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    Summary
    EudraCT Number:2020-005028-13
    Sponsor's Protocol Code Number:MK-6482-015
    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:2021-09-02
    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 number2020-005028-13
    A.3Full title of the trial
    A Phase 2 Study to Evaluate the Efficacy and Safety of Belzutifan (MK-6482, formerly PT2977) Monotherapy in Participants with Advanced Pheochromocytoma/Paraganglioma (PPGL) or Pancreatic Neuroendocrine Tumor (pNET)
    Estudio de fase 2 para evaluar la eficacia y la seguridad de belzutifán (MK-6482, anteriormente PT2977) en monoterapia en participantes con feocromocitoma/paraganglioma (FPGL) o tumor neuroendocrino pancreático (TNEp) avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study of belzutifan (MK-6482) Monotherapy in Participants with Advanced Pheochromocytoma/Paraganglioma (PPGL) or Pancreatic Neuroendocrine Tumor (pNET)
    Estudio de fase 2 de belzutifán (MK-6482) en monoterapia en participantes con feocromocitoma/paraganglioma (FPGL) o tumor neuroendocrino pancreático (TNEp) avanzado
    A.3.2Name or abbreviated title of the trial where available
    Belzutifan/MK-6482 for the treatment of PPGL or pNET
    Belzutifán/MK-6482 en el tratamiento del FPGL o TNEp
    A.4.1Sponsor's protocol code numberMK-6482-015
    A.5.4Other Identifiers
    Name:INDNumber:153,091
    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 SA
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    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 nameBelzutifan
    D.3.2Product code MK-6482
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBelzutifan
    D.3.9.2Current sponsor codeMK-6482
    D.3.9.4EV Substance CodeSUB207909
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.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
    Pheochromocytoma/Paraganglioma or Pancreatic Neuroendocrine Tumor
    Feocromocitoma/paraganglioma o tumor neuroendocrino pancreático
    E.1.1.1Medical condition in easily understood language
    Pheochromocytoma, Paraganglioma or Pancreatic Neuroendocrine Tumors
    Feocromocitoma, paraganglioma o tumor neuroendocrino pancreático
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10034876
    E.1.2Term Pheochromocytoma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10073860
    E.1.2Term Paraganglioma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10067518
    E.1.2Term Pancreatic neuroendocrine tumor
    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 evaluate the objective response rate (ORR) of belzutifan/MK-6482 per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR)
    1. Evaluar la tasa de respuesta objetiva (TRO) con belzutifán/MK-6482 conforme a los criterios RECIST 1.1 según una evaluación independiente central con enmascaramiento (EICE)
    E.2.2Secondary objectives of the trial
    1. To evaluate the duration of response (DOR) of belzutifan/MK-6482 in participants with a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR
    2. To evaluate the time to response (TTR) of belzutifan/MK-6482 in participants with a confirmed CR or PR per RECIST 1.1 by BICR
    3. To evaluate disease control rate (DCR) of belzutifan/MK-6482 per RECIST 1.1 by BICR
    4. To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving belzutifan/MK-6482
    5. To evaluate the overall survival (OS) of participants receiving belzutifan/MK-6482
    6. To evaluate the safety of belzutifan/MK-6482
    1. Evaluar la duración de la respuesta (DR) con belzutifán/MK-6482 en los participantes con una respuesta completa (RC) o respuesta parcial (RP) confirmada conforme a los criterios RECIST 1.1 según una EICE
    2. Evaluar el tiempo hasta la respuesta (THR) con belzutifán/MK-6482 en los participantes con una RC o RP confirmada conforme a los criterios RECIST 1.1 según una EICE
    3. Evaluar la tasa de control de la enfermedad (TCE) con belzutifán/MK-6482 conforme a los criterios RECIST 1.1 según una EICE
    4. Evaluar la supervivencia sin progresión (SSP) conforme a los criterios RECIST 1.1 según una EICE de los participantes tratados con belzutifán/MK-6482
    5. Evaluar la supervivencia global (SG) de los participantes tratados con belzutifán/MK-6482
    6. Evaluar la seguridad de belzutifán/MK-6482
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Cohort A1: Pheochromocytoma/Paraganglioma (PPGL)
    1. Has documented histopathological diagnosis (local report) of pheochromocytoma or paraganglioma
    2. Has locally advanced or metastatic disease that is not amenable to surgery or curative intent treatment
    3. Adequately controlled blood pressure defined as blood pressure ≤150/90 mm Hg (≤135/85 mm Hg for adolescents) and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment
    Cohort A2: Pancreatic Neuroendocrine Tumor (pNET)
    4. Has documented histopathological or cytopathological diagnosis (local report) of well-differentiated, low or intermediate grade (G1 or G2 pNET per 2017 WHO classification and grading) pNET
