E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small-Cell Lung Cancer |
Cáncer de pulmón no microcítico |
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E.1.1.1 | Medical condition in easily understood language |
Lung Cancer |
Cáncer 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 | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib, as measured by progression-free survival (PFS) assessed by the investigator. |
Determinar la eficacia de onartuzumab + erlotinib en comparación con placebo + erlotinib, evaluada mediante la supervivencia sin progresión (SSP) valorada por el investigador. |
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E.2.2 | Secondary objectives of the trial |
- To determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib as measured by overall survival (OS) - To determine the efficacy of onartuzumab+erlotinib compared with placebo+erlotinib as measured by objective response rate - To determine the impact of onartuzumab+erlotinib compared with placebo+erlotinib as measured by time to deterioration (TTD) in patient reported lung cancer symptoms - To compare other patient-reported outcomes (PROs) following treatment with onartuzumab+erlotinib versus placebo+erlotinib as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13 - To compare the safety of onartuzumab+erlotinib versus placebo+erlotinib, including serious adverse events (SAEs) - To evaluate the pharmacokinetics of onartuzumab - To evaluate serum levels and incidence of anti-therapeutic antibodies (ATAs) against onartuzumab |
- Determinar la eficacia de onartuzumab+erlotinib en comparación con placebo+erlotinib, evaluada mediante la supervivencia global (SG) - Determinar la eficacia de onartuzumab+erlotinib en comparación con placebo+erlotinib, evaluada mediante la tasa de respuestas objetivas - Determinar los efectos de onartuzumab+erlotinib en comparación con placebo+erlotinib, evaluados por el tiempo hasta el deterioro (THD) de los síntomas del cáncer de pulmón - Comparar otros resultados comunicados por los pacientes (RCP) después del tratamiento con onartuzumab+erlotinib en comparación con placebo+erlotinib, determinados mediante los cuestionarios QLQ-C30 y QLQ-LC13 de la EORTC - Comparar la seguridad de onartuzumab+erlotinib frente a placebo+erlotinib, incluidos los acontecimientos adversos graves (AAG) - Evaluar la farmacocinética del onartuzumab. - Evaluar las concentraciones séricas y la incidencia de anticuerpos antiterapéuticos (AAT) contra onartuzumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Ability and willingness to provide written informed consent and to comply with the study protocol - Male or female, 18 years of age or older - ECOG performance status of 0 or 1 - Histologically confirmed, unresectable Stage IIIB or IV NSCLC tumor - No prior treatment for unresectable Stage IIIB or IV NSCLC - MET positive status (>= 50% of tumor cells with membrane and/or cytoplasmic staining at moderate [IHC clinical score 2+] or high [3+] intensity) - An activating EGFR mutation (exon 19 deletion or L858R, G719X, or S768I point mutation), as determined by the central laboratory on an adequate tissue sample - Measurable radiographic evidence of disease according to RECIST v1.1 |
- Disposición y capacidad para otorgar el consentimiento informado por escrito y cumplir los requisitos del protocolo del estudio - Varones o mujeres de 18 años o más - Estado funcional del ECOG de 0 o 1 - CPNM en estadio IIIB o IV irresecable, confirmado por medios histológicos - Ausencia de tratamiento previo para el CPNM en estadio IIIB o IV irresecable - Positividad para MET (? 50 % de células tumorales con tinción de membrana o citoplasma de intensidad moderada [puntuación clínica IHQ de 2+] o alta [3+]) - Mutación activadora del EGFR (delección del exón 19 o mutaciones puntuales L858R, G719X o S768I), determinada por el laboratorio central en una muestra de tejido adecuada - Indicios radiográficos de enfermedad mensurable según los criterios RECIST v1.1 |
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E.4 | Principal exclusion criteria |
- Prior treatment for unresectable Stage IIIB or IV NSCLC - Patients who have received adjuvant or neoadjuvant therapy for non-metastatic disease in which relapse occurred > 12 months after final treatment are eligible. - Patients may have received prior radiation therapy provided they have recovered from any toxic effects thereof and that at least 7 days have elapsed between the last fraction and randomization. -Prior exposure to agents targeting either the HGF or MET pathway, including but not limited to crizotinib, cabozantinib, ficlatuzumab, rilotumumab, and tivantinib. - Exposure to an investigational or marketed agent that can act by EGFR inhibition. - Pleural effusion, pericardial fluid, or ascites requiring drainage every other week or more frequently. -Exon 20 insertion or the T790M point mutation in EGFR (which are activating but confer resistance to erlotinib), as determined by the central laboratory on an adequate tissue sample. - Brain metastasis or spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated central nervous system (CNS) metastases or spinal cord compression without evidence of clinically stable disease for ? 14 days. -History of another malignancy in the previous 5 years, unless cured by surgery alone and continuously disease free. - Radiographically evident interstitial lung disease (ILD; as evidenced by one or more of the following manifestations: interstitial pneumonia, pneumonitis, radiation pneumonitis, organizing pneumonia, pulmonary fibrosis, acute respiratory distress syndrome, lung infiltration, or alveolitis), concurrent infection, or a history of any of these conditions. - Abnormal haematologic, biochemical or organ function tests. - Significant medical co-morbidities. - Pregnancy or the lack of use of appropriate contraception. - Life expectancy <12 weeks. |
- Tratamiento previo para el CPNM en estadio IIIB o IV irresecable - los pacientes que hayan recibido tratamiento adyuvante o neoadyuvante para la enfermedad no metastásica y que hayan recidivado ? 12 meses después del final del tratamiento - Los pacientes pueden haber recibido radioterapia anteriormente siempre quese hayan recuperado de cualquier reacción adversa y que hayan transcurrido al menos 7 días entre la última fracción y la aleatorización - Exposición previa a fármacos que actúen en la vía del HGF o del MET, incluidos entre otros, crizotinib, cabozantinib, ficlatuzumab, rilotumumab y tivantinib - Exposición a un fármaco en investigación o comercializado que actúe mediante la inhibición del EGFR - Derrame pleural, derrame pericárdico o ascitis que precisen drenaje cada dos semanas o con mayor frecuencia - Inserción de exón 20 o la mutación puntual T790M del EGFR (que son activadoras, pero confieren resistencia al erlotinib), determinado por el laboratorio central en una muestra te tejido adecuada - Metástasis cerebrales o compresión de la médula espinal no tratadas definitivamente con cirugía o radioterapia, o metástasis en el sistema nervioso central (SNC) o compresión de la médula espinal previamente diagnosticadas y tratadas sin signos de enfermedad clínicamente estable durante ? 14 días - Antecedentes de otra neoplasia maligna en los 5 años anteriores, a menos que se haya curado solo con cirugía y que el paciente se haya mantenido constantemente sin enfermedad - Neumopatía intersticial (NI) demostrada radiológicamente (evidenciada por una o más de las siguientes manifestaciones: neumonía intersticial, neumonitis, neumonitis por radiación, neumonía organizada, fibrosis pulmonar, síndrome de dificultad respiratoria aguda, infiltración pulmonar o alveolitis), infección concurrente o antecedentes de cualquiera de estos procesos. - Anormalidades hematológicas, bioquímicas o de las pruebas de la función de los órganos - Comorbilidades médicas significativas - Mujeres embarazadas o que no estén utilizando métodos anticonceptivos adecuados - Esperanza de vida < 12 semanas. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- PFS, defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator using RECIST v1.1) or death, whichever occurs first |
- La SSP se define como el tiempo transcurrido entre la fecha de aleatorización y la fecha de la primera progresión de la enfermedad (se determinará a partir de la evaluación de investigador utilizando los criterios RECIST v1.1) o la muerte, lo que ocurra antes. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the time from randomization to disease-progression or death by any cause |
La SSP se define como el tiempo transcurrido entre la aleatorización y la progresión o la muerte por cualquier causa. |
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E.5.2 | Secondary end point(s) |
Overall Survival, ORR, PROs, PK and Safety |
Supervivencia global, TRO, THD, FC y seguridad. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis for all endpoints except OS, which will be assessed after 172 OS events, or approximately 53 months after the first patient is enrolled. |
El análisis final de todos los criterios de valoración excepto la SG, que tendrá lugar cuando se hayan observado 172 acontecimientos de SG, lo que está previsto que suceda alrededor de 53 meses después del reclutamiento del primer paciente. |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, QoL, Serum levels and incidence of anti-therapeutic antibodies (ATAs) against Onartuzumab |
Tolerabilidad, calidad de vida, concentraciones séricas y la incidencia de anticuerpos antiterapéuticos (AAT) contra onartuzumab |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
China |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Philippines |
Poland |
Singapore |
Spain |
Taiwan |
Thailand |
United States |
Vietnam |
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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
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The primary efficacy analysis will occur when 174 investigator-assessed PFS events in the ITT population have occurred. Survival follow-up will continue until 172 OS events have occurred; this is expected to be 53 months after the first patient enrolled, assuming the median OS in the control group is 22 months and the OS HR=0.65. Patients may be allowed to continue treatment, if no experienced disease progression and have not experienced intolerable toxicity, with continued safety follow up. |
El análisis principal de la eficacia ocurrirá cuando se hayan producido 174 acontecimientos de SSP evaluados por el investigador en IT. El seguimiento de la supervivencia continuará hasta que ocurran 172 acontecimientos de SG; esto se espera a los 53 meses después de la inclusión del primer paciente, suponiendo que la mediana de la SG en el grupo control=22 meses y RRI de la SG=0,65. Se permitirá seguir el tto si no presentan progresión ni toxicidad intolerable, con seguimiento de la seguridad. |
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |