E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent or metastatic disease (Stage IV), histologically or cytologically confirmed advanced nonsquamous Non-Small Cell Lung Cancer. |
Enfermedad recurrente o metastásica (etapa IV), CPNMne avanzado histológica o citológicamente confirmado. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced nonsquamous non-small cell lung cancer. |
Cáncer de pulmón no microcítico no escamoso avanzado |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
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 establish statistical equivalence in terms of efficacy (best overall response rate [ORR] ,proportion of patients with complete response [CR] plus partial response [PR]) until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or Avastin®. |
Establecer una equivalencia estadística en términos de eficacia (mejor tasa de respuesta global [TRG], proporción de pacientes con respuesta completa [RC] más respuesta parcial [RP]) hasta las 18 semanas del tratamiento de primera línea con BI 695502 más quimioterapia en comparación con Avastin® más quimioterapia seguido de monoterapia de mantenimiento con BI 695502 o Avastin®. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate further efficacy parameters, the safety and tolerability of BI 695502 versus Avastin®. Further objectives are to evaluate the PK of BI 695502 versus Avastin® as well as the presence of antidrug antibodies (ADAs) and neutralizing antidrug antibodies (nADAs). |
Los objetivos secundarios del ensayo consisten en evaluar otros parámetros de eficacia (supervivencia libre de progresión [SLP], supervivencia general [SG], duración de la respuesta) y la seguridad y tolerabilidad de BI 695502 en comparación con Avastin®. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Aged ?18 years (for Japan only: Age ?20 years at Visit 1) - Recurrent or metastatic disease (Stage IV) with an indication for therapy with paclitaxel + carboplatin + Avastin® - Negative epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation status. Patients harboring tumors with unknown or positive EGFR or ALK mutation may be included, provided chemotherapy is the site standard-of-care for those patients. -Patients must have at least one measurable lesion according to RECIST 1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. - Life expectancy >6 months based on clinical judgment. -Patients must have adequate hepatic, renal, and bone marrow function. |
- Edad ?18 años (solo para Japón: edad ?20 años en la Visita 1) - Enfermedad recurrente o metastásica (etapa IV) con indicación de la terapia con paclitaxel + carboplatino + Avastin® - Pacientes que alberguen tumores sin mutación activa del RFCE. Los pacientes con mutación desconocida o activa del RFCE pueden incluirse siempre que la quimioterapia sea la atención médica típica del centro. Pacientes que alberguen tumores sin mutación activa de la CLA. Los pacientes con mutación desconocida o activa de la CLA pueden incluirse siempre que la quimioterapia sea la atención médica típica del centro. - Pacientes que alberguen tumores sin mutación activa de la CLA. Los pacientes con mutación desconocida o activa de la CLA pueden incluirse siempre que la quimioterapia sea la atención médica típica del centro. - Al menos una lesión medible de acuerdo con la RECIST 1.1 en función de una revisión central independiente. - Esperanza de vida >6 meses según la opinión clínica - Pacientes con función hepática, renal y de médula ósea adecuada |
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E.4 | Principal exclusion criteria |
- Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF or VEGF receptors, including Avastin®. - Prior systemic therapy for metastatic disease ( Prior systemic therapy and/or radiotherapy for locally advanced disease permitted if completed >12 months prior to Screening) . - Symptomatic brain metastasis. - Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung, NSCLC NS (not specified) or NSCLC NOS (not otherwise specified). - Contraindication to bevacizumab |
- Terapia previa con anticuerpos monoclonales o micromoléculas inhibidoras del FCEV o de los receptores del FCEV, incluido Avastin®. - Terapia sistémica previa para la enfermedad metastásica. Terapia o radioterapia sistémicas contra el cáncer previas para el CPNMne localmente avanzado si finalizó menos de 12 meses antes de la selección. - Metástasis cerebral sintomática - Diagnóstico de carcinoma pulmonar microcítico, carcinoma pulmonar escamoso, CPNM no especificado o CPNM sin otra especificación. - Contraindication de bevacizumab |
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E.5 End points |
E.5.1 | Primary end point(s) |
Best ORR based on unconfirmed response assessment as assessed by central imaging review until 18 weeks after the start of treatment. |
Mejor TRG basada en la evaluación de la respuesta no confirmada según lo evaluado por la revisión mediante imagen central hasta 18 semanas después del inicio del tratamiento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy : Screening, Weeks 0, 6,12,18 visit |
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E.5.2 | Secondary end point(s) |
Efficacy: ? Progression-free survival (PFS) defined as the time from randomization until disease progression as per investigator assessment or death. ? Overall survival (OS) defined as the time from randomization until death of any cause. ? Duration of response defined as the time from first documented CR or PR until time of progression as per investigator assessment.
Safety: ? The proportion of patients with AEs ? The proportion of patients with AEs related to trial treatment ? The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0 ? The proportion of patients with Grade 3 or 4 AEs according to NCI-CTCAE version 4.0 related to trial treatment ? The proportion of patients with AEs potentially related to immunogenicity.
Other endpoints: Evaluation of PK of BI 695502 versus Avastin® and presence of antidrug antibodies (ADAs) and neutralizing antidrug antibodies (nADAs). |
Eficacia: - SLP definida como el intervalo de tiempo transcurrido desde la aleatorización hasta la progresión de la enfermedad, según la evaluación del investigador o hasta la muerte. - SG definida como el intervalo de tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa. - Duración de la respuesta definida como el intervalo de tiempo transcurrido desde la primera RC o RP documentada hasta la progresión, según la evaluación del investigador. Seguridad: ? La proporción de pacientes con acontecimientos adversos ? La proporción de pacientes con acontecimientos adversos relacionados con el tratamiento del ensayo ? La proporción de pacientes con AA de grado 3 o 4 de acuerdo con los CTCAA-ICN versión 4.0 ? La proporción de pacientes con AA de grado 3 o 4 de acuerdo con los CTCAA-ICN versión 4.0 relacionados con el tratamiento del ensayo ? La proporción de pacientes con AA potencialmente relacionados con la inmunogenicidad Otros: - Se evaluará la FC de BI 695502 en comparación con Avastin®, así como la presencia de anticuerpos contra el fármaco (ACF) y de anticuerpos contra el fármaco neutralizantes (ACFn). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy : Screening, Weeks 0, 6,12,18,27... End of Treatment (EOT) visit
Safety: Screening, Weeks 0,3,6,9,12,15,18,21,25,27 and onwards, End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit.
Other endpoints
Immunogenicity: Weeks 0, 3, 6, 12, 18, 27, then every 9 weeks until End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit.
Pharmacokinetics: Weeks 0,3,6,9,12,15,18,27 then every 9 weeks until End of Treatment (EOT) visit, and Safety Follow-up (SFU) visit. |
Eficacia: Selección, semanas 0,6, 12, 18, 27... visita fin de ensayo. Seguridad: Selección, semanas 0,3,6,9,12,15,18,21,25, 27 y siguientes, visita fin de ensayo y visita de seguimiento. |
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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 | 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 | 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) | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 137 |
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 |
Argentina |
Bosnia and Herzegovina |
Brazil |
Bulgaria |
Chile |
Colombia |
Croatia |
Denmark |
Egypt |
Germany |
Greece |
Hungary |
Indonesia |
Italy |
Japan |
Korea, Republic of |
Lebanon |
Malaysia |
Mexico |
Netherlands |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Sweden |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
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 trial will be closed when all randomized and treated patients have either died, are lost to follow-up, or have withdrawn consent, or for a maximum of 20 months after the last patient randomized plus the SFU visit, whichever occurs earlier. |
El ensayo será cerrado cuando todos los pacientes randomizados y tratados hayan muerto, hayan perdido para el seguimiento, hayan retirado su consentimiento o en un máximo de 20 meses después de la última paciente randomizado más la visita de seguimiento, lo que ocurra antes. |
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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |