E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Malignant Pleural Mesothelioma |
Mesotelioma pleural avanzado |
|
E.1.1.1 | Medical condition in easily understood language |
Mesothelioma that has progressed and has spread to other parts of the Body (metastatic) while or after standard treatment. |
Mesotelioma que haya progresado y se haya extendido a otras partes del cuerpo después o durante el tratamiento estandar |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10035605 |
E.1.2 | Term | Pleural mesothelioma malignant advanced |
E.1.2 | System Organ Class | 100000015981 |
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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 investigate whether pre-treated mesothelioma patients treated with pembrolizumab have a better outcome in terms of progression-free survival (PFS), as assessed by independent radiological review, compared to standard, institutional-choice chemotherapy (gemcitabine or vinorelbine). |
Investigar si los pacientes tratados con pembrolizumab tratados con pre-tratamiento tienen un mejor resultado en términos de supervivencia libre de progresión (PFS), evaluada mediante una revisión radiológica independiente, en comparación con la quimioterapia estándar de elección institucional (gemcitabina o vinorelbina). |
|
E.2.2 | Secondary objectives of the trial |
To evaluate secondary measures of clinical efficacy including objective response rate (ORR), investigator assessed progression free survival (PFS), overall survival (OS), and time to treatment failure (TTF).
To assess the safety and tolerability of the treatment. |
Evaluar medidas secundarias de eficacia clínica incluyendo la tasa de respuesta objetiva (ORR), supervivencia libre de progresión (PFS), la supervivencia global (OS) y el tiempo hasta el fracaso del tratamiento (TTF).
Evaluar la seguridad y tolerabilidad del tratamiento. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male and female patients aged 18 years and older - Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible) - Progressing after or on previous platinum based chemotherapy. - Availability of tumour tissue for translational research - ECOG performance status 0-1 (patients who capable of all self-care) - Life expectancy of at least 3 months - Measurable or evaluable disease according to RECIST 1.1 criteria - Adequate haematological function (Haemoglobin ≥90 g/L or ≥5.6 mmol/L; White Blood Cells ≥1.0 × 109/L; Lymphocytes ≥0.5 g/L; Absolute neutrophils count (ANC) ≥1.5 × 109/L; Platelet count ≥100 × 109/L) - Adequate renal function (Creatinine ≥1.5 × ULN OR calculated creatinine clearance ≥40 mL/min) - Adequate liver function (ALT and AST ≤2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤5 × ULN) - Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 35 days before randomisation (the test has to be repeated 72 hours before pembrolizumab treatment start). |
- Pacientes varones y mujeres mayores de 18 años - Mesotelioma pleural maligno histológicamente confirmado (todos los subtipos son elegibles) - Avanzando después o durante la quimioterapia anterior basada en platino. - Disponibilidad de tejido tumoral para la investigación translacional - ECOG 0-1 (pacientes que son capaces de auto-cuidado) - Expectativa de vida de al menos 3 meses - Enfermedad mensurable o evaluable de acuerdo con los criterios RECIST 1.1 - Función hematológica adecuada (Hemoglobina ≥ 90 g / L o ≥ 5,6 mmol / L, glóbulos blancos ≥ 1,0 × 109 / L, linfocitos ≥ 0,5 g / L, recuento de neutrófilos absolutos ≥1,5 × 109 / L; ≥100 x 109 / l) - Función renal adecuada (Creatinina ≥1,5 × ULN O un aclaramiento de creatinina calculado ≥40 mL / min) - Función hepática adecuada (ALT y AST ≤2,5 x ULN, si el paciente tiene metástasis hepáticas, ALT y AST deben ser ≤5 × LSN) - Las mujeres en edad fértil, incluidas las mujeres que tuvieron su último período menstrual en los últimos 2 años, deben someterse a una prueba negativa de suero u orina en los 35 días previos a la asignación al azar (la prueba debe repetirse 72 horas antes del inicio del tratamiento con pembrolizumab). |
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E.4 | Principal exclusion criteria |
- 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). - Prior therapy with gemcitabine or vinorelbine. - Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomisation and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to randomisation. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. - Known or suspected hypersensitivity to pembrolizumab or any of its excipients. - Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient’s capacity to participate in the trial. - Previous allogeneic tissue/solid organ transplant. - Live vaccines within 30 days prior to first dose of pembrolizumab. - Regular intake of immune-modulating drugs (such as interferon, methotrexate). - History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease (ILD) or active, non-infectious pneumonitis. - Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment. - Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy. - HIV infection. - Known active hepatitis B or hepatitis C. - Known history of active tuberculosis. - Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomisation. - Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical condition that could affect the patient’s capacity to participate in the trial. - Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the trial or evaluation of the trial results. - Women who are pregnant or in the period of lactation. - Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 120 days following cessation of trial treatment. |
