E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced adenocarcinoma of the lung |
Adenocarcinoma de pulmón avanzado |
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E.1.1.1 | Medical condition in easily understood language |
A specific type of lung cancer called "adenocarcinoma of the lung" |
Un tipo específico de cáncer de pulmón llamado "adenocarcinoma de pulmón" |
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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 | 10001164 |
E.1.2 | Term | Adenocarcinoma lung stage III |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10001165 |
E.1.2 | Term | Adenocarcinoma lung stage IV |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate whether the efficacy of JNJ-757 combined with nivolumab is better than the efficacy of nivolumab monotherapy for subjects with mesothelin-positive relapsed/refractory Stage IIIB or Stage IV adenocarcinoma of the lung, by PD-L1 level |
Evaluar si la eficacia de JNJ-757 combinado con nivolumab es superior a la eficacia de nivolumab en monoterapia en sujetos con adenocarcinoma de pulmón recidivado/resistente positivo para mesotelina, en estadios IIIB o IV, según el nivel de PD-L1. |
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E.2.2 | Secondary objectives of the trial |
- To compare the clinical benefit of JNJ-757 combined with nivolumab versus nivolumab monotherapy - To evaluate the safety of JNJ-757 - To correlate PD-L1 levels with clinical activity - To assess the blood culture and shedding profile of JNJ-757 - To assess the pharmacokinetics and immunogenicity of nivolumab |
-Comparar el beneficio clínico del JNJ-757 combinado con nivolumab frente a la monoterapia con nivolumab. -Evaluar la seguridad del JNJ-757 -Relacionar el nivel de PD-L1 con la actividad clínica -Evaluar el hemocultivo y el perfil de excreción de JNJ-757 -Evaluar la farmacocinética y la capacidad inmunógena de nivolumab |
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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 |
Optional translational sub-study: CT- or FDG-PET/CT-guided core needle tumor biopsy samples will be collected from approximately 20 subjects and correlated with mesothelin-directed peripheral adaptive immune response. |
Subestudio traslacional opcional: Se tomarán biopsias del tumor con aguja gruesa guiada por CT- o FDG-PET/CT a aproximadamente 20 pacientes y sus hallazgos se relacionarán con la respuesta inmunitaria adaptativa periférica dirigida por la mesotelina |
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E.3 | Principal inclusion criteria |
- Histologically documented adenocarcinoma of the lung - Stage IIIB or Stage IV disease - Biopsy material available for central assessment of PD-L1 and mesothelin - In Phase 2 only: Mesothelin-positive status - ECOG performance status of 0 or 1 - Progressive disease during or after platinum-based doublet chemotherapy, administered in the metastatic setting - Adequate bone marrow function, defined as: • Absolute neutrophil count (ANC) ≥1500/μL (or 1.5×10 to the power of 9/L) • Platelets ≥100,000/μL (or 100×10 to the power of 9/L) • Hemoglobin ≥10.0 g/dL - Adequate hepatic function, defined as: • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) • Total serum bilirubin ≤1.5xULN - Adequate renal function, defined as: • Calculated creatinine clearance ≥40 mL/min using the Cockcroft-Gault equation - A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 14 days before the first dose of nivolumab and a second negative test within 24 hours before the first dose of nivolumab. - Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies. Further details see protocol - A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction while on the study agent and for 5 months after the last dose of study agent - To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on the study agent and for 5 months (female subjects) or 7 months (male subjects) after the last dose of study agent. |
- Adenocarcinoma de pulmón con confirmación histológica documentada - Enfermedad estadio IIIB o IV - Material de biopsia para estudio centralizado de PD-L1 y mesotelina - Solo en fase 2: estado positivo para mesotelina - estado funcional del ECOG de 0 ó 1 - Los sujetos deben haber presentado enfermedad progresiva durante o después de un doblete de quimioterapia con platino, administrado en un entorno metastásico. - Adecuada función medular, definida como: o Recuento absoluto de neutrófilos (ANC) >o=1500/microL (o 1.5×10E9/L) o Plaquetas >o=100,000/microL (o 100×10E9/L) o Hemoglobina >o=10.0 g/dL - Adecuada función hepática, definida como: o aspartato aminotransferasa sérica (AST) y alanina aminotransferasa sérica (ALT) <o= 1.5 veces el límite superior de normalidad (ULN) o Bilirubina sérica total <o=1.5xULN o Aclaramiento de creatinica caalculada >o=40 mL/min usando la fórmula de Cockcroft-Gault. - Las mujeres potencialmente fértiles deben tener una prueba negativa en suero (gonadotropina coriónica humana [β-hCG]) o un test de embarazo de orina (sensibilidad mínima de 25UI/L unidades equivalentes de hCG) en los 14 dias previos a la primera dosis de nivolumab y un segundo test negativo las 24 horas antes de la primera dosis de nivolumab - Los métodos anticonceptivos usados por hombres y mujeres deben ser consistentes con la regulación local relativa a los métodos anticonceptivos de sujetos participantes en ensayos clínicos. Más detalles en el protocolo. - Las mujeres deben acceder a no donar óvulos (u oocitos) para reproducción asistida mientras estén recibiendo el producto del estudio y durante 5 meses después de la última dosis del producto de estudio. - Para evitar el riesgo de exposición al fármaco a través de la eyaculación (incluso los hombres con vasectomías), los pacientes deberán usar un condón durante la actividad sexual mientras que estén recibiendo el fármaco de estudio y durante 5 meses (mujeres) o 7 meses (hombres) después de la última dosis del agente de estudio. |
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E.4 | Principal exclusion criteria |
- Untreated brain metastases or other active central nervous system (CNS) metastases. Subjects with a history of brain metastasis must have completed treatment for brain metastasis for at least 28 days, and be neurologically stable and off steroids before enrollment (Phase 1b) or randomization (Phase 2). - Tumor with activating EGFR mutation or ALK translocation (EGFR and ALK results must be confirmed in the Screening Period for all non-smokers). - More than 1 prior line of chemotherapy for metastatic disease (not including therapy given in the maintenance setting, or neoadjuvant or adjuvant therapy for locally advanced disease). - History of symptomatic interstitial lung disease. - History of disallowed therapies, as follows: • In Phase 1b only: Prior exposure to anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody within 28 days before the first dose of study agent • In Phase 2 only: Prior exposure to anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody • History of listeriosis or vaccination with a Listeria-based vaccine or prophylactic vaccine (eg, influenza, pneumococcal, diphtheria, tetanus, and pertussis [dTP/dTAP]) within 28 days before the first dose of study agent • Chemotherapy within 28 days before the first dose of study agent • Radiation within 14 days before the first dose of study agent (exception: palliative radiotherapy for pain can be used ≥ 7 days before or after study agent) - Any uncontrolled active systemic infection, active noninfectious pneumonitis, or any life-threatening illness, medical condition, or organ system dysfunction - Any active autoimmune disease or a documented history of autoimmune disease - History of any other condition that may require the initiation of anti-tumor necrosis factor alpha (TNFα) therapies or other immunosuppressant medications during the study. - Known allergy to both penicillin/amoxicillin and trimethoprim/sulfamethoxazole. - Concurrent treatment with anti-TNFα therapies, systemic corticosteroids (prednisone dose >10 mg per day or equivalent), or other immunosuppressive drugs <14 days before randomization. Steroids that are topical, inhaled, nasal (spray), or ophthalmic solution are permitted. - Positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). - History of major implant(s) or device(s) - History of clinically significant cardiovascular disease within 6 months of randomization - Known active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface antigen (HBsAg) positivity and/or anti-hepatitis C virus (HCV) positivity, respectively. Subjects with clinically active or chronic liver disease, including liver cirrhosis, are also excluded. - Active second malignancy within 2 years prior to randomization (exceptions see protocol) - Evidence of active viral, bacterial, or systemic fungal infection requiring systemic treatment within 7 days before the first dose of the study agent. - Known allergies, hypersensitivity, or intolerance to JNJ-757 or nivolumab or its excipients |
- metástasis cerebrales no tratadas u otras metástasis activas del sistema nervioso central (SNC). Los pacientes con historial de metástasis deben haber completado el tratamiento para dichas metástasis al menos 28 días antes, y estar neurológicamente estables y sin esteroides antes del reclutamiento (fase 1b) o aleatorización (fase 2). - Tumor con mutación activadora del receptor del factor de crecimiento epidérmico o translocación de ALK (los resultados de EGFR y ALK deben ser confirmados en el periodo de selección para todos los no fumadores). - Más de 1 línea previa de quimioterapia para enfermedad metastásica (no incluida la terapia para mantenimiento o terapia neoadyuvante o adyuvante para la enfermedad localmente avanzada). - Antecedentes de neumopatía intersticial sintomática - Antecedentes de terapias no permitidas, tales como: • En fase 1b solo: exposición previa a anticuepos anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti antígeno 4 del linfocito T citotóxico (CTLA-4) en los 28 días antes de la primera dosis del agente de estudio • En fase 2 sólo: exposición previa a anticuepos anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti antígeno 4 del linfocito T citotóxico (CTLA-4) - Antecedentes de listeriosis o vacunación con vacunas basadas en Listeria o vacunas profilácticas (ej. Influenza, neumocócica, difteria, tétanos y tos ferina [dTP/dTAP]) en los 28 días antes de la primera dosis del agente de estudio - Quimioterapia en los 28 días antes de la primera dosis del agente de estudio - Radiación en los 14 días antes de la primera dosis del agente de estudio (excepción: puede usarse radioterapia paliativa para el dolor ≥ 7 días antes o después del agente de estudio) - alguna infección sistémica activa, neumonía no infecciosa active, o alguna enfermedad que amenace la vida, condición médica o disfunción orgánica. - alguna enfermedad autoinmune activa o antecedentes documentados de enfermedad autoinmune - antecedentes de cualquier otra condición que requiera el comienzo de terapias con anti factor de necrosis tumoral alfa (TNFα ) u otra medicación inmunosupresora durante el estudio. - Alergia a la penicilina/amoxicilina y trimetoprim/sulfametoxazol. -Tratamiento concurrente con terapias anti-TNFα, corticoesteroides sistémicos (dosis de prednisona > 10 mg por día o equivalente), u otras drogas inmunosupresivas < 14 días antes de la aleatorización. Se permiten esteroides tópicos, inhalados, nasales (aerosol), o solución oftálmica. -Resultado positivo para el virus de inmunodeficiencia humana (VIH) o síndrome de inmunodeficiencia adquirida (SIDA). - Antecedentes de implantes mayores o dispositivos. -Antecedentes de enfermedad cardiovascular clínicamente significativa en los 6 meses previos a la aleatorización - Hepatitis B activa o crónica o hepatitis C, evidenciado como positivo en antígeno de superficie (HBsAg) de la hepatitis B y/o positivo en anticuerpos del virus hepatitis C (HCV), respectivamente. También quedan excluidos los sujetos con enfermedad hepática clínicamente activa o crónica, incluyendo cirrosis hepática. - Malignidad secundaria activa dentro de 2 años antes de la aleatorización (excepciones ver protocolo) -evidencia de i9nfecciones activas virales, bacterianas o fúngicas sistémicas que requieren tratamiento sistémico dentro de 7 días antes de la primera dosis de lo agente de estudio. - Alergias conocidas, hipersensibilidad o intolerancia a JNJ-757 o nivolumab o a sus excipientes |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (complete response plus partial response, based on RECIST 1.1 criteria) |
Tasa de respuesta objetiva (respuesta completa más respuesta parcial, según los criterios RECIST 1.1) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 8 weeks (±7d) during the first year, and then every 12 weeks (±7d) thereafter. |
Cada 8 semanas (±7 días) durante el primer año, y a partir de entonces cada 12 semanas (±7 días). |
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E.5.2 | Secondary end point(s) |
- Disease control rate (stable disease for 16 weeks, complete response, or partial response) - Duration of objective response - Progression-free survival - Overall survival - Incidence of adverse events |
- Tasa de control de la enfermedad (enfermedad estable durante 16 semanas, respuesta completa o respuesta parcial) - Duración de la respuesta objetiva - Supervivencia sin progresión - Supervivencia global - Incidencia de acontecimientos adversos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DCR, DOR, PFS: Every 8 weeks (±7d) during the first year, and then every 12 weeks (±7d) thereafter. - OS: throughout the whole study, after discontinuation of treatment every 3 months - Adverse events: throughout the whole study until 100 days after the last dose of nivolumab |
TCE, DRO, SSP: Cada 8 semanas (±7 días) durante el primer año, y a partir de entonces cada 12 semanas (±7 días). SG: durante todo el estudio, y tras discontinuar el tratamiento, cada 3 meses. - Efectos adversos: durante todo el estudio y hasta 100 días después de la última dosis de nivolumab |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
nivolumab plus or minus JNJ-64041757 |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
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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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The end of the study will occur when 80% of the randomized subjects have died, or approximately 3 years after the last subject is randomized, or the sponsor terminates the study. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |