Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38482   clinical trials with a EudraCT protocol, of which   6323   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2015-005488-18
    Sponsor's Protocol Code Number:8628-006
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-02-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2015-005488-18
    A.3Full title of the trial
    A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid Tumors
    Ensayo de fase Ib de investigación de la dosis con MK-8628, un inhibidor de molécula
    pequeña de las proteínas con bromodominios y dominios extraterminales (BET), en pacientes con determinados tumores sólidos avanzados
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MK-8628 Solid Tumor Trial
    MK-8628 Ensayo de Tumor Sólido
    A.3.2Name or abbreviated title of the trial where available
    MK-8628 Solid Tumor Trial
    MK-8628 Ensayo de Tumor Sólido
    A.4.1Sponsor's protocol code number8628-006
    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 SponsorOncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp.
    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 supportOncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp
    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 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 nameMK-8628 (formerly known as OTX015)
    D.3.2Product code MK-8628 (formerly known as OTX015)
    D.3.4Pharmaceutical form Capsule
    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 INNOTX015
    D.3.9.1CAS number 204587-26-8
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMK-8628 (formerly known as OTX015)
    D.3.2Product code MK-8628 (formerly known as OTX015)
    D.3.4Pharmaceutical form Capsule
    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 INNOTX015
    D.3.9.1CAS number 204587-26-8
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    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 nameMK-8628 (formerly known as OTX015)
    D.3.2Product code MK-8628 (formerly known as OTX015)
    D.3.4Pharmaceutical form Capsule
    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 INNOTX015
    D.3.9.1CAS number 204587-26-8
    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
    NUT Midline Carcinoma
    Non-Small Cell Lung Cancer
    Triple-Negative Breast Cancer
    Castration-Resistant Prostate Cancer
    Carcinoma de estructuras de la línea media con anomalías en el gen
    NUT
    Cáncer de pulmón no microcítico
    Cáncer de mama triplemente negativo
    Cáncer de próstata resistente a la castración
    E.1.1.1Medical condition in easily understood language
    Advanced Solid Tumors
    Tumores sólidos avanzados
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung 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 18.1
    E.1.2Level LLT
    E.1.2Classification code 10076506
    E.1.2Term Castration-resistant prostate 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 18.1
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term Breast cancer
    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
    To determine the recommended phase II dose for single-agent MK-8628 administered orally to subjects with selected solid tumors.
    Determinar la dosis recomendada para la fase II de MK-8628 en monoterapia administrado por vía oral a sujetos con determinados tumores sólidos.
    E.2.2Secondary objectives of the trial
    For single-agent MK-8628 administered orally to subjects with selected solid tumors:
    (1)To assess the safety and tolerability;
    (2)To characterize pharmacokinetic and pharmacodynamic parameters;
    (3)To evaluate antitumor activity using objective response rate, duration of response and disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2) as assessed by investigator radiologic review.
    Para MK-8628 en monoterapia administrado por vía oral a sujetos con determinados tumores sólidos:
    (1) Evaluar la seguridad y la tolerabilidad;
    (2) Caracterizar los parámetros farmacocinéticos y farmacodinámicos
    (3) Evaluar la actividad antitumoral por medio de la tasa de respuesta objetiva, la duración de la respuesta y la tasa de control de la enfermedad conforme a los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1, o los criterios del Grupo de Trabajo para Ensayos Clínicos sobre el Cáncer de Próstata (PCWG2), según lo determinado por el investigador mediante evaluación radiológica.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible for participation in this trial, the subject must:
    1.Have signed informed consent/assent prior to initiation of any study-specific procedures and treatment. For study subjects who are legal minors, the parent or legal guardian must also sign the consent/assent form. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical research.
    2.Have histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the subject:
    a)NUT midline carcinoma (NMC)(ectopic expression of NUT protein as determined by IHC and/or detection of BRD-NUT gene translocation as determined by FISH)
    b)Non-small cell lung cancer (NSCLC): all comers without gene rearrangement or mutational restrictions
    c)Triple negative breast cancer (TNBC) defined according to ASCO recommendations
    d)Castration-resistant prostate cancer (CRPC)
    3.Have at least one measurable lesion as per RECIST version 1.1., except for CRPC subjects who may be enrolled with objective evidence of disease as per Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.
    4.For NSCLC, TNBC and CRPC subjects, be age > or = 18 years at the time of informed consent; for NMC subjects, be age > or = 16 years at the time of informed consent.
    5.Have a life expectancy > or = 3 months.
    6.Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ? 1.
    7.Demonstrate adequate organ function (adequate bone marrow reserve, renal and liver function)
    8.Have an interval of > or = 3 weeks since chemotherapy (> or = 6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy (including investigational) or surgical intervention resection, or > or = 3 half-lives for monoclonal antibodies, or > or = 5 half-lives for other non-cytotoxic agents (whichever is longer).
    9.CRPC subjects must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is < 50 ng/dL (<1.7 nmol/L).
    10.Subjects receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before initiating study treatment
    11.Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    12.Female subjects of childbearing potential should be willing to use an adequate method of contraception as outlined in section 5.7.3? Contraception, for the course of the study through 60 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
    13.Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.7.3 ? Contraception, starting with the first dose of trial treatment through 60 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
    Para poder participar en este ensayo, el sujeto deberá:
    1. Haber firmado el consentimiento o asentimiento informado antes de empezar cualquier procedimiento o tratamiento específico del estudio. En el caso de sujetos del estudio que sean menores legales, el padre o tutor también deberá firmar el documento de consentimiento o asentimiento. El sujeto también podrá otorgar su consentimiento o asentimiento para las investigaciones biomédicas futuras. No obstante, podrá participar en el ensayo principal sin necesidad de participar en investigaciones biomédicas futuras.
    2. Tener un diagnóstico confirmado por medios histológicos o citopatológicos de uno de los siguientes tumores sólidos avanzados o metastásicos para los cuales no existe un tratamiento convencional o este ha resultado ser ineficaz, intolerable o inaceptable para el sujeto:
    a) Carcinoma de estructuras de la línea media con anomalías en el gen NUT
    (CLMN) (expresión ectópica de la proteína NUT, determinada mediante IHQ, y/o
    detección de la traslocación del gen BRD-NUT mediante FISH).
    b) Carcinoma de pulmón no microcítico (CPNM): cualquier participante, sin
    restricciones relativas a reordenaciones o mutaciones génicas.
    c) Cáncer de mama triplemente negativo (CMTN), definido conforme a las
    recomendaciones de la ASCO.
    d) Cáncer de próstata resistente a la castración (CPRC).
    3. Tener al menos una lesión mensurable conforme a los RECIST, versión 1.1., excepto en el caso de los sujetos con CPRC, en los que la demostración objetiva del cáncer se basará en criterios del Prostate Cancer Clinical Trials Working Group (PCWG2).
    4. En los sujetos con CPNM, CMTN y CPRC, ser mayor o tener 18 años en el momento de firmar el consentimiento informado; en los sujetos con CLMN, ser mayor o tener 16 años en el momento de firmar el consentimiento informado.
    5. Tener una esperanza de vida de al menos 3 meses.
    6. Tener un estado funcional (EF) del Eastern Cooperative Oncology Group (ECOG) < o = 1.
    7. Presentar una función orgánica adecuada (reserva de la médula ósea y función renal y hepática adecuadas).
    8. Intervalo mínimo de 3 semanas desde la quimioterapia (6 semanas en el caso de las nitrosoureas o la mitomicina C), inmunoterapia, hormonoterapia o cualquier otro tratamiento antineoplásico (incluidos los tratamientos experimentales) o resección quirúrgica, o de al menos 3 semividas para los anticuerpos monoclonales y 5 semividas para otros fármacos no citotóxicos (lo que suponga más tiempo).
    9. Los sujetos con CPRC deben mantener el tratamiento de privación de andrógenos con un análogo o un antagonista de la gonadoliberina (GnRH) u orquiectomía siempre que la testosterona sérica sea < 50 ng/dl (< 1,7 nmol/l).
    10. Los sujetos en tratamiento con bisfosfonatos o denosumab deberán permanecer con dosis estables de estos medicamentos durante al menos 4 semanas antes de empezar el tratamiento del estudio.
    11. Las mujeres en edad fértil deberán tener un resultado negativo en la prueba de embarazo en orina o en suero realizada en las 72 horas anteriores a la administración de la primera dosis de la medicación del estudio. Cuando el resultado de la prueba en orina sea positivo o no pueda confirmarse que es negativo, será necesario hacer una prueba de embarazo en suero.
    12. Las pacientes en edad fértil deben estar dispuestas a utilizar un método anticonceptivo adecuado como se indica en la sección 5.7.3, Anticoncepción, durante el estudio y hasta 60 días después de la última dosis de la medicación del estudio. Nota: La abstinencia es aceptable si se adapta al modo de vida y es el método anticonceptivo preferido de la paciente.
    13. Los varones fértiles deberán comprometerse a utilizar un método anticonceptivo adecuado como se indica en la sección 5.7.3, Anticoncepción, desde la administración de la primera dosis del tratamiento del ensayo y hasta 60 días después de la última dosis de la medicación del estudio. Nota: La abstinencia es aceptable si se adapta al modo de vida y es el método anticonceptivo preferido de la paciente.
    E.4Principal exclusion criteria
    The subject must be excluded from participating in the trial if the subject:
    1.Has inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of MK-8628.
    2.Has persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ? grade 2 National Cancer Institute (NCI)-CTCAE v. 4.0 is accepted.
    3.Has known primary CNS malignancy or symptomatic or untreated CNS metastases.
    4.Has a history of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of signing informed consent.
    5.Has other serious illness or medical condition, such as active infection, unresolved bowel obstruction, psychiatric disorders, or cerebrovascular accident (within 1 year of study entry).
    6.Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    7.Has known active Hepatitis B (e.g. hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (e.g. hepatitis C viral [HCV] RNA [qualitative] is detected).
    8.Has any of the following cardiac-related conditions:
    a.Congestive heart failure or angina pectoris (except if medically controlled)
    b.Previous history of myocardial infarction (within 1 year of study entry)
    c.Uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg, and/or diastolic blood pressure > 90 mmHg, and not adequately managed by anti-hypertensive medication)
    d.Uncontrolled arrhythmias
    9.Has participated in another clinical trial or treatment with any investigational drug (excluding anticancer treatments) within 30 days prior to study entry.
    10.Has other concomitant anticancer treatment, except the use of anti-androgens in CRPC subjects.
    11.Has concomitant therapy with strong CYP3A4 inhibitors or inducers.
    12.Is currently using anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of MK-8628. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted.
    13.Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject?s participation for the full duration of the trial.
    14.Is pregnant or breast-feeding.
    Se excluirá de participar en el ensayo a todos los sujetos que cumplan alguno de los criterios siguientes:
    1. Ser incapaz de tragar medicamentos orales o presentar un trastorno digestivo (por ejemplo, malabsorción) que puede afectar a la absorción intestinal del MK-8628.
    2. Presentar toxicidad de importancia clínica de grado > 1 relacionada con el tratamiento antineoplásico precedente (a excepción de la alopecia); se acepta la neuropatía sensitiva estable de grado < or = 2 según los CTCAE del National Cancer Institute (NCI), versión 4.0.
    3. Presentar una neoplasia maligna primaria del SNC o metástasis sintomáticas o sin tratar en el SNC.
    4. Tener antecedentes de neoplasias malignas previas o concomitantes (aparte del cáncer de piel distinto del melanoma tratado quirúrgicamente o el carcinoma in situ del cuello uterino curado) en los 3 años anteriores a la firma del consentimiento informado.
    5. Presentar otras enfermedades importantes o condiciones médicas, como infección activa, obstrucción intestinal no resuelta, trastornos psiquiátricos o accidente cerebrovascular (en el año anterior a la incorporación al estudio).
    6. Tener antecedentes de infección por el virus de la inmunodeficiencia humana (VIH) (anticuerpos contra el VIH 1 o 2).
    7. Tener hepatitis B activa (por ejemplo, reactividad del antígeno de superficie de la hepatitis B [HBsAg]) o hepatitis C (por ejemplo, detección [cualitativa] de ARN del virus de la hepatitis C [VHC]).
    8. Presentar alguna de las enfermedades cardíacas siguientes:
    a. Insuficiencia cardíaca congestiva o angina de pecho (a menos que se
    encuentre controlada desde el punto de vista médico).
    b. Antecedentes de infarto de miocardio (en el año anterior a la incorporación al estudio).
    c. Hipertensión arterial no controlada (definida por una presión sistólica > 140
    mmHg y/o una presión diastólica > 90 mmHg, y que no se controlan suficientemente con medicación antihipertensiva).
    d. Arritmia no controlada.
    9. Haber participado en otro ensayo clínico o recibido tratamiento con cualquier
    fármaco en investigación (excepto tratamientos antineoplásicos) en los 30 días
    anteriores a la incorporación al estudio.
    10. Estar recibiendo otro tratamiento antineoplásico concomitante, con la excepción de los antiandrógenos en los sujetos con CPRC.
    11. Recibir tratamiento concomitante con inhibidores o inductores potentes de la enzima CYP3A4.
    12. Estar recibiendo anticoagulantes (por ejemplo, warfarina, heparina) en dosis
    terapéuticas en los 7 días anteriores a la primera dosis de MK-8628. Se permite el tratamiento con heparina de bajo peso molecular (HBPM) en dosis bajas
    (profiláctico).
    13. Tener antecedentes o signos actuales de cualquier proceso, tratamiento, anomalía analítica u otra circunstancia que pueda exponer al sujeto a un riesgo elevado por participar en el ensayo, confundir los resultados del ensayo o interferir en su participación durante todo el ensayo.
    14. Estar embarazada o en período de lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this trial is to determine the recommended phase II dose (RP2D) of MK-8628. Selecting the RP2D will involve a multi-faceted decision taking into account safety, tolerability, early efficacy signal, PK exposure and PD markers. The primary endpoint driving dose selection is the DLT rate, with weight given to the highest DL tolerated (<25% DLT rate). All other facets will be considered supportive. It is important to note that dose selection in this study aims to assess a RP2D range, with other factors aside from those mentioned above, such as target engagement, contributing to refining the dose selection for phase 2. This will be further evaluated in subsequent clinical investigations in either monotherapy or combination trials.
    El objetivo principal de este ensayo es determinar la dosis recomendada para los estudios de fase II (DRF2) de MK-8628. La toma de decisiones para la elección de la DRF2 será multifactorial y tendrá en cuenta la seguridad, los primeros indicios de eficacia, la exposición farmacocinética y los marcadores farmacodinámicos. El criterio de valoración principal que guiará la elección de la dosis será la tasa de TLD, dando importancia al mayor nivel de dosis
    tolerado (tasa de TLD < 25%). Todos los demás factores se considerarán complementarios. Cabe destacar que la elección de la dosis del presente estudio tiene como objetivo evaluar un intervalo de DRF2, y que otros factores aparte de los mencionados anteriormente, como la consecución de la acción deseada, contribuirán a mejorar la elección de la dosis para la fase II. Esto se evaluará más detenidamente en investigaciones clínicas posteriores, tanto en monoterapia como en politerapia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DLTs are monitored continuously during the first cycle of treatment (21 days) for each dose level.
    TLDs son monitorizadas continuamente durante el primer ciclo de tratamiento (21 días) para cada nivel de dosis.
    E.5.2Secondary end point(s)
    1.Secondary Safety Endpoints
    A secondary objective of this trial is to determine the safety and tolerability of MK-8628 across subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC) included in this trial. Safety will be assessed in subjects who have received MK-8628 by determining the RP2D and quantifying and grading reported Adverse Events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Attribution to drug, time-of-onset, duration of the event, resolution, and any concomitant medications administered will be recorded. AEs to be analyzed include but are not limited to all AEs, events of clinical interest (ECI), serious adverse events (SAE), fatal SAEs, and laboratory changes.
    Pharmacokinetic Endpoints
    Plasma parameters of MK-8628 as appropriate and according to analyses performed (non-compartmental or nonlinear mixed effect modelling) will be determined and may include trough (Cmin) and peak (Cmax) concentrations, time to peak concentration (Tmax), AUC[0-?], volume of distribution at steady state (Vdss), terminal half-life (t1/2), steady state, and total clearance (CL). PK data for MK-8628 will be interpreted in terms of safety findings and compared with historical data. Incidence and severity of AEs along with PK parameters will be analyzed in relation to the most pertinent biomarker(s), if any.
    Pharmacodynamic Endpoints
    Inhibition of BET proteins by MK-8628 leads to alterations in the transcription of messenger RNA (mRNA) at loci most sensitive to disruption of BET activity. These are considered target genes. Changes in expression, measured via mRNA, of prespecified target genes* will be used as PD biomarkers to assess target engagement of BET proteins by MK-8628. (*Note: the following non-exhaustive list of target genes may be considered for testing: Bcl2, IL7R, and MYC as down-regulated target genes; CSRNP2, HEXIM1, and HIST1H2BK as up-regulated target genes.) A range of PD biomarkers will be explored in surrogate samples from all subjects treated, using appropriate assays to establish target engagement. Rather than rely on gene expression changes in cancer cells, these PD biomarkers will be based on current PD knowledge from translational studies of mouse and human whole blood. Using RNA extracted from whole blood samples collected both prior to and following administration of MK-8628, messenger RNA transcript profiling may be performed to assess gene expression and evaluate whether changes in specific genes or sets of genes may represent a PD biomarker of response. Potential limitations of this assay include patient-to-patient variability and a small effect size of induction or repression upon treatment with MK-8628. Due to these limitations, the PD endpoint is considered to be qualitative given the assay may not be able to differentiate target engagement between the MK-8628 doses examined in this study.
    Secondary Efficacy Endpoints: RECIST or PCWG -based Response Rate
    A secondary efficacy objective of this trial is to evaluate the anti-tumor activity of MK-8628 in subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC). Secondary efficacy endpoints include (1) Objective Response Rate (ORR), defined as the percentage of subjects who have achieved confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2), as assessed by investigator radiologic review; (2) Duration of Response (DOR), defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first; and (3) Disease Control Rate (DCR), defined as the percentage of subjects who have achieved stable disease or confirmed CR or confirmed PR according to RECIST v1.1 or PCWG2, by the investigator review.
    1. Criterios de valoración secundarios de la seguridad
    Un objetivo secundario del ensayo es determinar la seguridad y la tolerabilidad del MK-8628 en los sujetos con determinados tumores sólidos avanzados (CLMN, CPNM, CMTN y CPRC) incluidos en el estudio. Para evaluar la seguridad en los sujetos que hayan recibido MK-8628 se determinará la DRF2 y se cuantificarán y graduarán los AA notificados conforme a los Criterios terminológicos comunes para acontecimientos adversos (CTCAE), versión 4.0. Se consignará la atribución de relación causal con el fármaco, el momento de
    aparición, la duración del acontecimiento, su resolución y los medicamentos concomitantes administrados. Los AA a analizar serán, entre otros, todos los AA, los acontecimientos de interés clínico (AIC), los acontecimientos adversos graves (AAG), los AAG mortales y las anomalías analíticas.
    Criterios de valoración farmacocinéticos
    Se determinarán los parámetros plasmáticos de MK-8628 según corresponda y conforme a los análisis efectuados (modelo de efectos mixtos no compartimental o no lineal), entre ellos la concentración mínima (Cmín) y máxima (Cmáx), el tiempo transcurrido hasta alcanzar la concentración máxima (Tmáx), el AUC[0-?], el volumen de distribución en estado de equilibrio (Vdee), la semivida terminal (t1/2), el estado de equilibrio y el aclaramiento total (Cl). Los datos farmacocinéticos de MK-8628 se interpretarán teniendo en cuenta los datos de seguridad y se compararán con los datos históricos. Se analizarán la incidencia y la intensidad de los AA y los parámetros farmacocinéticos en relación con los biomarcadores más pertinentes, en caso de haberlos.
    Criterios de valoración farmacodinámicos
    La inhibición de las proteínas BET por parte del MK-8628 provoca alteraciones de la transcripción del ARN mensajero (ARNm) en los loci más sensibles a la alteración de la actividad de las BET, los cuales se consideran genes diana. Las variaciones de la expresión de genes diana especificados de antemano*, cuantificadas mediante el ARNm, se utilizarán como biomarcadores farmacodinámicos para evaluar la acción deseada del MK-8628 sobre
    las proteínas BET. (*Nota: podrá plantearse el análisis de los genes de la lista siguiente, que no es exhaustiva: Bcl2, IL7R y MYC como genes diana inhibidos; CSRNP2, HEXIM1 y HIST1H2BK como genes diana estimulados.) Se investigarán diversos marcadores farmacodinámicos en muestras indirectas de todos los sujetos tratados, utilizando los análisis pertinentes para detectar la acción deseada. Estos marcadores farmacodinámicos no se basarán en los cambios de la expresión génica en las células tumorales, sino en la información farmacodinámica actual procedente de estudios traslacionales efectuados en
    sangre de ratón y humana.Utilizando ARN extraído de muestras de
    sangre completa obtenidas antes y después de la administración de MK-8628, se pueden determinar los perfiles de transcritos del ARN mensajero para evaluar la expresión génica y averiguar si las variaciones de genes específicos o grupos de genes representan un biomarcador farmacodinámico de la respuesta. Entre las posibles limitaciones de este análisis están la variabilidad entre pacientes y una pequeña magnitud del efecto de la inducción o represión secundaria al tratamiento con MK-8628. A causa de estas limitaciones, se
    considera que el criterio de valoración farmacodinámico es cualitativo, ya que el análisis no permite diferenciar la acción deseada entre las dosis de MK-8628 que se evaluarán en el estudio.
    Criterios de valoración secundarios de la eficacia: tasa de respuesta según los
    RECIST o los criterios del PCWG
    Un objetivo secundario de eficacia del ensayo es evaluar la actividad antitumoral del MK-8628 en sujetos con determinados tumores sólidos avanzados (CLMN, CPNM, CMTN y CPRC). Los criterios de valoración secundarios de la eficacia abarcan 1) la TRO, definida como el porcentaje de sujetos que alcanzan la respuesta completa (RC) confirmada o la respuesta parcial (RP) confirmada de acuerdo con los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1, o los criterios del Prostate Cancer Clinical Trials Working Group (PCWG2) (véase la sección 12.9), según lo determinado por el investigador mediante evaluación radiológica; 2) la DR, definida como el tiempo transcurrido desde la primera prueba documentada de RC o RP hasta la progresión de la enfermedad o la muerte por cualquier causa, lo que suceda antes; y 3) la TCE, definida como el porcentaje de sujetos que alcanzan la enfermedad estable o la RC o RP confirmada de acuerdo con los RECIST, versión 1.1, o los criterios del PCWG2, según lo determinado por el investigador.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary Safety Endpoints: AEs are monitored continuously.
    PK Endpoints: Cycle 1 - Day 1; immediately prior to the first dose T0 and 20 min±5min, 1h±10min, 2h15min±10min, 3h15min±10min, 8h±1h, and 12h±2h, Day 8 ±1 days, Day 15 ±2 days, and Day 22 ±3 days.
    Pharmacodynamic Endpoints: Cycle 1 - Day 1: immediately prior to the first dose T0 and 3h15min±10min, 8h±1h, and 12h±2h and Day 8 ±1 day.
    Secondary Efficacy Endpoints: For tumor evaluation, a CT, MRI and/or chest X-ray will be performed on Day 1 ± 3 days of every 2nd cycle A bone scan is mandatory for CRPC subjects and will be performed on Day 1 ± 3 days of every 4th cycle(every 3 months).Prostate Specific Antigen measurements will be performed every 4 cycles on a schedule coinciding with the CRPC subjects? bone scans.
    Variables secundarias seguridad: AAs son monitorizados continuamente
    Criterio valoración Farmacocinético: Ciclo1-Día 1; inmediatamente antes de la primera dosis T0 y 20min±5min, 1h±10min, 2h15min±10min, 3h15min±10 min, 8h±1h y 12h±2h, Día 8±1día, Día 15±2días, y Día 22±3días
    Criterio valoración Farmacodinámico: Ciclo 1-Día 1: inmediatamente antes de la primera dosis T0 y 3h15min±10min, 8h±1h, y 12h±2h y Día 8±1día
    Variables secundarias eficacia: El día 1±3días de cada dos ciclos, se hará una evaluación tumoral mediante TC, RM y/o radiografía de tórax. La gammagrafía ósea es obligatoria en sujetos con CPRC y se hará el día 1±3días de cada cuatro ciclos (cada 3 meses). La determinación del antígeno prostático específico se hará cada 4 ciclos haciéndola coincidir con la gammagrafía ósea
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose Escalation
    Escalada de dosis
    E.7.2Therapeutic exploratory (Phase II) No
    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.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Belgium
    Canada
    France
    Spain
    Switzerland
    United States
    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
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 5
    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: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 42
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the last treatment administration, subjects will be followed up for safety for 30 days and then until resolution of any AEs. A visit will be performed 30 days(±5 days)after the last MK-8628 intake. In subjects who discontinue study therapy without documented disease progression, continue monitoring their disease status by radiologic imaging every 2 cycles until the start of new anti-cancer treatment, documented disease progression, death, or the end of the study, whichever occurs first.
    Después de la última administración, los sujetos se seguirán por seguridad un máximo de 30 días y después hasta la resolución de cualquier AA. Una visita se hará 30 días(±5)después de la última toma de MK-8628. En sujetos que descontinuaron la terapia sin progresión documentada de la enfermedad, se continuará monitorizando su enfermedad por imágenes radiológicas cada 2 ciclos hasta el comienzo del nuevo tratamiento anticanceroso, documentada progresión de la enfermedad, muerte o fin de estudio.
    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 Decision2016-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-04-26
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA