E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ALK positive Locally Advanced or Metastatic Non-small Cell Lung Cancer |
Cáncer de pulmón localmente avanzado con ALK positiva o cáncer de pulmón no microcítico mestásico |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic or locally advanced non-small cell lung cancer |
Cáncer de pulmón localmente avanzado o metastásico |
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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 | 19.0 |
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 |
The objective of the study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC patients naive to ALK inhibitors, as evidenced by PFS. |
El objetivo principal del estudio es comparar la eficacia de brigatinib frente a la de crizotinib en pacientes con CPA ALK+ localmente avanzado o metastásico que no han recibido previamente inhibidores de ALK, demostrada mediante SLP |
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E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of brigatinib to that of crizotinib, as evidenced by confirmed ORR, time to/duration of response, disease control rate (DCR), and Overall Survival (OS) 2. To compare the efficacy in the CNS of brigatinib to that of crizotinib, as evidenced by intracranial response and intracranial PFS in those patients with intracranial CNS metastases at baseline 3. To assess the safety and tolerability of brigatinib in comparison with crizotinib 4. To determine pharmacokinetic (PK) parameters of brigatinib through population PK modeling 5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (v3.0) in patients treated with brigatinib compared to those treated with crizotinib |
1. Comparar la eficacia de brigatinib con la de crizotinib, como se demuestra por la TRO confirmada, el tiempo hasta la respuesta o la duración de la misma, tasa de control de la enfermedad (TCE) y supervivencia global (SG). 2. Comparar eficacia en el SNC de brigatinib con la de crizotinib, como se demuestra por la respuesta intracraneal y la SLP intracraneal en los casos con metástasis intracraneales en el SNC al inicio. 3. Evaluar seguridad y tolerabilidad de brigatinib en comparación con crizotinib. 4. Determinar parámetros farmacocinéticos (FC) de brigatinib con un modelo de FC poblacional. 5. Evaluar síntomas descritos por el paciente y calidad de vida relacionada con la salud utilizando el cuestionario de calidad de vida QLQ-C30 (v3.0) de la Organización Europea para Investigación y Tratamiento del Cáncer (European Organisation for Research and Treatment of Cancer, EORTC) en pacientes tratados con brigatinib comparados con los tratados con crizotinib. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed stage IIIB (and not a candidate for definitive multimodality therapy) or stage IV NSCLC. 2. Must have prior positive test results from an ALK test. 3. Have sufficient tumor tissue available for central analysis. 4. Have at least 1 measurable (i.e., target) lesion per RECIST v1.1. 5. Recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 grade < or = 1. 6. Are a male or female patient > or = 18 years old. 7. Have adequate organ function, as defined by the study protocol. 8. Have Eastern Cooperative Oncology Group (ECOG) performance status <2. 9. Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ?450 milliseconds (msec) in males or ?470 msec in females. 10. For female patients of childbearing potential, have a negative pregnancy test documented prior to randomization. 11. For female and male patients who are fertile, agree to use a highly effective form of contraception, as defined by the study protocol. 12. Provide signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating. 13. Have the willingness and ability to comply with scheduled visit and study procedures. |
1. Tener un CPA confirmado histológica o citológicamente en estadio IIIB (y no ser candidato para un tratamiento multimodal definitivo) o estadio IV. 2. Deben tener test previo con resultado positivo para ALK. 3. Tener tejido tumoral disponible suficiente para el análisis central. 4. Tener al menos 1 lesión medible (es decir, objetivo) según los criterios RECIST v1.1. 5. Estar recuperado de las toxicidades relacionada con el tratamiento antineoplásico previo de grado < o = 1 según los CTCAE del NCI v 4.0. 6. Ser un paciente hombre o mujer > o = 18 años de edad. 7. Presentar una función orgánica adecuada, según el protocolo. 8. Tener un estado funcional del Eastern Cooperative Oncology Group (ECOG) < 2 9. Tener un intervalo QT normal en el ECG de selección, definido como un intervalo QT corregido (fórmula de Fridericia) (QTcF) ? 450 milisegundos (ms) en los hombres o ? 470 ms en las mujeres. 10. En cuanto a las mujeres en edad fértil, debe documentarse una prueba de embarazo negativa antes de la aleatorización. 11. En cuanto a los pacientes de ambos sexos que sean fértiles, aceptarán usar un método anticonceptivo muy eficaz con sus parejas sexuales durante su participación en el estudio. 12. Proporcionará el consentimiento informado firmado y fechado en el que se indicará que se ha informado al paciente de todos los aspectos pertinentes del estudio, incluidos los posibles riesgos, y está dispuesto a participar. 13. Estar dispuesto y ser capaz de cumplir las visitas y procedimientos programados del estudio. |
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E.4 | Principal exclusion criteria |
1. Previously received an investigational antineoplastic agent for NSCLC. 2. Previously received any prior TKI, including ALK-targeted TKIs. 3. Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease. 4. Received chemotherapy or radiation within 14 days of first dose of study drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT). 5. Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug. 6. Had major surgery within 30 days of the first dose of study drug, minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. 7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy. 8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization. 9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed. 10. Be pregnant, planning a pregnancy, or breastfeeding 11. Have significant, uncontrolled, or active cardiovascular disease, as defined by the study protocol. 12. Have uncontrolled hypertension. 13. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis. 14. Have an ongoing or active infection. 15. Have a known history of human immunodeficiency virus (HIV) infection. 16. Have a known or suspected hypersensitivity to brigatinib or its excipients and/or crizotinib or its excipients. 17. Have malabsorption syndrome or other gastrointestinal (GI) illness or condition. 18. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the study drug. |
1. Haber recibido previamente un fármaco antineoplásico en investigación para el CPA. 2. Haber recibido con anterioridad cualquier TKI, incluidos los TKI dirigidos a ALK. 3. Haber recibido con anterioridad más de 1 pauta de tratamiento antineoplásico sistémico para la enfermedad localmente avanzada o metastásica. 4. Haber recibido quimioterapia o radioterapia en los 14 días anteriores a la primera dosis de fármaco del estudio, salvo radiocirugía estereotáctica (RCE) o radioterapia corporal estereotáctica (RCTE). 5. Haber recibido anticuerpos monoclonales antineoplásicos en los 30 días previos a la primera dosis del fármaco del estudio. 6. Haberse sometido a una cirugía mayor en los 30 días anteriores a la primera dosis del fármaco del estudio, pero se permiten procedimientos quirúrgicos menores como implantación de un catéter o procedimientos de biopsia mínimamente invasivos. 7. Haber sido diagnosticado de otro neoplasia maligna primaria distinto del CPA, salvo para el tratamiento adecuado del cáncer de piel no melanoma o el cáncer cervicouterino in situ, cáncer de próstata no metastásico tratado definitivamente u otro tipo de neoplasia maligna primaria que haya recidivado después de al menos 3 años desde el diagnóstico de la otra neoplasia maligna primaria. 8. Tener metástasis sintomáticas en el SNC (parenquimatosas o leptomeníngeas) en la selección o enfermedad asintomática que requiera aumentar la dosis de corticoesteroides para controlar los síntomas en los 7 días anteriores a la aleatorización. 9. Tener actualmente compresión de la médula espinal (sintomática o asintomática, y detectada en el estudio radiográfico). Se permite participar a pacientes con enfermedad leptomeníngea y sin compresión medular. 10. Estar embarazada, planear estar embarazada o en período de lactancia 11. Sufrir enfermedad cardiovascular significativa, no controlada o activa, según se indica en el protocolo. 12. Tener hipertensión no controlada. 13. Tener antecedentes o presencia al inicio de enfermedad intersticial pulmonar, neumonitis relacionada con el fármaco o neumonitis por radiación. 14. Tener una infección en curso o activa. 15. Tener antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH). 16. Tener una reacción de hipersensibilidad conocida o sospechada ante brigatinib o sus excipientes. 17. Tener una reacción de hipersensibilidad conocida o sospechada ante crizotinib o sus excipientes. 18. Presentar síndrome de malabsorción u otra enfermedad gastrointestinal (GI) que pudiera afectar la absorción oral del fármaco del estudio. 19. Tener una afección o enfermedad que, en opinión del investigador, podría poner en peligro la seguridad del paciente o interferir con la evaluación del fármaco del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) as assessed by a blinded Independent Review Committee (bIRC) |
Supervivencia libre de progresión (SLP) evaluada por el Comité Independiente de Revisión del estudio (CRIE) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At least up to 36 months |
Al menos hasta el mes 36 |
|
E.5.2 | Secondary end point(s) |
1. ORR 2. Intracranial ORR 3. Intracranial PFS 4. OS 5. Duration of response 6. Time to response 7. DCR 8. Safety and tolerability 9. Health Related Quality of Life (HRQoL) |
1. TRO 2. TRO intracraneal 3. SLP intracraneal 4. SG. 5. Duración de la respuesta 6. Tiempo hasta la respuesta 7. Tasa de control de la enfermedad 8. Seguridad y tolerabilidad 9. Síntomas comunicados por el paciente y puntuaciones de la CdVRS |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-8. At least upto 36 months
9. Until 30 days after the last dose of study treatment. |
1-8: Al menos hasta 36 meses 9: Hasta 30 días tras la última dosis de tratamiento |
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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 | 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 |
To evaluate exploratory biomarkers |
Evaluar biomarcadores exploratorios |
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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 | 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 | 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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 98 |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hong Kong |
Hungary |
Italy |
Korea, Republic of |
Luxembourg |
Netherlands |
Norway |
Portugal |
Singapore |
Spain |
Sweden |
Switzerland |
Taiwan |
United Kingdom |
United States |
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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
|
Last visit after treatment with interventional therapy is completed prior to entering long term follow-up for survival. |
Última visita tras el tratamiento con terapia intervencionista que se realiza antes de entrar en la fase de seguimiento de supervivencia a largo plazo. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 |