E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed or refractory Primary Mediastinal Large B-Cell Lymphoma |
Linfoma mediastínico primario de linfocitos B grandes recidivante o resistente |
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E.1.1.1 | Medical condition in easily understood language |
relapsed or refractory Primary Mediastinal Large B-Cell Lymphoma |
Linfoma mediastínico primario de linfocitos B grandes recidivante o resistente |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the Overall Response Rate (ORR) of pembrolizumab by independent central review according to the International Working Group (IWG) response criteria (Cheson, 2007) |
Evaluar la tasa de respuesta global (TRG) del pembrolizumab mediante una revisión central independiente, según los criterios de respuesta del Grupo de Trabajo Internacional (IWG) (Cheson, 2007 [1]). |
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E.2.2 | Secondary objectives of the trial |
Evaluate Overall Response Rate, Progression Free Survival, Duration of Response, Disease Control Rate, Overall Survival and safety and tolerability of pembrolizumab. |
Evaluar la tasa de respuesta global, la supervivencia sin progresión, la duración de la respuesta, la tasa de control de la enfermedad, la supervivencia global , y la seguridad y tolerabilidad del pembrolizumab. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
Merck realizará investigaciones biomédicas futuras con las muestras obtenidas para tal finalidad durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores con el fin de abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los pacientes que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras es estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal información para desarrollar fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco en el momento preciso. |
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E.3 | Principal inclusion criteria |
- Confirmed diagnosis of Primary Mediastinal Large B-cell lymphoma by independent central review, according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues (WHO Criteria 2008 [52]. - Subject must be able to provide an evaluable core or excisional lymph node biopsy for confirmation of PMBCL diagnosis from an archival or newly obtained biopsy at Screening. In addition subjects may be asked to provide additional biopsy samples, if possible, at Week 12 and at the time of discontinuation due to progression for biomarker analysis. - Have relapsed*a or refractory*b Primary Mediastinal Large B-cell lymphoma and: - Have relapsed after auto-SCT or have failed to achieve a Complete Response within 60 days of auto-SCT. Subjects may have received intervening therapy after auto-SCT for relapsed or refractory disease, in which case they must have relapsed after or be refractory to their last treatment. OR - For subjects who are ineligible for auto-SCT, have received at least ? 2 lines of prior therapy and have failed to respond to or relapsed after their last line of treatment. For subjects who received consolidative local radiotherapy after systemic therapy, local radiotherapy will not be considered as a separate line of treatment. - Must have been previously exposed to rituximab as part of prior lines of treatment. - Have radiographically measureable disease by independent central review, defined as at least one lesion that can be accurately measured in at least two dimensions with spiral computed tomography (CT) scan. Minimum measurement must be > 15 mm in the longest diameter. - Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale |
- Diagnóstico de linfoma mediastínico primario de linfocitos B grandes confirmado mediante revisión centralizada independiente según la clasificación de la OMS de neoplasias de los tejidos hematopoyético y linfoide (WHO Criteria, 2008 [52]). - El sujeto debe poder proporcionar una muestra de biopsia de ganglios linfáticos evaluable para confirmar el diagnóstico de LMPLB, en concreto, una biopsia con aguja gruesa o por escisión, de archivo u obtenida recientemente en la selección. Además, se puede pedir a los sujetos que proporcionen más muestras de biopsia para análisis de biomarcadores, si es posible, en la semana 12 y en el momento de la retirada por progresión. - Presentar linfoma mediastínico primario de linfocitos B grandes recidivante o resistente y: -Haber recidivado después de TCM autólogo o no haber alcanzado una respuesta completa durante los 60 días siguientes al TCM autólogo. Los sujetos pueden haber recibido tratamiento de la enfermedad recidivante o resistente después del TCM autólogo, y en tal caso deben haber recidivado después de dicho tratamiento o haber mostrado resistencia a éste. O BIEN - En el caso de sujetos no candidatos al TCM autólogo, haber recibido al menos 2 líneas de tratamiento previo y no haber respondido o haber recidivado después de la última línea de tratamiento. En el caso de los sujetos que hayan recibido radioterapia local de consolidación después de un tratamiento sistémico, dicha radioterapia no se considerará una línea de tratamiento distinta. - Exposición previa a rituximab como parte de líneas de tratamiento anteriores. - Presentar enfermedad mensurable radiológicamente según una revisión centralizada independiente, definida como al menos una lesión que puede medirse con precisión en dos dimensiones como mínimo mediante tomografía computarizada (TC) helicoidal. La lesión deberá medir como mínimo >15 mm en su diámetro mayor. - Presentar un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1. |
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E.4 | Principal exclusion criteria |
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. - Has a known history of immunosuppression or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. - Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. < or = Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or has had prior radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e. < or = Grade 1 or at baseline) from adverse events due to a previously administered agent. - Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD). - Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. - Has known active CNS involvement. Subjects with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for CSF disease) and clinical remission. - Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment - Has evidence of active, non-infectious pneumonitis. - Has an active infection requiring intravenous systemic therapy. - Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). - Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection. - Has received a live vaccine within 30 days prior to first dose. |
- Está participando o ha participado en un estudio de un fármaco en investigación y está recibiendo o ha recibido el tratamiento o ha utilizado un producto sanitario en investigación en las 4 semanas previas a la administración de la primera dosis del tratamiento. - Tiene antecedentes documentados de inmunodepresión o está reciviendo esteroides sistémicos o algún otro tipo de tratamiento inmunodepresor sistémico en los 7 días anteriores a la administración de la primera dosis del tratamiento del ensayo. El uso de dosis fisiológicas de corticosteroides podrá autorizarse previa consulta con el promotor. - Ha recibido un anticuerpo monoclonal en las 4 semanas previas al día 1 del estudio o no se ha recuperado (a un grado < o = 1 o al nivel basal) de acontecimientos adversos provocados por fármacos administrados más de 4 semanas antes. - Ha recibido quimioterapia previa o un tratamiento dirigido con moléculas pequeñas durante las 2 semanas anteriores al día 1 del estudio o radioterapia en las 4 semanas anteriores al día 1 del estudio o no se ha recuperado (a un grado < o = 1 o al valor basal) de acontecimientos adversos provocados por un fármaco administrado anteriormente. - Ha recibido un alotrasplante de células madre hematopoyéticas en los 5 años precedentes. (Si el trasplante se realizó más de 5 años antes, el paciente podrá participar siempre que no presente síntomas de enfermedad de injerto contra huésped [EICH].) - Presenta otro tumor maligno conocido que esté en progresión o necesite tratamiento activo. Son excepciones el carcinoma basocelular de piel, el carcinoma espinocelular de piel y el cáncer de cuello uterino in situ que haya recibido un tratamiento potencialmente curativo. - Presenta afectación demostrada activa del SNC. Los sujetos que han presentado en el pasado afectación del SNC pueden incluirse si está en remisión radiológica, citológica (para enfermedad del LCR) y clínica. - Presenta enfermedad autoinmunitaria activa que ha necesitado tratamiento sistémico en los dos años precedentes (con medicamentos modificadores de la enfermedad, corticosteroides o inmunodepresores). El tratamiento de sustitución (p. ej., tiroxina, insulina o corticosteroides en dosis fisiológicas para una insuficiencia suprarrenal o hipofisaria, etc.) no se considera una forma de tratamiento sistémico. - Tener indicios de neumonitis no infecciosa activa. - Presentar una infección activa con necesidad de tratamiento sistémico por vía intravenosa. - Ha recibido tratamiento previo con un anticuerpo anti PD 1, anti PD L1, anti PD L2, anti CD137 o anti CTLA 4 (antígeno asociado a los linfocitos T citotóxicos 4) (como ipilimumab o cualquier otro anticuerpo o fármaco dirigido específicamente contra la coestimulación de linfocitos T o contra vías que actúen de punto de control). - Tener antecedentes de infección por el virus de la inmunodeficiencia humana (VIH), Hepatitis B (VHB) o infección por Hepatitis C (VHC). - Haber recibido una vacuna de microbios atenuados en los 30 días anteriores a la administración de la primera dosis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Confirm efficacy of pembrolizumab monotherapy in subjects relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) - To evaluate the Overall Response Rate (ORR) of pembrolizumab by independent central review according to the International Working Group (IWG) response criteria (Cheson, 2007) |
-Confirmar la eficacia del pembrolizumab en monoterapia en sujetos con Linfoma mediastínico primario de linfocitos B grandes recidivante o resistente. - Evaluar la tasa de respuesta global (TRG) de pembrolizumab evaluada mediante una revisión central independiente, según los criterios de respuesta del Grupo de Trabajo Internacional (IWG) (Cheson, 2007). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
up to 2 years |
hasta los 2 años |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Colombia |
France |
Germany |
Italy |
Netherlands |
New Zealand |
Russian Federation |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |