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    Summary
    EudraCT Number:2019-003152-37
    Sponsor's Protocol Code Number:MK3475-A18/ENGOT-cx11
    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:2020-02-28
    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 number2019-003152-37
    A.3Full title of the trial
    A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer (KEYNOTE-A18 / ENGOT-cx11)
    Estudio en fase III, aleatorizado y doble ciego de quimiorradioterapia con o sin pembrolizumab para el tratamiento del cáncer de cuello uterino localmente avanzado de alto riesgo (KEYNOTE-A18/ENGOT-cx11)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer
    Quimiorradioterapia con o sin pembrolizumab para el tratamiento del cáncer de cuello uterino localmente avanzado de alto riesgo
    A.4.1Sponsor's protocol code numberMK3475-A18/ENGOT-cx11
    A.5.4Other Identifiers
    Name:KEYNOTENumber:KEYNOTE-A18
    Name:ENGOTNumber:ENGOT-cx11
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck &Co.,Inc
    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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España S.A.
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressC/ Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28037
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34913210590
    B.5.6E-mailensayos_clinicos@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 namePEMBROLIZUMAB
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form 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 codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Yes
    D.2.1.1.1Trade name KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution 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
    High-risk locally advanced cervical cancer
    Cáncer de cuello uterino localmente avanzado de alto riesgo
    E.1.1.1Medical condition in easily understood language
    Locally Advanced Cervical Cancer
    Cáncer de cuello uterino localmente avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10008229
    E.1.2Term Cervical cancer
    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
    1. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review or by histopathologic confirmation of suspected local disease progression (in the absence of radiographic disease progression per RECIST 1.1)
    2. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival (OS)
    1. Comparar la quimiorradioterapia concomitante más pembrolizumab con la quimiorradioterapia concomitante más un placebo en cuanto a la supervivencia sin progresión conforme a los criterios RECIST 1.1, evaluada mediante una revisión central independiente y enmascarada o mediante confirmación histopatológica de la sospecha de progresión local de la enfermedad (en ausencia de progresión radiológica de la enfermedad conforme a los criterios RECIST 1.1).
    2. Comparar la quimiorradioterapia concomitante más pembrolizumab con la quimiorradioterapia concomitante más un placebo en cuanto a la supervivencia global.
    E.2.2Secondary objectives of the trial
    1. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to:
    - PFS at 2 years per RECIST 1.1
    - OS at 3 years
    - Complete response rate at 12 weeks per RECIST 1.1
    - Objective response rate per RECIST 1.1
    - OS and PFS per RECIST 1.1 by programmed cell death 1 ligand 1 (PD-L1) status
    - PFS after next-line treatment (PFS 2) following discontinuation of study treatment administration
    - Change from baseline score in global quality of life and physical function using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
    - Change from baseline score in cervical cancer symptom experience using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Symptom Score for Cervical Cancer (EORTC CX24)
    2. To evaluate the safety and tolerability of pembrolizumab in combination with concurrent chemoradiotherapy
    1. Comparar quimiorradioterapia concomitante más pembrolizumab con quimiorradioterapia concomitante más placebo en cuanto a:
    - La SSP a los 2 años y SG y 3 años según criterios RECIST 1.1
    - La TRC a las 12 semanas y TRO según criterios RECIST 1.1
    - La SG y SSP según criterios RECIST 1.1 según el estado de PDL-1
    - La SSP después del tratamiento de siguiente línea SSP2 tras suspensión del tratamiento del estudio
    - Variación con respecto al momento basal de la puntuación global de calidad de vida y función física utilizando la escala de estado de salud general/calidad de vida y la subescala de función física del Cuestionario de calidad de vida de la EORTC QLQ-C30 de la EORTC
    - Variación con respecto al momento basal de la puntuación de la experiencia sintomática utilizando la escala específica de los síntomas CX24 del Cuestionario de calidad de vida de la EORTC
    2. Evaluar la seguridad y la tolerabilidad de pembrolizumab en combinación con quimiorradioterapia concomitante
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (Blood and Tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    Merck realizará Investigaciones Biomédicas Futuras con muestras de ADN (sangre y tejido) recogidas durante este ensayo clínico. Esa investigación servirá para responder preguntas emergentes acerca de la evaluación de biomarcadores no descritas en otras partes del protocolo (como parte del ensayo principal) y solamente se recogerán de sujetos que hayan consentido adecuadamente. El objetivo de recoger muestras para Investigaciones Biomédicas Futuras es explorar e identificar biomarcadores que informen la comprensión científica de las enfermedades y / o sus tratamientos terapéuticos. El objetivo general es usar esa información para desarrollar fármacos más seguros, más efectivos y / o asegurar que los sujetos reciben la dosis correcta del fármaco correcto en el momento correcto.
    E.3Principal inclusion criteria
    1. Has high-risk LACC (a or b below):
    a. FIGO 2014 Stage IB2-IIB (with node-positive disease) – must meet criteria below for positive pelvic lymph node OR para-aortic lymph node involvement
    Pelvic lymph node involvement as assessed by one of the following criteria:
    - Histopathologic, biopsy-proven pelvic node involvement, or
    - 2 or more positive pelvic nodes by MRI or CT (≥1.5 cm shortest dimension), or
    - 2 or more positive pelvic nodes by PET / CT with SUV ≥2.5
    Para-aortic lymph node involvement as assessed by one of the following criteria:
    - Histopathologic, biopsy-proven para-aortic node involvement, or
    - 1 or more positive para-aortic nodes by MRI or CT (≥1.5 cm shortest dimension), or
    - 1 or more positive para-aortic nodes by PET / CT with SUV ≥2.5
    b. FIGO 2014 Stages III-IVA (either node-positive or node-negative disease)
    2. Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.
    3. Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer and is immunotherapy-naïve.
    4. Has an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study intervention
    5. Is female, at least 18 years of age at the time of signing the informed consent.
    6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a WOCBP
    OR
    - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention
    - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
    - The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
    7. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
    8. Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the local site investigator/radiology
    9. Has provided a tissue sample from a core or excisional biopsy of a tumor lesion for confirmation of adequacy by the central vendor prior to randomization. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides
    10. Has adequate organ function. Specimens must be collected within 7 days prior to the start of study intervention
    1. Presenta un CCULA de alto riesgo (a o b a continuación):
    a. Estadio IB2-IIB según la clasificación FIGO 2014 (enfermedad con ganglios positivos): debe cumplir los criterios siguientes de ganglio linfático pélvico positivo O afectación de ganglios linfáticos paraaórticos.
    Afectación de los ganglios linfáticos pélvicos evaluada mediante uno de los criterios siguientes:
    -Afectación histopatológica de los ganglios linfáticos pélvicos confirmada mediante biopsia, o
    -Dos o más ganglios pélvicos positivos mediante RM o TC (≥ 1,5 cm en su dimensión menor), o
    -Dos o más ganglios pélvicos positivos mediante PET/TC con un SUV ≥2,5.
    Afectación de los ganglios linfáticos paraaórticos evaluada mediante uno de los criterios siguientes:
    -Afectación histopatológica de los ganglios paraaórticos confirmada mediante biopsia o
    -Uno o más ganglios paraaórticos positivos mediante RM o TC (≥ 1,5 cm en su dimensión menor), o
    -Uno o más ganglios paraaórticos positivos mediante PET/TC con un SUV ≥ 2,5.
    b. Estadio III-IVA según la clasificación FIGO 2014 (enfermedad con ganglios positivos o negativos).
    2. Presenta carcinoma epidermoide, adenocarcinoma o carcinoma adenoepidermoide del cuello uterino confirmado histológicamente.
    3. No ha recibido previamente ningún tratamiento quirúrgico, de radioterapia ni sistémico definitivo para el cáncer de cuello uterino y no ha recibido inmunoterapia previa.
    4. Presenta un estado funcional del ECOG de 0 o 1 en los 7 días previos a la primera dosis del tratamiento del estudio.
    5. Las participantes son mujeres de al menos 18 años de edad en el momento de firmar el consentimiento informado.
    6. Podrán participar en el estudio las mujeres que no estén embarazadas, no estén dando el pecho y cumplan al menos una de las condiciones siguientes:
    -No es una MEF.
    O
    -Es una MEF y utiliza un método anticonceptivo muy eficaz (con un índice de fallos < 1 % anual) con baja dependencia de la usuaria o practica la abstinencia de relaciones heterosexuales como modo de vida preferido y habitual (abstinencia a largo plazo y persistente), durante el período de intervención y durante, como mínimo, 120 días después de recibir la última dosis de pembrolizumab o placebo y 180 días después del final de la quimiorradioterapia. El investigador deberá evaluar la posibilidad de fracaso del método anticonceptivo (es decir, incumplimiento, inicio reciente) antes de la primera dosis de la intervención del estudio.
    -Las MEF deberán dar negativo en una prueba de embarazo de alta sensibilidad (en orina o suero, según exija la normativa local) realizada en las 24 horas previas a la primera dosis de la intervención del estudio.
    -Cuando no pueda confirmarse que el resultado de una prueba en orina es negativo (por ejemplo, resultado ambiguo), será necesario hacer una prueba de embarazo en suero. En tal caso, la participante será excluida si el resultado de la prueba de embarazo en suero es positivo.
    -El investigador es responsable de revisar los antecedentes médicos, los antecedentes menstruales y la actividad sexual reciente para reducir el riesgo de incluir a una mujer con un embarazo de poco tiempo no detectado.
    7. La participante (o su representante legal cuando proceda) otorga su consentimiento informado por escrito para el estudio. También podrá otorgar su consentimiento para investigaciones biomédicas futuras. No obstante, la participante podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    8. Presencia de enfermedad evaluable radiológicamente, medible o no medible conforme a los criterios RECIST 1.1, según la evaluación del investigador o radiólogo del centro.
    9. Ha proporcionado una muestra de tejido procedente de una biopsia con aguja gruesa o por escisión de una lesión tumoral para que el laboratorio central confirme su idoneidad antes de la aleatorización. Se prefieren los bloques de tejido fijados en formol e incluidos en parafina a los cortes.
    10. Presenta una función orgánica adecuada. Las muestras se obtendrán en los 7 días previos al comienzo de la intervención del estudio.
    E.4Principal exclusion criteria
    1. Has histological subtypes other than those allowed per inclusion criterion 2 (eg, sarcoma, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancer).
    2. Has FIGO 2014 Stage IVB disease.
    3. Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy.
    4. Has bilateral hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy
    5. Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy
    6. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
    7. Has received treatment with systemic immunostimulatory agents such as bacterial or viral vaccines, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
    8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell recepto (eg, CTLA-4, OX-40, CD137).
    9. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
    10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
    11. Has any contraindication to the use of cisplatin.
    12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
    13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
    14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    15. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
    16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    17. Has an active infection requiring systemic therapy.
    18. Has a known history of HIV infection.
    19. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
    20. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
    21. Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study.
    22. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
    23. Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy.
    24. Has had an allogenic tissue/solid organ transplant.
    1. Presencia de subtipos histológicos distintos de los permitidos según el criterio de inclusión 2 (p. ej., sarcoma, carcinoma microcítico con diferenciación neuroendocrina o cáncer no epitelial).
    2. Presencia de enfermedad en estadio IVB según la clasificación FIGO 2014.
    3. Realización de una histerectomía previa, definida como la extirpación completa del útero, o previsión de una histerectomía como parte del tratamiento inicial del cáncer de cuello uterino.
    4. Presencia de hidronefrosis bilateral, excepto que al menos un lado haya sido tratado con endoprótesis o se haya resuelto mediante una nefrostomía.
    5. Anatomía o geometría del tumor o cualquier otro motivo o contraindicación que no pueda tratarse con braquiterapia intracavitaria o con una combinación de braquiterapia intracavitaria e intersticial.
    6. Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis de la intervención del estudio. Son ejemplos de vacunas de microorganismos vivos, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela/zóster, contra la fiebre amarilla, antirrábica, BCG y antitifoidea. Las vacunas inyectables contra la gripe estacional contienen, por lo general, virus muertos y están permitidas; en cambio, las vacunas antigripales intranasales (p. ej., FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
    7. Recepción de tratamiento con inmunoestimuladores sistémicos, como vacunas bacterianas o virales, factores estimuladores de colonias, interferones, interleucinas y combinaciones de vacunas, en las 6 semanas o 5 semividas del fármaco, lo que sea más breve, antes del día 1 del ciclo 1.
    8. Recepción de tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti- PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    9. Recepción de un tratamiento antineoplásico sistémico previo, incluidos fármacos en investigación, en las cuatro semanas previas a la aleatorización.
    10. Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la aleatorización.
    11. Presenta alguna contraindicación para el uso de cisplatino.
    12. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de prednisona o equivalente) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis de la medicación del estudio.
    13. Presencia de otra neoplasia maligna conocida que esté en progresión o que haya precisado tratamiento activo en los últimos tres años.
    14. Presencia de hipersensibilidad grave (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus excipientes.
    15. Presencia de una enfermedad autoinmunitaria activa que haya precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años. El tratamiento de reposición (p. ej., tiroxina, insulina o corticoides en dosis fisiológicas por insuficiencia suprarrenal o hipofisaria) no se considera una forma de tratamiento sistémico y se permitirá su uso.
    16. Antecedentes de neumonitis (no infecciosa) que haya precisado la administración de esteroides o presencia de una neumonitis activa.
    17. Infección activa con necesidad de tratamiento sistémico.
    18. Antecedentes de infección por el VIH.
    19. Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección activa por el virus de la hepatitis C (definida como detección de ARN del virus de la hepatitis C [VHC] [cualitativo]).
    20. Antecedentes conocidos de tuberculosis activa (TB; Bacillus tuberculosis).
    21. Antecedentes o signos actuales de cualquier enfermedad, tratamiento, anomalía analítica u otra circunstancia que pueda aumentar el riesgo asociado a la participación en el estudio o a la administración de la intervención del estudio o que pueda interferir en la interpretación de los resultados del estudio y, en opinión del investigador o el promotor podría motivar que la participante no fuera apta para incorporarse a este estudio.
    22. Presencia de un trastorno psiquiátrico o por abuso de sustancias que podría dificultar la capacidad de la participante para colaborar en el cumplimiento de los requisitos del estudio.
    23. Embarazo, en período de lactancia o intención concebir un hijo durante el período previsto del estudio, desde la visita de selección hasta 120 días después de la última dosis de pembrolizumab o placebo y 180 días tras el final de la quimiorradioterapia.
    24. Recepción de un alotrasplante de órgano sólido o tejidos.
    E.5 End points
    E.5.1Primary end point(s)
    1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    2. Overall Survival (OS)
    1. Supervivencia sin progresión (SSP) según los Criterios de Evaluación de la Respuesta en Tumores Sólidos Versión 1.1 (RECIST 1.1)
    2. Supervivencia global (SG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 38 months
    2. Up to approximately 46 months
    1. Hasta aproximadamente 38 meses
    2. Hasta aproximadamente 48 meses
    E.5.2Secondary end point(s)
    1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24
    2. Overall Survival (OS) at Month 36
    3. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12
    4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    5. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
    6. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
    7. Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
    8. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score
    9. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
    10. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24) Score
    11. Number of Participants Who Experience One or More Adverse Events (AEs)
    12. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
    1. Supervivencia Sin Progresión (SSP) según los Criterios de Evaluación de la Respuesta en Tumores Sólidos Versión 1.1 (RECIST 1.1) al mes 24.
    2. Supervivencia Global (SG) al mes 36
    3. Respuesta Completa (RC) según los Criterios de Evaluación de la Respuesta en Tumores Sólidos Versión 1.1 (RECIST 1.1) a la semana 12.
    4. Tasa de Respuesta Objetiva (TRO) según los Criterios de Evaluación de la Respuesta en Tumores Sólidos Versión 1.1 (RECIST 1.1).
    5. Supervivencia Sin Progresión (SSP) según los Criterios de Evaluación de la Respuesta en Tumores Sólidos Versión 1.1 (RECIST 1.1) en participantes PD-L1 positivos.
    6. Supervivencia Global (SG) en participantes PD-L1 positivos.
    7. Supervivencia Sin Progresión (SSP) después del tratamiento de siguiente línea (supervivencia sin progresión 2) tras la suspensión de la administración del tratamiento del estudio.
    8. Variación con respecto al momento basal de la puntuación global del estado de salud en el Cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ-C30 de la EORTC).
    9. Variación con respecto al momento basal de la puntuación global de la función física en el Cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ-C30 de la EORTC).
    10. Variación con respecto al momento basal de la puntuación del Cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (Puntuación de síntomas del cáncer de cuello uterino) de la EORTC.
    11. Número de participantes que experimentan uno o más acontecimiento Adversos (AAs).
    12. Número de participantes que discontinúan el tratamiento del estudio por algún Acontecimiento Adverso (AA).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 38 months
    2. Up to approximately 46 months
    3. Up to approximately 38 months
    4. Up to approximately 46 months
    5. Up to approximately 38 months
    6. Up to approximately 46 months
    7. Up to approximately 46 months
    8. Baseline and up to approximately 46 months
    9. Baseline and up to approximately 46 months
    10. Baseline and up to approximately 46 months
    11. Up to approximately 46 months
    12. Up to approximately 46 months
    1. Hasta aproximadamente 38 meses.
    2. Hasta aproximadamente 46 meses.
    3. Hasta aproximadamente 38 meses.
    4. Hasta aproximadamente 46 meses.
    5. Hasta aproximadamente 38 meses.
    6. Hasta aproximadamente 46 meses.
    7. Hasta aproximadamente 46 meses.
    8. Basal y hasta aproximadamente 46 meses.
    9. Basal y hasta aproximadamente 46 meses.
    10. Basal y hasta aproximadamente 46 meses.
    11. Hasta aproximadamente 46 meses.
    12. Hasta aproximadamente 46 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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    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
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Chile
    China
    Colombia
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Guatemala
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Norway
    Peru
    Russian Federation
    Spain
    Sweden
    Taiwan
    Thailand
    Turkey
    Ukraine
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months63
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months63
    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: 833
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 147
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 342
    F.4.2.2In the whole clinical trial 980
    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
    Ninguno
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Network of Gynaecological Oncological Trial groups (ENGOT)
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-31
    P. End of Trial
    P.End of Trial StatusOngoing
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