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    Summary
    EudraCT Number:2019-001992-35
    Sponsor's Protocol Code Number:MS200647_0055
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-01-10
    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 number2019-001992-35
    A.3Full title of the trial
    A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without M7824 (bintrafusp alfa) as First-line Treatment of Biliary Tract Cancer
    Estudio en fase II/III, multicéntrico, aleatorizado, controlado con placebo, de gemcitabina más cisplatino con o sin M7824 (bintrafusp alfa) como tratamiento de primera línea de cáncer de las vías biliares
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    1L BTC Phase II/III Gemcitabine Plus Cisplatin With or Without M7824
    Fase II/III de gemcitabina más cisplatino con o sin M7824 en CVB de 1L
    A.3.2Name or abbreviated title of the trial where available
    1L BTC Phase II/III Gemcitabine Plus Cisplatin With or Without M7824
    A.4.1Sponsor's protocol code numberMS200647_0055
    A.5.4Other Identifiers
    Name:IND numberNumber:140345
    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 Healthcare KGaA
    B.1.3.4CountryGermany
    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 KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+34932275402
    B.5.5Fax number+49 6151 72 2000
    B.5.6E-mailservice@merckgroup.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2112
    D.3 Description of the IMP
    D.3.1Product namebintrafusp alfa
    D.3.2Product code M7824
    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 INNbintrafusp alfa
    D.3.9.2Current sponsor codeM7824
    D.3.9.3Other descriptive nameMSB0011359C
    D.3.9.4EV Substance CodeSUB179957
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Biliary Tract Cancer
    Cáncer de vías biliares
    E.1.1.1Medical condition in easily understood language
    Biliary Tract Cancer
    Cáncer de vías biliares
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028982
    E.1.2Term Neoplasm biliary tract
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10073077
    E.1.2Term Intrahepatic cholangiocarcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074879
    E.1.2Term Extrahepatic cholangiocarcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10017614
    E.1.2Term Gallbladder cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10034442
    E.1.2Term Periampullary carcinoma metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10034443
    E.1.2Term Periampullary carcinoma non-resectable
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10034445
    E.1.2Term Periampullary carcinoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Open-label Safety Run-in: To assess if M7824 2400 mg Q3W is safe and tolerable and to confirm this dose as the recommended Phase II dose for the randomized, double-blind part of the study.

    Randomized, Double-blind Part: To assess Progression Free Survival (PFS) and Overall Survival (OS) with M7824 in combination with gemcitabine plus cisplatin versus placebo with gemcitabine plus cisplatin in participants with advanced or metastatic BTC who have not received chemotherapy/immunotherapy in the advanced/metastatic setting
    Preinclusión de seguridad abierta: valuar si M7824 2400 mg C3S es seguro y tolerable y confirmar esta dosis como la dosis recomendada para la fase II de la parte aleatorizada doble ciego del estudio.
    Parte aleatorizada doble ciego: evaluar la supervivencia sin progresión (SSP) y la supervivencia global (SG) con M7824 en combinación con gemcitabina más cisplatino frente a placebo con gemcitabina más cisplatino en participantes con cáncer de las vías biliares (CVB) avanzado o metastásico que no han recibido quimioterapia/inmunoterapia en el contexto avanzado/metastásico.
    E.2.2Secondary objectives of the trial
    •To evaluate clinical efficacy of M7824 based on objective response (ORR)
    •To evaluate clinical efficacy of M7824 based on duration of response (DOR)
    •To evaluate clinical efficacy of M7824 based on durable response rate (DRR)
    •To evaluate ORR, DOR, DRR and PFS by Investigator read
    •To evaluate safety profile of M7824 or placebo in combination with gemcitabine plus cisplatin
    •To characterize the pharmacokinetic (PK) profile of M7824
    •To characterize the immunogenicity of M7824 and to correlate it to exposure
    •Evaluar la eficacia clínica de M7824, en función de la tasa de respuesta objetiva (TRO).
    •Evaluar la eficacia clínica de M7824, en función de la duración de la respuesta (DdR).
    •Evaluar la eficacia clínica de M7824, en función de la tasa de respuesta duradera (TRD).
    •Evaluar la TRO, la DdR, la TRD y la SSP mediante la lectura del investigador.
    •Evaluar el perfil de seguridad de M7824 o placebo en combinación con gemcitabina más cisplatino.
    •Determinar el perfil farmacocinético (FC) de M7824.
    •Determinar la inmunogenia de M7824 y correlacionarla con la exposición.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients aged ≥ 18 years of age at the time of signing the informed consent.

    2. Participants with histologically or cytologically confirmed locally advanced or metastatic BTC, including intrahepatic CCA and extrahepatic CCA, gallbladder cancer and ampulla of Vater’s cancer.

    3. Naïve to chemotherapy, immunotherapy, and interventional radiological treatment (transaortic chemo-embolization, transaortic embolization, transaortic infusion) for locally advanced or metastatic BTC. Participants whose disease has recurred ≥ 6 months after completion of neoadjuvant or adjuvant treatments will be considered eligible.

    4. Availability of tumor tissue (primary or metastatic) (fresh or archival biopsies) before the first administration of study intervention. Availability of tumor tissue is mandatory except for the safety run-in part. Transductal aspirates, brush cytology, and cell blocks are not acceptable. Tumor tissue (fresh or archival) must be suitable for biomarker assessment as described in the Laboratory Manual.

    5. At least 1 measurable lesion according to RECIST 1.1 verified independently by 2 separate IRC readers. Participants in the safety run-in part do not require a measurable lesion at baseline and IRC verification is not required.

    6. ECOG PS of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing.

    7. Life expectancy of ≥ 12 weeks, as judged by the Investigator.

    8. Adequate hematological function defined by white blood cell count ≥ 2.0 × 10^9/Lwith absolute neutrophil count ≥ 1.0 × 10^9/L, lymphocyte count ≥ 0.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, and hemoglobin (Hgb) ≥ 9 g/dL (participants may have been transfused) at study entry and at Week 1 Day 1 prior to dosing. Previously transfused participants are allowed in the study with a stable Hgb of ≥ 9 g/dL at the time of study entry.

    9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase level ≤ 3.0 × ULN, and an alanine aminotransferase level ≤ 3.0 × ULN. For participants with liver involvement, aspartate aminotransferase ≤ 5.0 × ULN and alanine aminotransferase ≤ 5.0 × ULN are acceptable.

    10. Adequate renal function defined by an estimated creatinine clearance (CrCl) > 50 mL/min according to the Cockcroft-Gault formula or by measure of CrCl from 24-hour urine collection.
    CrCl (mL/min) = (140-age) × weight (kg) / (72 × serum creatinine [Crjaffe])
    If female, × 0.85
    If creatinine is measured by the enzymatic method, add 0.2 and use as Crjaffe = 0.2 + Crenzyme.

    11. Albumin ≥ 2.8 g/dL.

    12. Adequate coagulation function defined as prothrombin time or international normalized ratio ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.

    13. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (eg, entecavir, tenofovir, or lamivudine; adefovir or interferon is not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of approved antiviral.
    1. Pacientes de ≥18 años en el momento de firmar el formulario de consentimiento informado.
    2. Participantes con CVB localmente avanzado o metastásico confirmado histológica o citológicamente, incluyendo el colangiocarcinoma (CCA) intrahepático y extrahepático, el cáncer de vesícula biliar y el cáncer de la ampolla de Vater.
    3. Sin tratamiento previo con quimioterapia, inmunoterapia y tratamiento radiológico intervencionista (quimioembolización transaórtica, embolización transaórtica, perfusión transaórtica) para el CVB localmente avanzado o metastásico. Se considerará aptos a los participantes que presenten enfermedad recurrente ≥6 meses después de la finalización del tratamiento neoadyuvante o adyuvante.
    4. Disponibilidad de tejido tumoral (primario o metastásico), de archivo o biopsias recientes, antes de la primera administración de la intervención del estudio. La disponibilidad de tejido tumoral es obligatoria salvo para la parte de preinclusión de seguridad. Los aspirados transductales, la citología cervical y los bloques de células no son aceptables. El tejido tumoral (reciente o de archivo) debe ser apto para la evaluación de biomarcadores, tal como se describe en el Manual del laboratorio.
    5. Al menos 1 lesión medible según los criterios RECIST 1.1 verificada de forma independiente por dos lectores del CRI. Los participantes en la parte de preinclusión de seguridad no requieren una lesión medible al inicio y no es necesaria la verificación del CRI.
    6. EG ECOG de 0 o 1 en el momento de la inclusión en el estudio y en el día 1 de la semana 1 antes de la administración de la dosis.
    7. Esperanza de vida ≥12 semanas, según el criterio del investigador.
    8. Función hematológica adecuada definida por un recuento de leucocitos ≥2,0 × 10^9/l, con un recuento absoluto de neutrófilos ≥1,5 × 10^9/l, recuento de linfocitos ≥0,5 × 10^9/l, recuento de plaquetas ≥100 × 10^9/l y hemoglobina (Hgb) ≥9 g/dl (los participantes pueden haberse sometido a una transfusión) en el momento de la inclusión en el estudio y en el día 1 de la semana 1 antes de la administración de la dosis. A los participantes que se han sometido anteriormente a una transfusión se les permite participar en el estudio con un nivel de Hgb de ≥9 g/dl en el momento de la inclusión en el estudio.
    9. Función hepática adecuada, definida por un nivel de bilirrubina total ≤1,5 × el límite superior de la normalidad (LSN), un nivel de aspartato aminotransferasa ≤3,0 × LSN y un nivel de alanina aminotransferasa ≤3,0 × LSN. Para los participantes con afectación hepática, los niveles de aspartato aminotransferasa ≤5,0 × LSN y alanina aminotransferasa ≤5,0 × LSN son aceptables.
    10. Función renal adecuada definida mediante un aclaramiento de creatinina (ACr) estimado >50 ml/min de acuerdo con la fórmula de Cockcroft-Gault o mediante una recogida de orina de 24 horas para medir el ACr.
    ACr (ml/min) = (140-edad) × peso (kg) /(72 × creatinina sérica [Crjaffe])
    Si es una mujer, × 0,85
    Si el valor de creatinina se mide mediante el método enzimático, añadir 0,2 y usar como Crjaffe = 0,2 + Crenzima.
    11. Albúmina ≥2,8 g/dl.
    12. Función de coagulación adecuada, definida como tiempo de protrombina o índice internacional normalizado ≤1,5 × LSN, a menos que el participante esté recibiendo tratamiento anticoagulante.
    13. Los pacientes positivos para el ácido desoxirribonucleico (ADN) del virus de la hepatitis B (VHB) deben estar en tratamiento y recibir una dosis estable de antivirales (p. ej., entecavir, tenofovir, o lamivudina; adefovir e interferón no están permitidos) en el momento de incorporación al estudio y contar con un control y tratamiento planificados, que incluyen la cantidad inicial de ADN del VHB de conformidad con las pautas aprobadas pertinentes.
    Los participantes que reciben tratamiento activo contra el virus de la hepatitis C (VHC) deben recibir una dosis estable en el momento de incorporación al estudio y contar con un control y tratamiento planificados de conformidad con las pautas aprobadas del antiviral autorizado.
    E.4Principal exclusion criteria
    1. Previous and/or intercurrent cancers. With the exception of: curatively-treated cancers with no recurrence in > 3 years or early cancers treated with curative intent, including but not limited to cervical carcinoma in situ, superficial, noninvasive bladder cancer, basal cell carcinoma, squamous cell carcinoma in situ, or endoscopically resected gastrointestinal cancers limited in mucosal layer.

    2. Rapid clinical deterioration not related to malignancy which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures.

    3. Participants with symptomatic central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they are judged to have fully recovered from treatment.

    4. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (eg, corneal transplant, hair transplant).

    5. Significant acute or chronic infections including:
    - Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
    - Active tuberculosis (presence of clinical symptoms, physical or radiographic findings of active tuberculosis).
    - Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage.
    - Active bacterial or fungal infection requiring systemic therapy.

    6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
    - Participants with type 1 diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    - Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg of prednisone or equivalent per day.
    - Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is acceptable.

    7. History of, or concurrent, interstitial lung disease.

    8. Known history of hypersensitivity reactions to M7824 or its products or known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.

    9. Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification ≥ Class II), or serious cardiac arrhythmia.

    10. Other severe, acute, or chronic medical conditions, including immune colitis, inflammatory bowel disease, immune pneumonitis, or psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior.

    11. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.

    12. Concurrent treatment with nonpermitted drugs. Participants who have completed prior adjuvant therapy > 6 months prior to randomization are eligible.

    13. Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints), including but not limited to anti-PD-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, or anti-4-1BB antibody is not allowed, inclusive of localized administration of such agents.

    14. Prior therapy with any antibody/drug targeting TGFβ/TGFβ receptor.

    15. Radiation within 14 days other than focal palliative bone-directed radiotherapy.

    16. Systemic therapy with immunosuppressive agents within 7 days before the start of study intervention; or use of any investigational drug within 28 days before the start of study intervention.

    17. Live vaccine administration within 4 weeks of study intervention administration.

    18. Participation in any concurrent interventional clinical study for BTC.

    19. Unable to tolerate CT or magnetic resonance imaging (MRI) in the opinion of the Investigator and/or allergy to contrast material.

    20. Major surgery within 28 days before the start of study intervention (excluding prior diagnostic biopsy and stenting/percutaneous transhepatic biliary drainage for the purpose of releasing biliary tract obstruction).

    21. Pregnancy or breastfeeding.

    22. Known alcohol or drug abuse.

    23. Legal incapacity or limited legal capacity
    1. Cánceres anteriores y/o intercurrentes. A excepción de: casos de cáncer tratados curativamente sin recurrencia en >3 años o casos de cáncer precoz tratados con intención curativa, incluidos, entre otros, carcinoma cervical in situ, cáncer de vejiga superficial no invasivo, carcinoma de células basales, carcinoma de células escamosas in situ o cáncer gastrointestinal resecado endoscópicamente limitado en la capa de la mucosa.
    2. Rápido deterioro clínico no relacionado con neoplasia maligna que, en opinión del investigador, pueda predisponer a la incapacidad para tolerar el tratamiento o los procedimientos del estudio.
    3. Participantes con metástasis sintomáticas del (SNC) están excluidos. participantes con antecedentes de metástasis tratadas en el SNC (mediante cirugía o radioterapia) no son aptos, a menos que se considere que se han recuperado por completo del tratamiento.
    4. Receptor de cualquier trasplante de órgano, incluido alotrasplante de células madre, pero a excepción de los trasplantes que no requieran inmunosupresión (p. ej., trasplante de córnea, trasplante capilar).
    5. Infecciones agudas o crónicas de consideración, incluidas:
    - Antecedentes conocidos de prueba positiva para el virus (VIH) o el síndrome de la inmunodeficiencia adquirida.
    - Tuberculosis activa (presencia de síntomas clínicos, físicos o hallazgos radiográficos de tuberculosis activa).
    - Infección de las vías biliares no controlada. La obstrucción de las vías biliares debe aliviarse mediante la colocación de una endoprótesis vascular o un drenaje biliar transhepático percutáneo.
    - Infección bacteriana, fúngica o viral activa (a excepción de hepatitis B y hepatitis C) que requiera tratamiento sistémico.
    6. Enfermedad autoinmunitaria activa que pueda empeorar al recibir un inmunoestimulante:
    - Son aptos los participantes con diabetes tipo 1, vitíligo, alopecia, psoriasis, hipotiroidismo o hipertiroidismo que no requieran tratamiento inmunodepresor.
    - Son aptos los participantes que requieran restitución hormonal con corticoesteroides si estos se administran únicamente con el objetivo de la restitución hormonal y en dosis diarias de ≤10 mg de prednisona o equivalente.
    - Se acepta la administración de corticoesteroides para otras afecciones a través de una vía que se considere que provoca una exposición sistémica mínima (vías tópica, intranasal, intraocular o inhalatoria).
    7. Antecedentes de o enfermedad pulmonar intersticial concurrente.
    8. Antecedentes conocidos de reacciones de hipersensibilidad a M7824 o sus productos o reacciones conocidas de hipersensibilidad grave a antic. monoclonales (grado ≥3 de la versión 5.0 de los Criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional contra el Cáncer (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), cualquier antecedente de anafilaxia o antecedentes recientes (en los últimos 5 meses) de asma no controlada.
    9. Enfermedad cardiovascular/cerebrovascular clínicamente significativa, como: accidente cerebrovascular/ictus (<6 meses antes de la inscripción), infarto de miocardio (<6 meses antes de la inscripción), angina de pecho inestable, insuficiencia cardíaca congestiva (clase ≥II según la clasificación de la New York Heart Association) o arritmia cardíaca grave.
    10. Otras afecciones médicas graves, agudas o crónicas, incluidas colitis inmunitaria, enfermedad inflamatoria intestinal, neumonitis inmunitaria o trastornos psiquiátricos, incluidos pensamientos o comportamientos suicidas recientes (en el último año) activos.
    11. Exacerbación de enfermedad pulmonar obstructiva crónica o de otra enfermedad respiratoria que requiera hospitalización o que impida el tratamiento del estudio en un plazo de 30 días antes de la aleatorización.
    12. Participantes que son candidatos para trasplante de hígado y que pueden recibir el trasplante dentro de un período médicamente aceptable.
    13. Tratamiento concomitante con fármacos no permitidos. Son aptos los participantes que hayan completado el tratamiento adyuvante previo >6 meses antes de la aleatorización.
    14. No se permite el tratamiento previo con anticuerpos/fármacos dirigidos a las proteínas correguladoras de linfocitos T (puntos de control inmunitario), incluidos, entre otros, anticuerpos anti-PD-1, anti-PD-L1, anticuerpo contra el antígeno 4 asociado al linfocito T citotóxico (CTLA-4) o anticuerpo anti-4-1BB, incluida la administración localizada de dichos fármacos.
    15. Tratamiento previo con anticuerpos/fármacos dirigidos a los receptores de TGFβ/TGFβ.
    16. Radioterapia en un plazo de 14 días distinta a radioterapia ósea paliativa.
    17. Tratamiento sistémico con inmunodepresores en los 7 días anteriores al inicio de la intervención del estudio; o uso de algún fármaco en investigación en los 28 días anteriores al inicio de la intervención del estudio.

    Refer to protocol section 5.2
    E.5 End points
    E.5.1Primary end point(s)
    Open-label Safety Run-in
    1. Occurrence of DLTs during the DLT evaluation period

    Randomized, Double-blind Part
    1. PFS according to RECIST 1.1 as assessed by IRC
    2. OS
    Preinclusión de seguridad abierta
    1. Aparición de TLD durante el periodo de evaluación de la TLD
    Parte aleatorizada doble ciego
    1. SSP según RECIST 1.1, evaluada por el CRI
    2. SG
    E.5.1.1Timepoint(s) of evaluation of this end point
    Open-label Safety Run-in
    1. From the Occurrence of DLTs during the DLT evaluation period

    Randomized, Double-blind Part
    1. PFS according to RECIST 1.1 as assessed by IRC and overall survival
    Preinclusión de seguridad abierta
    1. Desde la aparición de TLD durante el periodo de evaluación de la TLD
    Parte aleatorizada doble ciego
    1. SSP según RECIST 1.1, evaluada por el CRI, y supervivencia global
    E.5.2Secondary end point(s)
    Open-label Safety Run-in
    Occurrence of TEAEs and AEs
    Occurrence of abnormalities (Grade ≥ 3) in laboratory tests

    Randomized, Double-blind Part
    1. Confirmed objective response according to RECIST 1.1 as assessed by IRC
    2. DOR assessed by confirmed complete response or partial response until progression of disease or death, according to RECIST 1.1 as assessed by IRC
    3. Durable confirmed response of at least 6 months according to RECIST 1.1 as assessed by IRC
    4. ORR, DOR, and PFS according to RECIST 1.1 by Investigator
    5. Occurrence of TEAEs and treatment-related AEs, including adverse events of special interest
    6. PK profile of M7824 in terms of Ceoi and Ctrough for
    participants in the M7824 arm. PK profile of M7824 in terms of AUC0-t, AUC0-∞, Cmax, tmax, and t½ for participants in the safety run-in part of the study only
    7. Immunogenicity as measured by antidrug antibody assays at baseline and on-treatment for participants in the M7824 arm
    Preinclusión de seguridad abierta
    Aparición de AAST y AA
    Aparición de anomalías (grado ≥3) en las pruebas analíticas.

    Parte aleatorizada doble ciego
    1. Respuesta objetiva confirmada según RECIST 1.1, evaluada por el CRI.
    2. DdR evaluada según la respuesta completa o respuesta parcial confirmada hasta la progresión de la enfermedad o la muerte, de conformidad con los criterios RECIST 1.1, evaluada por el CRI.
    3. Respuesta duradera confirmada de al menos 6 meses, según los criterios RECIST
    1.1, evaluada por el CRI.
    4. TRO, DdR y SSP evaluadas según RECIST 1.1 por el investigador.
    5. Aparición de AAST y AA relacionados con el tratamiento, incluidos los acontecimientos adversos de especial interés.
    6. Perfil FC de M7824, en términos de Cfdi y Cmínima para los participantes en el grupo de M7824. Perfil FC de M7824, en términos de ABC0-t, ABC0-∞, Cmáx., tmáx.y t½ para los participantes en la parte de preinclusión de seguridad del estudio solamente.
    7. Inmunogenia determinada mediante análisis de anticuerpos antifármaco al inicio y durante el tratamiento para los participantes en el grupo de M7824
    E.5.2.1Timepoint(s) of evaluation of this end point
    Open-label Safety Run-in
    Multiple and variable timepoints throughout the study - please refer to protocol

    Randomized, Double-blind Part
    Items 1 - 5: Multiple and variable timepoints throughout the study - please refer to protocol
    Items 6 and 7 - multiple timepoints throughout study, please see Protocol table 4, (Schedule of Activities for Biomarkers, PK, and Immunogenicity Sampling: Randomized, Double-blind Part) page 29/ 168
    Preinclusión de seguridad abierta
    Varios momentos y variables a lo largo del estudio; consulte el protocolo.
    Parte aleatorizada doble ciego
    Ítems 1 a 5: varios momentos y variables a lo largo del estudio; consulte el protocolo.
    Ítems 6 y 7: varios momentos a lo largo del estudio; consulte la tabla 4 del protocolo (Calendario de actividades para biomarcadores, FC y obtención de muestras de inmunogenia: parte aleatorizada doble ciego), página 29/168.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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) Yes
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Chile
    China
    France
    Germany
    Japan
    Korea, Republic of
    Poland
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the data cutoff for the primary OS analysis when 353 participants have died. If the study is not expanded into Phase III but continues as a Phase II study, the end of study is defined accordingly, as the data cutoff date for the primary OS analysis when 103 participants have died.
    Under some circumstances, follow-up may continue after the stipulated end of study until the last participant has died or at the discretion of the Sponsor.
    Se define como la fecha de corte de los datos para el análisis ppal de la SG cuando 353 partic. han muerto. Si el estudio no se amplía a la FIII, pero continúa como un estudio en FII, el final del estudio se define, según corresponda, como la fecha de corte de los datos para el análisis ppal de la SG cuando 103 partic. han muerto.En algunas circunst., el seguimiento puede continuar dsp del final del estudio estipulado hasta que el último partic. haya fallecido o según el criterio del Promotor
    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 months9
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days8
    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: 256
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 256
    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 state95
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 224
    F.4.2.2In the whole clinical trial 512
    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)
    Participants will be followed for survival and AEs as specified in the Schedule of Activities.
    The Sponsor will not provide any additional care to participants after they leave the study because such care would not differ from what is normally expected for patients with BTC.
    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 Decision2020-01-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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