-Tratamiento previo con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-citotóxico asociado a linfocitos T (CTLA-4) (incluyendo ipilimumab o cualquier otro Anticuerpo o fármaco dirigido específicamente a la co-estimulación de células T o vías de control). - Tratamiento previo con gemcitabina o vinorelbina. - Metástasis activa del sistema nervioso central (SNC) y / o meningitis carcinomatosa. Los pacientes con metástasis cerebrales previamente tratadas pueden participar siempre que sean estables (sin evidencia de progresión por imágenes durante al menos 4 semanas antes de la asignación al azar y cualquier síntoma neurológico ha regresado a la línea de base), no tienen evidencia de metástasis cerebrales nuevas o de agrandamiento y no son Utilizando esteroides durante al menos 7 días antes de la asignación al azar. Esta excepción no incluye la meningitis carcinomatosa, que se excluye independientemente de la estabilidad clínica. - Hipersensibilidad conocida o presunta al pembrolizumab o a cualquiera de sus excipientes. - Toxicidad quirúrgica o toxicidad relacionada con la quimioterapia no resuelta que comprometería la capacidad del paciente para participar en el ensayo. - Trasplante alogénico de tejido / órgano sólido anterior. - Vacunas vivas dentro de los 30 días previos a la primera dosis de pembrolizumab. - Ingesta regular de fármacos inmunomoduladores (como interferón, metotrexato). - Antecedentes de neumonitis (no infecciosa) que requirió de esteroides, evidencia de enfermedad pulmonar intersticial (ILD) o neumonitis activa no infecciosa. - Enfermedad autoinmune activa que ha requerido tratamiento sistémico en los últimos 2 años (es decir, con el uso de agentes modificadores de la enfermedad, corticosteroides o fármacos inmunosupresores). La terapia de reemplazo (es decir, tiroxina, insulina o terapia de reemplazo de corticosteroides fisiológica para insuficiencia suprarrenal o pituitaria, etc.) o terapia tópica (por ejemplo, esteroides) para psoriasis o eczema no se considera una forma de tratamiento sistémico. - Infecciones clínicamente graves en curso que requieren antibióticos sistémicos o antivirales, antimicrobianos o terapia antimicótica. - Infección por VIH. - Hepatitis B activa conocida o hepatitis C. - Historia conocida de tuberculosis activa. - Pacientes con diagnóstico de inmunodeficiencia o que reciben terapia sistémica con esteroides o cualquier otra forma de terapia inmunosupresora dentro de los 7 días anteriores a la asignación al azar. - Pacientes con otras enfermedades graves o condiciones clínicas, incluyendo pero no limitado a infección activa no controlada y cualquier otra condición médica subyacente grave que pueda afectar la capacidad del paciente para participar en el ensayo. - Abuso de sustancias, condiciones médicas, psicológicas o sociales que puedan interferir con la participación del paciente en el ensayo o la evaluación de los resultados del ensayo. - Mujeres embarazadas o en periodo de lactancia. - Hombres y mujeres sexualmente activas en edad fértil que no estén dispuestas a utilizar un método anticonceptivo eficaz durante el ensayo y hasta 120 días después del cese del tratamiento. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival according to RECIST 1.1 criteria based on independent radiological review. |
Supervivencia libre de progresión de acuerdo con los criterios RECIST 1.1 basado en una revisión radiológica independiente |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from the date of randomisation until documented progression or death |
Tiempo desde la fecha de randomización hasta la progresión documentada |
|
E.5.2 | Secondary end point(s) |
• Objective Response (OR) determined by RECIST 1.1 criteria • Overall survival (OS) • Time to treatment failure • Investigator assessed progression-free survival (PFS) determined according to RECIST 1.1 criteria • Tolerability assessed by adverse events graded according CTCAE v4.0
Correlative endpoints: • Responses according to PD-L1 expression levels, measured by IHC • TILs analysis • Mutation load |
• Respuesta objetiva (OR) determinada por criterios RECIST 1.1 • Supervivencia global (SO) • Tiempo hasta el fracaso del tratamiento • Supervivencia libre de progresión (PFS) determinada de acuerdo con los criterios RECIST 1.1 • Tolerabilidad evaluada por eventos adversos clasificados según CTCAE v4.0 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
-OR: across all assessment time-points during period from randomisation to termination of trial treatment. -OS: time from the date of randomisation until death from any cause - Time to treatement failure: time from the date of randomisation to discontinuation of treatment for any reason - Investigator assessed PFS: Time from the date of randomisation until documented progression or death -Tolerability: across all assessment time-points every 3 weeks during period from randomisation to termination of trial treatment |
-OR: período comprendido entre la asignación al azar y la terminación del tratamiento del ensayo. -OS: tiempo desde la fecha de la asignación al azar hasta la muerte por cualquier causa - Tiempo hasta el fracaso del tratamiento: tiempo desde la fecha de la asignación al azar hasta la suspensión del tratamiento por cualquier razón - PFS: Tiempo desde la fecha de asignación al azar hasta progresión documentada o muerte -Tolerabilidad: evaluación cada 3 semanas durante el período desde la asignación al azar hasta la terminación del tratamiento del ensayo |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Patient accrual is expected to be completed within 19 months including a run-in period of 6 months. The trial treatment phase will continue for a maximum of 2 years from the inclusion of the last patient and the trial is expected to end at all sites approximately 43 months after the inclusion of the first patient. |
La inclusión de pacientes se espera que se complete dentro de 19 meses, incluyendo un período de ejecución de 6 meses. El tratamiento continuará durante un máximo de 2 años a partir de la inclusión del último paciente y se espera que el ensayo finalice en todos los hospitales aproximadamente 43 meses después de la inclusión del primer paciente. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |