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    Summary
    EudraCT Number:2018-002816-29
    Sponsor's Protocol Code Number:205207
    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:2019-04-11
    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 number2018-002816-29
    A.3Full title of the trial
    A Phase I/II Single Arm Open-Label Study to Explore Safety and Clinical Activity of GSK2857916 Administered in Combination with Pembrolizumab in Subjects with Relapsed/Refractory Multiple Myeloma (DREAMM 4)
    Estudio de fase I/II, abierto y de un solo grupo para evaluar la seguridad y la actividad clínica de GSK2857916 en combinación con pembrolizumab en sujetos con mieloma múltiple en recaída/refractario (DREAMM 4).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open-label single-arm study of GSK2857916 in combination with Pembrolizumab in subjects with relapsed/refractory multiple myeloma
    Estudio abierto y de un solo grupo de GSK2857916 en combinación con pembrolizumab en sujetos con mieloma múltiple en recaída/refractario
    A.4.1Sponsor's protocol code number205207
    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 SponsorGlaxoSmithKline, S.A.
    B.1.3.4CountrySpain
    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 supportGlaxoSmithKline, Research and Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointCentro de Información
    B.5.3 Address:
    B.5.3.1Street AddressC/Severo Ochoa, 2 (P.T.M.)
    B.5.3.2Town/ cityTres Cantos (Madrid)
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34 902202700
    B.5.5Fax number+34 918070479
    B.5.6E-mailes-ci@gsk.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 nameGSK2857916
    D.3.2Product code GSK2857916
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHumanized IgG1 antibody drug conjugate
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeGSK2857916
    D.3.9.3Other descriptive nameGSK2857916
    D.3.9.4EV Substance CodeSUB130430
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) 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 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 Yes
    D.3.11.13.1Other medicinal product typeGSK2857916 is a Humanized afucosylated, maleimidocaproyl monomethyl auristatin phenylalanine (mcMMAF) conjugated IgG1 antibody.
    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 namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.3Other descriptive nameMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) 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
    Relapsed/Refractory Multiple Myeloma
    mieloma múltiple en recaída/refractario
    E.1.1.1Medical condition in easily understood language
    Relapsed/Refractory Multiple Myeloma
    mieloma múltiple en recaída/refractario
    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 10028228
    E.1.2Term Multiple myeloma
    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
    Part 1: To determine safety, tolerability and to establish the RP2D of the combination of GSK2857916 with pembrolizumab in subjects with RRMM)

    Part 2: To assess the clinical activity of the combination treatment with GSK2857916 and pembrolizumab in subjects with RRMM
    Parte 1: Determinar la seguridad y la tolerabilidad y establecer la dosis recomendada para la fase 2 (DRF2) de la combinación de GSK2857916 y pembrolizumab en sujetos con MMRR

    Parte 2: Evaluar la actividad clínica del tratamiento combinado con GSK2857916 y pembrolizumab en sujetos con MMRR.
    E.2.2Secondary objectives of the trial
    Part 1:
    - To evaluate clinical activity of the combination of GSK2857916 and pembrolizumab in subjects with RRMM
    -To evaluate the pharmacokinetic profile of GSK2857916 when administered intravenously in combination with pembrolizumab
    -To assess anti-drug antibodies (ADAs) against GSK2857916

    Part 2:
    -To further evaluate the safety of GSK2857916 administered in combination with pembrolizumab in subjects with RRMM
    -To further assess the clinical activity of the combination treatment with GSK2857916 and pembrolizumab in subjects with RRMM
    -To evaluate the pharmacokinetic profile of GSK2857916 when administered intravenously in combination with pembrolizumab
    -To assess ADAs against GSK2857916
    Parte 1:
    - Evaluar la actividad clínica de la combinación de GSK2857916 y pembrolizumab en sujetos con MMRR.
    - Evaluar el perfil farmacocinético de GSK2857916 cuando se administra por vía intravenosa en combinación con pembrolizumab
    - Evaluar la aparición de anticuerpos contra el fármaco (ACF) dirigidos contra GSK2857916

    Parte 2:
    - Evaluar más detenidamente la seguridad de GSK2857916 en combinación con pembrolizumab en sujetos con MMRR.
    - Definir mejor la actividad clínica del tratamiento combinado con GSK2857916 y pembrolizumab en sujetos con MMRR.
    - Evaluar el perfil farmacocinético de GSK2857916 cuando se administra por vía intravenosa en combinación con pembrolizumab
    - Evaluar la aparición de anticuerpos contra el fármaco (ACF) dirigidos contra GSK2857916
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for enrolment in the study must meet all of the following criteria:
    1. Provide signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
    2. Male or female, 18 years or older (at the time consent is obtained)
    3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2 of the protocol)
    4. Subjects must:
    -Has histologically or cytologically confirmed diagnosis of MM, as defined by IMWG, 2014 [Rajkumar, 2014], and
    -Has undergone stem cell transplant or is considered transplant ineligible, and
    - Has been treated with at least 3 prior lines of prior anti-myeloma treatments including an IMiD (eg. lenalidomide or pomalidomide), a proteasome inhibitor (eg. bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody alone or in combination. Line of therapy are defined by consensus panel of the
    International Myeloma Workshop [Rajkumar, 2011].
    -Has measurable disease defined as one the following:
    a) Serum M-protein ≥0.5 g/dL (≥5 g/L)
    b) Urine M-protein ≥200 mg/24h
    c) Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an
    abnormal serum free light chain ratio (<0.26 or >1.65)
    5. Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
    a) transplant was > 100 days prior to study enrolment
    b) no active infection (s)
    c) subject meets the remainder of the eligibility criteria outlined in this
    protocol
    6. Adequate organ system functions as defined in Table 3 of the study protocol
    7. All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.03, 2010) [NCI, 2010] must be ≤ Grade 1 at the time of enrollment except for alopecia and Grade 2 neuropathy.
    8. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of childbearing potential (WOCBP)
    OR
    -Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 8 of the protocol during the intervention period and for at least 120 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention.
    Additional requirements for pregnancy testing during and after study intervention are located in Appendix 8 of the protocol.
    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.
    9. Male subjects:
    Male subjects are eligible to participate if they agree to the following during the intervention period and for at least 140 days after the last dose of study intervention:
    -Refrain from donating sperm
    PLUS either:
    -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/barrier as detailed below:
    Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year as described in Appendix 8 when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
    En el estudio podrán participar los sujetos que cumplan todos los criterios siguientes:
    1. Otorgamiento del consentimiento informado por escrito firmado, lo que incluye el cumplimiento de los requisitos y restricciones citados en el documento de consentimiento.
    2. Varón o mujer mayor de 18 años (en el momento de obtener el consentimiento informado).
    3. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1 (Apéndice 2 del Protocolo).
    4. Los sujetos deberán:
    - Tener un diagnóstico de MM confirmado histológica o citológicamente, según la definición del IMWG de 2014 [Rajkumar, 2014].
    - Haberse sometido a un trasplante de células madre o no ser considerados aptos para dicho trasplante.
    - Haber recibido anteriormente un mínimo de tres líneas previas de tratamiento contra el mieloma, incluido un IMi (p. ej., lenalidomida o pomalidomida), un inhibidor del proteosoma (p. ej., bortezomib, ixazomib o carfilzomib) y un anticuerpo anti-CD38 solo o en combinación. La línea de tratamiento se define conforme al grupo de consenso del International Myeloma Workshop [Rajkumar, 2011].
    - Presentar enfermedad mensurable, definida como una de las circunstancias siguientes:
    a) Proteína M en suero ≥ 0,5 g/dl (≥ 5 g/l).
    b) Proteína M en orina ≥ 200 mg/24 h.
    c) Análisis de cadenas ligeras libres (CLL) en suero: concentración de CLL afectadas ≥ 10 mg/dl (≥ 100 mg/l) y cociente anormal de CLL en suero (≤ 0,26 o > 1,65).
    5. Los sujetos con antecedentes de autotrasplante de células madre podrán participar en el estudio siempre que cumplan los siguientes criterios de elegibilidad:
    a) Trasplante realizado más de 100 días antes de la inclusión en el estudio.
    b) Ausencia de infección activa.
    c) El sujeto cumple los demás criterios de elegibilidad descritos en este protocolo.
    6. Función orgánica adecuada, según se define en la Tabla 3 del Protocolo.
    7. Toda la toxicidad relacionada con el tratamiento previa (definida según los Criterios de toxicidad comunes para acontecimientos adversos del National Cancer Institute (NCI-CTCAE), versión 4.03, 2010) [NCI, 2010] deberá ser de grado ≤ 1 en el momento de inclusión, salvo alopecia y neuropatía de grado 2.
    8. Una mujer podrá participar si no está embarazada ni en periodo de lactancia y si se cumple al menos una de las condiciones siguientes:
    - No es una mujer en edad fértil (MEF)
    O
    - Es una MEF y utiliza un método anticonceptivo muy eficaz (con una tasa de fallos < 1% anual), preferiblemente con baja dependencia de la usuaria, tal como se describe en el apéndice 8, durante el período de intervención y, como mínimo, hasta 120 días después de la última dosis de la intervención del estudio y se compromete a no donar óvulos para fines de reproducción durante este período. El investigador deberá evaluar la eficacia del método anticonceptivo en relación con la primera dosis de la intervención del estudio.
    Las MEF deberán dar negativo en una prueba de embarazo en suero de alta sensibilidad (según exija la normativa local) en las 72 horas previas a la primera dosis de la intervención del estudio.
    En el apéndice 8 se recogen otros requisitos relacionados con las pruebas de embarazo durante y después de la intervención del estudio.
    El investigador es responsable de revisar los antecedentes médicos, los antecedentes menstruales y la actividad sexual reciente para reducir el riesgo de inclusión de una mujer con un embarazo inicial no detectado.
    9. Varones:
    - Los varones podrán participar si se comprometen a lo siguiente durante el período de intervención y, como mínimo, hasta 140 días después de la última dosis de la intervención del estudio:
    - Abstenerse de donar semen.
    MAS:
    - Abstinencia de relaciones heterosexuales como modo de vida habitual y preferido (abstinencia a largo plazo y persistente) y compromiso de mantenerla.
    O
    - Compromiso de utilizar métodos anticonceptivos/de barrera tal como se detalla a continuación.
    - Compromiso de utilizar preservativo masculino y que la pareja utilice otro método anticonceptivo muy eficaz con una tasa de fallos < 1% anual, tal como se describe en el apéndice 8, cuando mantenga relaciones sexuales con una mujer en edad fértil que no esté embarazada.
    E.4Principal exclusion criteria
    A subject will not be eligible for inclusion in this study if any of the following criteria apply:
    1. Systemic anti-myeloma therapy or an investigational drug ≤14 days or five half-lives, whichever is shorter, preceding the first dose of study drug
    2. Plasmapheresis within 7 days prior to the first dose of study drug
    3. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs
    4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune related adverse event (irAE)
    5. Current corneal epithelial disease except mild punctate keratopathy
    6. Any major surgery within the last four weeks prior to the first dose of study therapy
    7. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect subject’s safety). Subjects with isolated proteinuria resulting from MM are eligible, provided they fulfill criteria given in Table 3 of the protocol
    8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures.
    9. Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects must have recovered from all radiation-related toxicities, not requite corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
    10. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis
    11. Current active liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if subject otherwise meets entry criteria
    12. Malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (RRMM). Subjects with curatively treated non-melanoma skin cancer are allowed.
    13. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study therapy
    14. Evidence of cardiovascular risk including any of the following:
    a. QTcF interval ≥470 msecs.
    NOTE: The QT interval should be corrected for heart rate by Fridericia’s formula (QTcF).
    b. Evidence of current clinically significant uncontrolled arrhythmias;
    i. including clinically significant ECG abnormalities including 2nd degree
    (Type II) or 3rd degree atrioventricular (AV) block.
    c. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening.
    d. Class III or IV heart failure as defined by the New York Heart Association functional classification system (Appendix 4 of the protocol)
    e. Uncontrolled hypertension
    f. Presence of cardiac pacemaker (or defibrillator) with a predominantly ventricular paced rhythm, limiting ECG/QTcF analysis.
    g. Abnormal cardiac valve morphology (≥Grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate
    valvular thickening should not be entered on study.
    15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2857916 or pembrolizumab, or any of the components of the study treatment.
    16. Pregnant or lactating female.
    17. Known active infection requiring antibiotic, antiviral, or antifungal treatment.
    18. Known HIV infection.
    19. Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at screening or within 3 months prior to first dose of study treatment.

    Please see the protocol Section 5.2 Exclusion Criteria for a complete list of exclusion criteria
    No podrán participar en el estudio los sujetos que cumplan cualquiera de los siguientes criterios:
    1. Tratamiento sistémico contra el mieloma o un fármaco experimental en los 14 días previos, o el equivalente a cinco semividas, lo que suponga menos tiempo, a la primera dosis del fármaco del estudio
    2. Plasmaféresis en los 7 días previos a la primera dosis del fármaco del estudio.
    3. Tratamiento con un anticuerpo monoclonal en los 30 días previos a la primera dosis del fármaco del estudio.
    4. Recepción de un tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137) y suspensión de dicho tratamiento por un acontecimiento adverso relacionado con la inmunidad (AAri) de grado 3 o superior.
    5. Presencia de una epiteliopatía corneal, excepto una queratopatía punteada leve.
    6. Cualquier intervención de cirugía mayor en las cuatro semanas previas a la primera dosis del tratamiento del estudio.
    7. Presencia de una nefropatía activa (infección, necesidad de diálisis o cualquier otro trastorno que pueda afectar a la seguridad del sujeto). Podrán participar sujetos con proteinuria aislada debida al MM, siempre que cumplan los criterios indicados en la Tabla 3 del Protocolo.
    8. Presencia de cualquier trastorno médico, psiquiátrico o de otro tipo grave o inestable (incluidas anomalías analíticas) que pueda interferir en la seguridad del sujeto, la obtención del consentimiento informado o el cumplimiento de los procedimientos del estudio.
    9. Recepción de radioterapia en las dos semanas previas al comienzo del tratamiento del estudio. Los sujetos deberán haberse recuperado de toda la toxicidad relacionada con la radiación, no precisar corticoides y no haber sufrido una neumonitis por radiación. Se permite un reposo farmacológico de una semana en caso de radioterapia paliativa (≤2 semanas de radioterapia) por enfermedad que no afecta al sistema nervioso central (SNC).
    10. Antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroides o presencia de una neumonitis activa.
    11. Presencia de una enfermedad hepática o biliar activa según la evaluación del investigador, definida por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas, ictericia persistente o cirrosis. Nota: Se aceptará una hepatopatía crónica estable (como síndrome de Gilbert o colelitiasis asintomática) o afectación hepatobiliar por neoplasia maligna si el sujeto cumple los demás criterios de participación.
    12. Quedan excluidos los sujetos con neoplasias malignas distintas de la enfermedad en estudio, excepto cualquier otra neoplasia maligna de la que el participante haya permanecido sin enfermedad durante más de dos años y que, en opinión de los investigadores principales y el monitor médico de GSK, no vaya a afectar a la evaluación de los efectos del tratamiento de este ensayo clínico sobre la neoplasia maligna objeto de estudio (MMRR). Se permite la participación de sujetos con cáncer de piel distinto del melanoma tratado con intención curativa.
    13. Presencia de metástasis activas en el SNC o de meningitis carcinomatosa. Los sujetos con metástasis cerebrales tratadas anteriormente podrán participar siempre que se encuentren radiológicamente estables, es decir, sin signos de progresión durante al menos cuatro semanas en estudios de imagen repetidos (hay que señalar que durante la selección para el estudio deberán realizarse nuevos estudios de imagen), clínicamente estables y sin necesidad de tratamiento con esteroides durante al menos 14 días antes de la primera dosis del tratamiento del estudio.
    14. Signos de riesgo cardiovascular, lo que comprende cualquiera de los siguientes: a. Intervalo QTcF ≥470 ms.
    NOTA: Intervalo QT corregido en función de la frecuencia cardíaca según la fórmula de Fridericia (QTcF).
    b. Signos de arritmias no controladas clínicamente significativas, i. Incluidas anomalías clínicamente significativas en el electrocardiograma (ECG), como bloqueo auriculoventricular (AV) de segundo (tipo II) o tercer grado.
    c. Antecedentes de infarto de miocardio, síndromes coronarios agudos (incluida angina de pecho inestable), angioplastia coronaria o implantación de endoprótesis o injerto de derivación en los seis meses previos a la selección.
    d. Insuficiencia cardíaca de clase III o IV según el sistema de clasificación funcional de la New York Heart Association (apéndice 4).
    e. Hipertensión no controlada.
    f. Presencia de un marcapasos cardíaco (o desfibrilador) con ritmo estimulado predominantemente ventricular, lo que limita el análisis del ECG/QTcF.
    Consulte la Sección 5.2 del Protocolo para una lista completa de los criterios de exclusión.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1:
    -Percent of subjects with AEs, changes in clinical signs and laboratory parameters
    -Number of subjects with dose limiting toxicities (DLTs)

    Part 2:
    -Overall Response Rate (ORR), defined as the percentage of subjects with a confirmed PR or better (i.e., PR, VGPR, CR and sCR), according to the IMWG Response Criteria [Kumar, 2016].
    Parte 1:
    -Porcentaje de sujetos con acontecimientos adversos (AA) y variaciones de los signos clínicos y parámetros analíticos.
    - Número de sujetos con toxicidad limitante de la dosis (TLD).

    Parte 2:
    - Tasa de respuesta global (TRG), definida como el porcentaje de participantes con una RP o mejor (es decir, RP, RPMB, RC y RCe) confirmada, conforme a los criterios de respuesta del IMWG [Kumar, 2016].
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1:
    -approximately 6 months to reach end of Part 1 Dose Escalation

    Part 2:
    -at final analysis
    Parte 1:
    -aproximadamente 6 meses antes del final de la Parte 1: Aumento escalonado de la dosis

    Parte 2:
    - en el análisis final.
    E.5.2Secondary end point(s)
    Part 1:
    -Overall Response Rate (ORR), defined as the percentage of subjects with a confirmed partial response (PR) or better (i.e., PR, very good partial response [VGPR], complete response [CR] and stringent complete response [sCR]), according to the International Myeloma Working Group (IMWG) Response Criteria [Kumar, 2016].
    -Pharmacokinetic parameters following IV administration as data permit (e.g., AUCs, Cmax, time of Cmax [tmax], terminal phase half-life [t½]) after the first dose; concentration at trough (Ctrough), and end of infusion concentration in the subsequent cycles when measured.
    -Incidence and titers of ADAs against GSK2857916

    Part 2:
    -Number of subjects with AEs, changes in clinical signs and laboratory parameters
    -Ocular finding on ophthalmic exam
    -Clinical benefit rate (CBR), defined as the percentage of participants with a confirmedminimal response (MR) or better per IMWG
    -Duration of response (DoR), defined as: the time from first documented evidence of PR or better, to the time when disease progression (PD) is documented per IMWG; or death due to PD occurs among subjects who achieve an overall response, i.e. confirmed PR or better
    -Time to response (TTR), defined as: the time between the date of first dose and the first documented evidence of response (PR or better) among participants who achieved a confirmed response of PR or better
    -Time to best response, defined as the time between the date of first dose and the first best documented response (PR or better) among subjects who achieved a confirmed response of PR or better
    -Progression-free survival (PFS), defined as: the time from first dose until the earliest date of PD per IMWG, or death due to any cause
    -Time to disease progression (TTP), defined as: the time from first dose until the earliest date of PD per IMWG, or death due to PD
    -Overall Survival (OS), defined as the time from first dose until death due to any cause
    -Pharmacokinetic parameters following IV administration as data permit (e.g., AUCs, Cmax, time of Cmax [tmax], terminal phase half-life [t½]) after the first dose; concentration at trough (Ctrough), and end of infusion concentration in the subsequent cycles when measured.
    -Incidence and titer of ADA to GSK2857916
    Parte 1:
    -Tasa de respuesta global (TRG), definida como el porcentaje de sujetos con una respuesta parcial (RP) o mejor (es decir, RP, respuesta parcial muy buena [RPMB], respuesta completa [RC] y respuesta completa estricta [RCe]) confirmada, conforme a los criterios de respuesta del International Myeloma Working Group (IMWG) [Kumar, 2016].
    - Parámetros farmacocinéticos (FC) tras la administración IV, según lo permitan los datos (por ejemplo, área bajo la curva [AUC], concentración máxima media [Cmáx], tiempo en alcanzar la Cmáx [tmáx], semivida de la fase terminal [t½]), después de la primera dosis, concentración mínima (Cmín) y concentración al final de la infusión en los ciclos posteriores, cuando se determinen.
    - Incidencia y títulos de ACF contra GSK2857916.

    Parte 2:
    - Número de sujetos con AA y variaciones de los signos clínicos y parámetros analíticos.
    - Hallazgos oculares en la exploración oftalmológica.
    -Tasa de beneficio clínico (TBC), definida como el porcentaje de participantes con una respuesta mínima (RM) o mejor confirmada según los criterios del IMWG.
    - Duración de la respuesta (DR), definida como el tiempo transcurrido entre el primer signo documentado de RP o mejor y el momento en que se documente progresión de la enfermedad (PE) según los criterios del IMWG o la muerte por PE en los sujetos que logren una respuesta global, es decir, RP o mejor confirmada.
    - Tiempo hasta la respuesta (THR), definido como el tiempo transcurrido entre la fecha de la primera dosis y el primer signo documentado de respuesta (RP o mejor) en los sujetos que logren una respuesta de RP o mejor confirmada.
    - Tiempo hasta la mejor respuesta, definido como el tiempo transcurrido entre la fecha de la primera dosis y la primera mejor respuesta documentada (RP o mejor) en los sujetos que logren una respuesta de RP o mejor confirmada.
    - Supervivencia libre de progresión (SLP), definida como el tiempo transcurrido entre la primera dosis y la fecha de PE según los criterios del IMWG o la muerte por cualquier causa, lo que ocurra antes.
    - Tiempo hasta la progresión de la enfermedad (THP), definido como el tiempo transcurrido entre la primera dosis y la fecha de PE según los criterios del IMWG o la muerte por PE, lo que ocurra antes.
    - Supervivencia global (SG), definida como el tiempo transcurrido entre la primera dosis y la muerte por cualquier causa.
    - Parámetros farmacocinéticos (FC) tras la administración IV, según lo permitan los datos (por ejemplo, área bajo la curva [AUC], concentración máxima media [Cmáx], tiempo en alcanzar la Cmáx [tmáx], semivida de la fase terminal [t½]), después de la primera dosis, concentración mínima (Cmín) y concentración al final de la infusión en los ciclos posteriores, cuando se determinen.
    - Incidencia y títulos de ACF contra GSK2857916
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be evaluated during the dosing schedule under evaluation and at the end of study. For subjects who elect to continue to receive the IMP beyond the dose cohort, all other safety parameters and adverse events are followed until the patient discontinues the study.
    Las variables secundarias se evaluarán durante el periodo de dosis y al final del estudio. Para los sujetos que elijan continuar recibiendo el medicamento en investigación más allá de la cohorte de dosis, se hará seguimiento de los parámetros de seguridad y acontecimientos adversos hasta que el sujeto sea discontinuado del estudio
    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 ranging
    rango de dosis
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    Germany
    Spain
    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
    LSLV
    Última visita del último paciente.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 14
    F.4.2.2In the whole clinical trial 40
    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)
    The investigator is responsible for ensuring that consideration has been given for the post study care of the subject’s medical condition whether or not GSK is providing specific post-study treatment. If a subject remains on treatment at the time end of study is achieved they may be offered an option to extend treatment.
    El investigador es responsable de garantizar que se haya tenido en cuenta el tratamiento posterior al estudio de la enfermedad del sujeto, con independencia de que GSK suministre o no un tratamiento específico después del estudio. Si un sujeto sigue en tratamiento en el momento en que se alcance el final del estudio, se le podrá ofrecer la opción de ampliar el tratamiento.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-26
    P. End of Trial
    P.End of Trial StatusOngoing
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