN
    c.Hepatic function:
    •Total Bilirubin: within institutional normal ranges
    •Aspartate aminotransferase/ serum glutamic oxaloacetic transaminase (AST/SGOT) and Alanine amino transferase/ serum glutamate-pyruvate transaminase (ALT/SGPT): ≤2.5xULN OR ≤5xULN for subjects with liver metastases
    d.Coagulation:
    •INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    •aPTT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    11.Subjects must use effective contraception:
    a.Female subjects must be of non-childbearing potential or, if of childbearing potential, must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons):
    •≥45 years of age and has not had menses for over 2 years
    •Amenorrhoeic for > 2 years without a hysterectomy and oophorectomy and a Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon pretrial (Screening) evaluation
    •Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation at least 6 weeks prior to Screening. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the Screening visit through 120 days after the last dose of study therapy. Information must be captured appropriately within the site's source documents
    b.Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
    1.18 años o más.
    2.Los pacientes deben firmar un consentimiento antes de ser admitidos en el estudio.
    3.Confirmación histológica (con biopsia anterior o reciente) de adenocarcinoma pancreático metastásico no resecable, incluida la neoplasia papilar mucinosa intraductal
    4.Presentar enfermedad mensurable (≥ 1 lesión mensurable) determinada por el equipo del estudio del centro según RECIST v1.1. Las lesiones tumorales situadas en un área radiada previamente se consideran mensurables si se ha demostrado la progresión de esas lesiones
    5.Líneas terapéuticas anteriores:
    a.Cohorte 1: presentar progresión radiográfica objetiva comprobada tras suspender el trat. de elección o posterior, es decir, quimio y radioterapia. La cirugía sin trat. neoadyuvante posterior no se considerará trat. de elección
    b.Cohorte 2: presentar progresión radiográfica objetiva comprobada tras suspender el trata. de quimio con gemcitabina como fármaco de elección. Solo se permitirá la participación de pacientes con cáncer metastásico primario. No se permitirá la participación de pacientes que se hayan sometido previamente a una cirugía del cáncer de páncreas
    6.Personas dispuestas a proporcionar una muestra válida de tejido tumoral, preferiblemente de metástasis en el hígado, a menos que se considere que el tumor es inaccesible o que la biopsia no es en beneficio del paciente
    7.Resolución completa de los efectos tóxicos de la quimio anterior más reciente hasta alcanzar un grado 1 o menor (a excepción de la alopecia). Si la persona se sometió a una cirugía mayor o a radioterapia de > 30 Gy, deberá haberse recuperado de la toxicidad o las complicaciones de la intervención
    8.Estado en la escala ECOG ≤ 1
    9.Esperanza de vida ≥ 3 meses
    10.Funcionamiento adecuado de los órganos en el momento basal, como se define a continuación. Todos los análisis deben realizarse en los primeros 10 días tras el inicio del tratamiento
    a.Análisis hemáticos:
    •Nº leucocitos ≥ 2500/mm^3
    •Nº absoluto de neutrófilos:
    -Cohorte 1: ≥ 1000 /mm^3
    -Cohorte 2: ≥ 1500 /mm^3
    •Nº de trombocitos ≥ 100 000/mm^3
    •Hemoglobina ≥9 g/dl o ≥5,6 mmol/l
    •Hematocrito ≥30 %
    b.Pruebas de función renal:
    •Niveles de creatinina ≤ 1,5 veces el límite sup. de la normalidad (LSN) O aclaramiento de la creatinina (CrCl) medido o calculado > 60 ml/min para personas con niveles de creatinina > 1,5 veces el LSN del centro. (También puede utilizarse la velocidad de filtración glomerular [GFR] en lugar del nivel de creatinina o del CrCl.)
    c.Pruebas de función hepática:
    •Bilirrubina total: dentro del rango de normalidad del centro
    •Aspartato aminotransferasa/glutamato-oxalacetato transaminasa sérica (AST/SGOT) y alanina transaminasa/glutamato-piruvato transaminasa sérica (ALT/SGPT): ≤ 2,5 veces el LSN O ≤ 5 veces el LSN en personas con metástasis en el hígado
    d.Coagulación:
    •IIN o TP: ≤ 1,5 veces el LSN, a menos que la persona reciba anticoagulantes y siempre que el TP y el TTP se encuentren dentro del rango indicado para el uso de anticoagulantes.
    •Tiempo de tromboplastina parcial activado (TTPa): ≤ 1,5 veces el LSN, a menos que la persona reciba anticoagulantes y siempre que el TP y el TTP se encuentren dentro del rango indicado para el uso de anticoagulantes.
    11.Las personas deben usar métodos anticonceptivos eficaces:
    a.Las mujeres no deben tener posibilidad de quedarse embarazadas o, si tienen posibilidad de quedarse embarazadas, deben someterse a una prueba de embarazo de orina o suero en las 72 horas previas a la administración del medicamento del estudio. Si la prueba de embarazo en orina diese un resultado positivo o que no puede confirmarse como negativo, será necesario realizar una prueba en suero. La prueba de embarazo en suero debe arrojar un resultado negativo para que la persona cumpla los requisitos. Sin posibilidad de quedar embarazada se define como (además de por razones médicas):
    •Mujer ≥ 45 años que no ha menstruado desde hace más de 2 años
    •Mujer amenorreica durante > 2 años, sin histerectomía ni ooforectomía y con niveles de la hormona foliculoestimulante (FSH) dentro del rango posmenopáusico en la evaluación previa al ensayo (selección)
    •Mujer sometida a histerectomía, ooforectomía bilateral, salpingectomía bilateral o ligadura de trompas bilateral al menos 6 semanas antes del período de selección. La histerectomía y la ooforectomía deben confirmarse con la historia clínica de la intervención o con una ecografía. La ligadura de trompas debe confirmarse con la historia clínica de la intervención o la mujer deberá estar dispuesta a usar dos métodos anticonceptivos de barrera durante el estudio, desde la visita de selección y hasta 120 días después de la última administración del trat. del estudio. La información debe registrarse adecuadamente en los docs del centro
    b.Los hombres deben aceptar usar un método anticonceptivo adecuado desde la primera administración del trat. del estudio y hasta 120 días después de la última admin. del trat. del estudio
    E.4Principal exclusion criteria
    1. Pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell carcinoma. Vater and periampullary duodenal or common bile duct malignancies.
    2.For Cohort 2 only: subjects with a bowel obstruction.
    3. Active infection requiring systemic therapy or uncontrolled infection.
    4. Known additional malignancy that is progressing or requires active treatment. Exceptions are adequately treated basal cell or squamous cell carcinoma that has undergone potentially curative therapy or carcinoma in situ of the cervix.
    5. An underlying medical condition that precludes study participation.
    6. Has a disease that is suitable for therapy administered with curative intent.
    7. Currently participating and receiving study therapy or has participated in a study of an investigational agent or device and received study therapy within 4 weeks of the first dose of treatment.
    8. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study.
    9. Had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤Grade 1 or at Baseline) from AE due to agents administered more than 4 weeks earlier.
    10. Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or has not recovered (i.e. ≤Grade 1 or at Baseline) from AE due to a previously administered agent.
    11. An active autoimmune disease that required systemic treatment in the 2 years preceding the study (i.e. with the use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
    12. Received transfusions of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1.
    13.History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    14. History of interstitial lung disease.
    15. O2 saturation < 92% (on room air).
    16. For both Cohorts: unstable angina, new onset angina within the last 3 months, myocardial infarction within the last 6 months, and current congestive heart failure New York Heart Association Class III or higher. For Cohort 2: ventricular arrhythmias or uncontrolled blood pressure, or severe arterial thromboembolic events less than 6 months prior to study initiation.
    17. History or current evidence of any condition, therapy, or laboratory abnormality that might confound study results, interfere with the subject’s participation for the duration of the trial, or is not in the best interest of the subject in the opinion of the treating Investigator.
    18. Known psychiatric or substance abuse disorders that would interfere with cooperation with study requirements.
    19. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 120 days after the last dose of trial treatment. Women with a positive pregnancy test within 72 hours from Baseline.
    20. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or previously participated in Merck MK-3475 clinical trials.
    21. Positive HIV test at Screening or at any time prior to Screening. Patients without a prior positive HIV test result will undergo an HIV test at Screening, unless not permitted per local regulations.
    22. Known active Hepatitis B (defined as a positive Hepatitis B surface antigen (HBsAg) test at Screening) or Hepatitis C (defined as a positive HCV antibody test or a positive HCV RNA test at Screening)
    23. Known history of Chronic Hepatitis B or C
    24. Received a live vaccine within 30 days of the planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted.
    25. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or computerized tomography (CT) scan, for at least four weeks prior to the first dose of trial treatment and neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases and are not using steroids for at least 14 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    26. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    27. Cohort 2: clinical ascites requiring treatment
    1.Tener un tumor pancreático dif. del adenocarcinoma, como: carcinoma de células acinares, pancreatoblastoma, neoplasia quística maligna, neoplasia endocrina, carcinoma epidermoide. Tener neoplasia maligna de la ampolla de Vater, duodenal periampular o del conducto colédoco.
    2.cohorte 2: presentar oclusión intestinal
    3.Presentar infección que requiera un trat. sistémico o una infección no controlada
    4.Presentar neoplasia maligna adicional que progresa o que requiere trat. activo. Se consideran excepciones a esto las personas con carcinoma basocelular o carcinoma epidermoide tratadas adecuadamente que hayan seguido un trat. potencialmente curativo o aquellas con carcinoma de cuello uterino in situ
    5.Tener una enfermedad preexistente que imposibilite participar en el estudio
    6.Tener una enfermedad apta para un trat. administrado con intención curativa
    7.Estar participando en un estudio y recibir un trat. del estudio, o bien haber participado en el estudio de un fármaco en fase de inv. y haber recibido un trat. del estudio o usado un producto en fase de inv. en las 4 semanas anteriores a la 1ª admin. del trat.
    8.Ser diagnosticada con inmunodeficiencia o recibir un trat. sistémico con corticoesteroides o cualquier otro tipo de trat. inmunodepresor en los 7 días anteriores a la 1ª admin. del trat. del ensayo
    9.Haber recibido un anticuerpo monoclonal antineoplásico en las 4 semanas anteriores al día 1 del estudio o no haberse recuperado de un EA (es decir, ≤ grado 1 o valor basal) causado por fármacos admin. más de 4 semanas antes
    10.Haber recibido quimio, un trat. dirigido tradicional o radio en las 2 semanas anteriores al día 1 del estudio o no haberse recuperado de un EA (es decir, ≤ grado 1 o valor basal) causado por un fármaco admin. previamente
    11.Tener una enfermedad autoinmunitaria activa que haya requerido un trat. sistémico en los 2 años anteriores al estudio. Nota: Los trat. sustitutivos no se consideran trat. sistémicos y, por tanto, están permitidos
    12.Haber recibido transfusiones de hemoderivados (trombocitos o eritrocitos) o factores estimulantes de colonias (G-CSF, GM-CSF o epoetina) en las 4 semanas anteriores al día 1 del estudio
    13.Tener antecedentes de neumonitis (no infecciosa) que requiriese corticoesteroides o presentar neumonitis en la actualidad
    14.Tener antecedentes de enfermedad pulmonar intersticial
    15.Saturación de O2 < 92 % (en aire ambiente)
    16.ambas cohortes: tener angina inestable, angina de nueva aparición en los 3 últimos meses, infarto de miocardio en los últimos 6 meses o insuficiencia cardíaca congestiva de clase III o superior, según la Asociación Neoyorquina de Cardiología. Cohorte 2: presentar arritmia ventricular o presión arterial no controlada, o bien episodios tromboembólicos arteriales en los 6 meses anteriores al inicio del estudio
    17.Tener antecedentes o signos actuales de cualquier enfermedad, trat. o anomalía en los análisis que pudiese confundir los resultados del ensayo, interferir en la participación de la persona durante la totalidad del ensayo o provocar que la participación de la persona no sea beneficiosa para esta
    18.Tener trastornos psiquiátricos o de abuso de sustancias conocidos
    19.Estar embarazada o amamantando, esperar concebir o procrear durante la duración prevista del ensayo, desde la visita de selección y hasta 120 días después de la última admin. del trat. del ensayo. Mujeres con prueba + de embarazo en las 72 horas posteriores al momento basal
    20.Haber recibido previamente un trat. con un agente anti-PD-1, anti-PD-L1 o anti-PD-L2 o haber participado anteriormente en los ensayos clínicos de MK-3475 de Merck
    21. + en la prueba de VIH en el período de selección o anteriormente a este período. Los pacientes sin un resultado positivo anterior en la prueba del VIH se someterán a una prueba de VIH en el período de selección
    22.Tener hepatitis B activa o hepatitis C
    23.Tener antecedentes conocidos de hepatitis B o C crónica
    24.Haber recibido una vacuna elaborada con microbios vivos en los 30 días anteriores al inicio programado del trat. del estudio. Las vacunas para la gripe sin virus vivos están permitidas
    25.Tener metástasis activa en el SNC o meningitis carcinomatosa. Nota: Las personas que hayan recibido algún trat. previo para la metástasis en el cerebro pueden participar siempre y cuando se encuentren estables (sin signos de progresión en las pruebas diagnósticas por imagen usando la misma técnica en cada evaluación, durante al menos 4 semanas antes de la 1ª admin. del trat. del ensayo y con todos los síntomas de nuevo en niveles basales), no presenten signos de metástasis nueva o de mayor tamaño en el cerebro y no hayan usado corticoesteroides al menos durante 14 días antes del trat. del ensayo. Esta excepción no incluye la meningitis carcinomatosa
    26.Presenta hipersensibilidad (≥ grado 3) a pembrolizumab o cualquiera de sus excipientes
    27. Cohorte 2: presenta ascitis clínica que requiere trat.
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response Rate (ORRRECIST1.1) determined according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria.
    Tasa de respuesta objetiva (ORRRECIST1.1) determinada de acuerdo con los criterios de evaluación de respuesta en tumores sólidos (RECIST) v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    June 2020
    Junio 2020
    E.5.2Secondary end point(s)
    • Objective Response Rate (ORRirRECIST) determined according to irRECIST criteria.
    • Overall Survival.
    • Progression Free Survival.
    • Disease Control according to RECISIT 1.1 (DCRECIST1.1) is defined as the sum of partial responses (PRs), CRs and SDs.
    • Tasa de respuesta objetiva (ORRRECIST1.1) determinada de acuerdo con los criterios RECIST v1.1.
    • Supervivencia general
    • Supervivencia sin progresión
    • Control de enfermedades según RECISIT 1.1 (DCRECIST1.1), definido como la suma de respuestas parciales (PR), CRs y SDs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    June 2021
    Junio 2021
    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 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Israel
    Korea, Republic of
    Spain
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Ultima visita del ultimo 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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 80
    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)
    None
    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 Decision2019-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-05
    P. End of Trial
    P.End of Trial StatusCompleted
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