    5. Has locally advanced disease or metastatic disease that is:
    a. Not amenable for surgery, radiation, locoregional therapies or combination modality of such treatments with curative intent
    b. Experienced disease progression on or after at least 1 line of prior systemic therapy that includes an approved targeted agent such as everolimus (mTOR inhibitor) or sunitinib (antiVEGF targeted agent). Participants who have received >3 prior systemic therapies will be capped to ≤20% of the cohort
    Cohorts A1 and A2
    6. Has disease progression within the past 12 months from screening
    7. Has measurable disease per RECIST v1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified in real time by BICR. BICR must confirm the presence of radiologically measurable disease per RECIST 1.1 for the participant to be eligible for the study
    a. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth since completion of radiation
    b. Metastatic lesions situated in the brain are not considered measurable and should be considered nontarget lesions
    c. Only lesions of the primary indication for the cohort may be evaluated for measurability; other neoplastic lesions will be documented by the investigator and this information provided to the independent reviewers to ensure that such lesions are not included in the RECIST assessment
    8. Is male or female, 12 years of age inclusive (≥40 kg for adolescents [12-17 years of age]), at the time of signing the informed consent
    9. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study intervention:
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
    OR
    • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
    - Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
    • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    10. 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, during the intervention period and for at least 30 days after the last dose of study intervention
    • A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine or 72 hours for serum before the first dose of study intervention
    • If a urine test cannot be confirmed as negative, a serum pregnancy test is required
    • 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
    • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    11. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR
    12. Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (not previously irradiated). FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue if the lesion is accessible and a biopsy is not clinically contraindicated
    13. Has an ECOG performance status of either 0 or 1, as assessed within 7 days of treatment initiation
    14. Has adequate organ function
    Cohorte A1: Feocromocitoma/paraganglioma (FPGL)
    1.Diagnóstico histopatológico documentado de feocromocitoma o paraganglioma
    2.Enfermedad localmente avanzada o metastásica no susceptible de cirugía o tto. con intención curativa
    3.Presión arterial controlada ≤150/90 mm Hg (≤135/85 mm Hg en adolescentes) y sin modificaciones del tto. antihipertensivo (en participantes con hipertensión concomitante) durante al menos 2 semanas antes del comienzo del tto.
    Cohorte A2: Tumor neuroendocrino pancreático (TNEp)
    4.Diagnóstico histopatológico o citopatológico documentado de TNEp bien diferenciado de grado bajo o intermedio (G1 o G2 según clasificación y gradación de la OMS de 2017)
    5.Enfermedad localmente avanzada o metastásica que:
    a.No sea susceptible de cirugía, radioterapia, ttos. locorregionales o modalidad combinada con intención curativa
    b.Progresión de la enfermedad durante o después de al menos una línea previa de tto. sistémico que incluya un fármaco dirigido aprobado.Los participantes que hayan recibido>3 ttos. sistémicos previos quedarán limitados a≤20% de la cohorte
    Cohortes A1 y A2
    6.Progresión de la enfermedad en los 12 meses previos a la selección
    7.Enfermedad mensurable conforme a los criterios RECIST v1.1 mediante TC o RM, según la evaluación del IP y verificada en tiempo real según una EICE. La EICE deberá confirmar la presencia de enfermedad mensurable radiológicamente conforme criterios RECIST 1.1 para que el candidato pueda participar
    a.Las lesiones irradiadas o tratadas con ttos. locorregionales no podrán utilizarse como lesiones diana a menos que muestren claramente crecimiento desde la finalización de la irradiación
    b.Las lesiones metastásicas cerebrales no se consideran mensurables y han de considerarse lesiones no diana
    c.Solo podrán evaluarse en cuanto a mensurabilidad las lesiones de la indicación principal correspondientes a la cohorte; el investigador documentará otras lesiones neoplásicas y esta información se facilitará a evaluadores independientes para garantizar que tales lesiones no se incluyan en la evaluación RECIST
    8.Varón o mujer de 12 años de edad, inclusive (≥40 kg en los adolescentes [12-17 años]), en el momento de firmar el CI
    9.En el estudio podrán participar varones que se comprometan a todo lo siguiente durante el período de intervención y hasta, como mínimo, 7 días después de recibir la última dosis de la intervención del estudio:
    •Abstenerse de mantener relaciones heterosexuales, como modo de vida habitual y preferido (abstinencia a largo plazo y persistente), y compromiso de mantener dicha abstinencia;
    O
    •Comprometerse a usar métodos anticonceptivos, a menos que se confirme la presencia de azoospermia (por vasectomía o secundaria a una causa médica), tal como preservativo masculino + uso por la pareja de un método anticonceptivo adicional cuando mantengan relaciones sexuales con penetración vaginal con MEF que no estén embarazadas
    •El uso de anticonceptivos por varones deberá cumplir la normativa local sobre métodos anticonceptivos para participantes en estudios clínicos
    10.En el estudio podrán participar mujeres que no estén embarazadas ni en período de lactancia y que cumplan al menos una de las condiciones siguientes:
    •No es MEF;
    O
    •Es MEF y utiliza un método anticonceptivo muy eficaz, con escasa dependencia de la usuaria, o practica abstinencia de relaciones heterosexuales como modo de vida preferido y habitual, durante el período de intervención y hasta, como mínimo, 30 días después de recibir la última dosis
    •MEF deberán dar negativo en una prueba de embarazo de alta sensibilidad realizada en las 24 horas (orina) o las 72 horas (suero) previas a la 1a dosis de la intervención del estudio
    •Cuando no pueda confirmarse que el resultado de una prueba en orina es negativo será necesario hacer una prueba de embarazo en suero
    •El investigador es responsable de revisar los antecedentes médicos, menstruales y la actividad sexual reciente para reducir el riesgo de incluir a una mujer con un embarazo no detectado
    •El uso de anticonceptivos por las mujeres deberá cumplir la normativa local sobre métodos anticonceptivos para participantes en estudios clínicos
    11.El participante otorga su CI por escrito para el estudio. El participante también podrá otorgar su consentimiento para investigaciones biomédicas futuras. No obstante, podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras
    12.Envío de una muestra de tejido tumoral de archivo o de una biopsia reciente, con aguja gruesa o por escisión, de una lesión tumoral no irradiada previamente. Se prefieren los bloques de tejido FFIP a las extensiones. Se prefieren las biopsias de obtención reciente al tejido de archivo si la lesión es accesible y la biopsia no está clínicamente contraindicada.
    13.Estado funcional del ECOG de 0 o 1 determinado en los 7 días previos al comienzo del tratamiento
    14.Función orgánica adecuada
    E.4Principal exclusion criteria
    1. Is unable to swallow orally administered medication or has a disorder that might affect the absorption of belzutifan
    2. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years with the following exceptions:
    a) Participants with history of VHL disease will be permitted provided concurrent lesions (other than PPGL for Cohort A1 and pNET for Cohort A2) are localized without immediate need for intervention
    b) Prior history of surgical resection(s) for concurrent localized VHL disease-associated tumors is allowed provided there is no history of metastatic disease from concurrent tumors; history of systemic therapy for concurrent tumors will be exclusionary
    c) Participants with history of other genetic syndromes will be allowed provided concurrent tumors (outside of the organ affected in Cohort A1 and Cohort A2, respectively) are localized and do not require immediate intervention; history of metastatic disease in concurrent tumors or history of systemic therapy for concurrent tumors will be exclusionary
    3. Has known CNS metastases and/or carcinomatous meningitis
    4. Has any of the following:
    • Hypoxia as defined by a pulse oximeter reading <92% at rest, or
    • Requires intermittent supplemental oxygen, or
    • Requires chronic supplemental oxygen
    5. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, or arterial bypass (CABG) or PTCA ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Concurrent uncontrolled hypertension defined as blood pressure >150/90 mm Hg despite optimal antihypertensive medications within 2 weeks prior to the first dose of study treatment
    6. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
    7. Has had major surgery ≤4 weeks prior to first dose of study intervention
    8. Has received prior treatment (except somatostatin analogs) with chemotherapy, targeted therapy, or other investigational therapy within the past 4 weeks of study entry, or prior biologics or immunotherapy within the past 6 weeks of study entry
    9. Has received prior locoregional therapies or radiation within the past 4 weeks of study entry
    10. Has received prior treatment with PRRT/radionuclide therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with pNET
    11. Has received meta-iodobenzylguanidine (MIBG) therapy or other radiopharmaceutical therapy within the past 12 weeks from screening for participants with PPGL
    12. Has received prior treatment with any HIF-2α inhibitor (including belzutifan)
    13. Has a known hypersensitivity to the study treatment and/or any of its excipients
    14. Has toxicities from prior locoregional or systemic or any other therapies that is not recovered to baseline or CTCAE ≤Grade 1 (with the exception of alopecia)
    15. Has received colony-stimulating factors ≤28 days prior to the first dose of study intervention
    16. Is currently receiving strong inhibitors of CYP3A4 that cannot be discontinued for the duration of the study
    17. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
    18. Is currently enrolled in and receiving study therapy, was enrolled in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks (28 days) of the first dose of study intervention
    19. Has an active infection requiring systemic therapy
    20. Has a known history of HIV infection
    21. Has a known history of hepatitis B (defined as HBsAg reactive) or known active HCV (defined as detection of HCV RNA [qualitative]) infection
    22. Participant has resting electrocardiogram (ECG) indicating uncontrolled cardiac conditions, as judged by the investigator, or participant has congenital long QT syndrome
    23. For Cohort A2, has a tumor histology consistent with poorly differentiated pNET, neuroendocrine carcinoma, or NET of nonpancreatic origin
    24. For Cohort A2, participants who have uncontrolled symptoms from functional pNETs at study entry
    25. In the judgment of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study
    26. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator
    1.Incapacidad de tragar medicación por vía oral o presencia de un trastorno que afectara a la absorción de belzutifán
    2.Antecedentes de una 2ª neoplasia maligna, a menos que se haya completado un tto. potencialmente curativo sin signos de neoplasia maligna durante 2 años, con las siguientes excepciones:
    -Podrán participar pacientes con antecedentes de enfermedad VHL siempre que las lesiones concurrentes (distintas de FPGL en cohorte A1 y de TNEp en cohorte A2) sean localizadas y no requieran intervención inmediata
    -Se permiten antecedentes de resección quirúrgica de tumores localizados concurrentes asociados a la enfermedad VHL siempre que no haya antecedentes de metástasis de los tumores concurrentes; los antecedentes de tto. sistémico por tumores concurrentes serán motivo de exclusión
    -Se permitirá la participación de pacientes con antecedentes de otros síndromes genéticos siempre que los tumores concurrentes (fuera del órgano afectado en cohortes A1 y A2, respectivamente) sean localizados y no requieran una intervención inmediata; los antecedentes de metástasis de los tumores concurrentes o los antecedentes de tto. sistémico por tumores concurrentes serán motivo de exclusión
    3.Presencia de metástasis en el SNC y/o meningitis carcinomatosa
    4.Presencia de cualquiera de las circunstancias siguientes:
    •Hipoxia definida como lectura de pulsioxímetro<92% en reposo
    •Necesidad de oxigenoterapia intermitente o crónica.
    5.Presencia de cardiopatía clínicamente significativa, como angina de pecho inestable, infarto agudo de miocardio, derivación arterial (revascularización coronaria) o ACTP en los 6 meses previos al día 1 de administración del fármaco. Hipertensión no controlada concomitante, definida como presión arterial>150/90 mm Hg a pesar de recibir tto antihipertensivo 2 semanas antes de la 1a dosis del tto. del estudio
    6.Trastorno psiquiátrico o por abuso de sustancias conocido que pueda dificultar el cumplimiento de los requisitos del estudio
    7.Antecedentes de una intervención de cirugía mayor en las 4 semanas previas a la 1a dosis del estudio
    8.Recepción de tto. previo (excepto análogos de la somatostatina) con quimioterapia, tto. dirigido u otro tto. experimental en las 4 semanas previas a la incorporación al estudio o de biofármacos o inmunoterapia en las 6 semanas previas a la incorporación al estudio
    9.Recepción de ttos. locorregionales o radioterapia en las 4 semanas previas a la incorporación al estudio
    10.Recepción de tto. previo con PRRT/terapia con radionúclidos u otro radiofármaco en las 12 semanas previas a la selección en los participantes con TNEp
    11.Recepción de tto. con metayodobencilguanidina u otro radiofármaco en las 12 semanas previas a la selección en los participantes con FPGL
    12.Recepción de tto. previo con cualquier inhibidor de HIF-2α (incluido belzutifán)
    13.Hipersensibilidad conocida al tto. del estudio y/o a cualquiera de sus excipientes
    14.Toxicidad locorregional o sistémica previa de cualquier otro tto. que no se haya recuperado hasta la situación basal o un grado≤1 según los CTCAE (con excepción de alopecia)
    15.Recepción de factores estimuladores de colonias en los 28 días previos a la 1a dosis del estudio
    16.Recepción activa de inhibidores potentes de la enzima CYP3A4 que no puedan suspenderse durante el estudio
    17.Recepción activa de inductores potentes (fenobarbital, enzalutamida, fenitoína, rifampicina, rifabutina, rifapentina, carbamazepina, nevirapina o hipérico) o moderados (p. ej., bosentán, efavirenz o modafinilo) de la enzima CYP3A4 que no puedan suspenderse durante el estudio
    18.Participación activa o pasada en un estudio de un fármaco experimental y recepción o uso, activo o pasado, de un tto. o producto sanitario experimental en las 4 semanas (28 días) previas a la administración de la 1a dosis de la intervención del estudio
    19.Presencia de una infección activa con necesidad de tto. sistémico
    20.Antecedentes de infección por VIH
    21.Antecedentes conocidos de hepatitis B o infección activa conocida por el VHC
    22.Electrocardiograma (ECG) en reposo que indica la existencia de cardiopatías no controladas, según el criterio del investigador, o existencia de un síndrome de QT largo congénito
    23.En la cohorte A2, histología del tumor compatible con TNEp poco diferenciado, carcinoma neuroendocrino o TNE de origen extrapancreático
    24.En la cohorte A2, presencia de síntomas no controlados de TNEp funcionales al incorporarse al estudio
    25.En opinión del investigador, es improbable que el participante cumpla los procedimientos, restricciones y requisitos del estudio
    26.Antecedentes o datos presentes de cualquier proceso, tto. o anomalía analítica que, en opinión del investigador responsable del tto., podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o motivar que la participación no sea lo más conveniente para la posible participante
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective Response (OR): a confirmed complete response (CR) or partial response (PR)
    1. Respuesta objetiva (RO): respuesta completa (RC) o respuesta parcial (RP) confirmada
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 4 years
    1. Hasta aproximadamente 4 años
    E.5.2Secondary end point(s)
    1. Duration of response: the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first
    2. Time to response, defined as the time from first dose of belzutifan/MK-6482 to first documented evidence of CR or PR
    3. Disease control: a confirmed CR, PR, or stable disease (SD)
    4. Progression-free survival: the time from first dose of belzutifan/MK-6482 to the first documented progressive disease (PD) or death from any cause, whichever occurs first
    5. Overall survival: the time from first dose of belzutifan/MK-6482 until death from any cause
    6. Number of Participants Who Experienced One or More Adverse Events (AEs)
    7. Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
    1. Duración de la respuesta: el tiempo desde la primera evidencia documentada de RC o RP hasta la progresión de la enfermedad o la muerte por cualquier causa, lo que ocurra primero
    2. Tiempo hasta la respuesta, definido como el tiempo desde la primera dosis de belzutifan / MK-6482 hasta la primera evidencia documentada de RC o PR
    3. Control de la enfermedad: RC, RP o enfermedad estable (EE) confirmada
    4. Supervivencia libre de progresión: el tiempo desde la primera dosis de belzutifan / MK-6482 hasta la primera Progresión de la Enfermedad (PE) documentada o la muerte por cualquier causa, lo que ocurra primero
    5. Supervivencia general: el tiempo desde la primera dosis de belzutifan / MK-6482 hasta la muerte por cualquier causa
    6. Número de participantes que experimentaron uno o más eventos adversos (EA)
    7. Número de participantes que discontinuaron el fármaco del estudio debido a un evento adverso (EA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 4 years
    2. Up to approximately 4 years
    3. Up to approximately 4 years
    4. Up to approximately 4 years
    5. Up to approximately 4 years
    6. Up to approximately 4 years
    7. Up to approximately 4 years
    1. Hasta aproximadamente 4 años
    2. Hasta aproximadamente 4 años
    3. Hasta aproximadamente 4 años
    4. Hasta aproximadamente 4 años
    5. Hasta aproximadamente 4 años
    6. Hasta aproximadamente 4 años
    7. Hasta aproximadamente 4 años
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Canada
    Russian Federation
    Turkey
    United States
    Denmark
    France
    Germany
    Hungary
    Italy
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 4
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 4
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 68
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 88
    F.4.2.2In the whole clinical trial 140
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-06-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-06
    P. End of Trial
    P.End of Trial StatusOngoing
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