| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Completely resected, Stage IB (tumors ≥ 4 cm) to Stage IIIA, Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC). |
| Carcinoma de pulmón no microcitico (CPNM) positivo para la cinasa (ALK) del linfoma anaplasico en estadio IB (tumores ≥ 4 cm) a IIIA completamente extirpado |
|
| E.1.1.1 | Medical condition in easily understood language |
| Resected, Stage IB to Stage IIIA ALK-positive, NSCLC is a lung cancer that has a rearrangement in the ALK gene, might have spread to areas near the lungs and has been removed by surgery. |
| CPNM positivo para ALK estadio IB-IIIA extirpado es un cáncer de pulmón que tiene un reordenamiento en el gen ALK y que podría extenderse a áreas cerca de los pulmones y que se ha quitado con cirugia |
|
| 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 | 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029520 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIA |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 the efficacy of alectinib compared with platinum-based chemotherapy in patients with completely resected Stage IB (tumors ≥ 4 cm) to Stage IIIA, ALK-positive NSCLC based on investigator assessed disease-free survival |
| Evaluar la eficacia de alectinib en comparación con la quimioterapia con un derivado del platino en pacientes con CPNM positivo para ALK en estadio IB (tumores ≥ 4 cm) a IIIA completamente extirpado basado en supervivencia libre de progresión evaluada por el investigador |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of alectinib compared with platinum-based chemotherapy in patients with completely resected Stage IB (tumors ≥ 4 cm) to Stage IIIA, ALK-positive NSCLC based on overall survival
•To evaluate the safety and tolerability of alectinib compared with platinum-based chemotherapy in patients with completely resected Stage IB (tumors ≥ 4 cm) to Stage IIIA, ALK-positive NSCLC
For alectinib arm only
•To characterize the pharmacokinetics (PK) of alectinib and its major metabolite(s) in patients with completely resected Stage IB (tumors ≥ 4 cm) to Stage IIIA, ALK-positive NSCLC
•At Japanese sites only: To characterize the pharmacokinetics of alectinib and its major metabolite(s) in Japanese patients |
•Evaluar la eficacia de alectinib en comparación con la quimioterapia con un derivado del platino en pacientes con CPNM positivo para ALK en estadio IB (tumores ≥ 4 cm) a IIIA completamente extirpado basada en superviviencia global
•Evaluar la seguridad y la tolerabilidad de alectinib en comparación con la quimioterapia con un derivado del platino en pacientes con CPNM positivo para ALK en estadio IB (tumores ≥ 4 cm) a IIIA completamente extirpado.
Solo en el grupo de alectinib
•Caracterizar la farmacocinética (PK) de alectinib y su(s) principal(es) metabolito(s) en pacientes con CPNM positivo para ALK en estadio IB (tumores ≥ 4 cm) a IIIA completamente extirpado.
Solo en los centros de Japón:
•Caracterizar la farmacocinética de alectinib y sus principales metabolitos en los pacientes japoneses. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Age ≥ 18 years
-Complete resection of histologically confirmed Stage IB (tumor >= 4 cm) to Stage IIIA (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) NSCLC as per American Joint Committee on Cancer, 7th edition, with negative margins, at 4-12 weeks before enrollment
-Systematic mediastinal lymph node sampling, at a minimum, for patients for whom mediastinoscopy was not performed preoperatively
-Documented ALK-positive disease according to an FDA-approved and CE-marked test
-Eligible to receive a platinum-based chemotherapy regimen according to the local labels
-Eastern Cooperative Oncology Group Performance Status of Grade 0 or 1
-Adequate hematologic and renal function
-For women of childbearing potential: agreement to remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of alectinib or according to local label for chemotherapy
-For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm for at least 90 days after the last dose of alectinib or according to local label for chemotherapy. Men must refrain from donating sperm during this same period
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures |
-Edad ≥ 18 años
-Extirpación completa de un CPNM confirmado histológicamente en estadio IB (tumor >=4 cm) a IIIA (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) según la 7.ª edición del AJCC, con márgenes limpios, 4-12 semanas antes de la inclusión.
-Muestreo sistemático como mínimo de ganglios linfáticos mediastínicos en los pacientes que no se sometieron a una mediastinoscopia antes de la intervención.
-Enfermedad positiva para ALK documentada mediante una prueba aprobada por la FDA y con marcado CE.
-Elegible para recibir un régimen de quimioterapia con un derivado del platino de conformidad con las fichas técnicas locales.
-Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
-Función hematológica y renal adecuada
-Mujeres en edad fértil: compromiso de practicar la abstinencia (abstenerse de mantener relaciones heterosexuales) o utilizar métodos anticonceptivos con un índice de fallos < 1 % anual durante el período de tratamiento y durante al menos 90 días después de la última dosis de alectinib o de conformidad con la ficha técnica local de la quimioterapia
- Para los varones: compromiso de practicar la abstinencia o utilizar métodos anticonceptivos y de no donar semen durante, como mínimo, 90 días después de recibir la última dosis de alectinib o de conformidad con la ficha técnica local de la quimioterapia. Los varones deberán abstenerse de donar semen durante este mismo período.
-Capacidad y voluntad de cumplir las visitas programadas, los planes de tratamiento, las pruebas analíticas y los demás procedimientos del estudio. |
|
| E.4 | Principal exclusion criteria |
-Pregnant or breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of alectinib or according to local label for chemotherapy
-Prior adjuvant radiotherapy for NSCLC
-Prior exposure to systemic chemotherapy and ALK inhibitors
-Known sensitivity to any component of study drug to which the patient may be randomized. This includes, but is not limited to, patients
with galactose intolerance, a congenital lactase deficiency or glucosegalactose
malabsorption.
-Malignancies other than NSCLC within 5 years prior to enrollment, except for curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, ductal carcinoma in situ, papillary thyroid cancer, or any cured cancer that is considered to have no impact on disease free survival or overall survival for the current NSCLC
-Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection
-Liver disease characterized by aspartate transaminase and alanine transaminase >= 3 × upper limit of normal or impaired excretory function or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, or bleeding from esophageal varices or acute viral or active autoimmune, alcoholic, or other types of acute hepatitis
-Japanese patients participating in the serial/intensive PK sample collection only: administration of strong/potent CYP450 3A inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with alectinib up to Week 3
-Any exclusion criteria based on the local labels of the chemotherapy regimen
-Patients with symptomatic bradycardia
-History of organ transplant
-Known HIV positivity or AIDS-related illness
-Any clinically significant concomitant disease or condition that could interfere with-or for which the treatment might interfere with the conduct of the study or the absorption of oral medications or that would pose an unacceptable risk to the patients in this study, in the opinion of the Principal Investigator
-Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry |
-Embarazo o lactancia, o intención de quedarse embarazada durante el estudio o en los 90 días siguientes a la última dosis de alectinib o de conformidad con la ficha técnica local de la quimioterapia.
-Radioterapia adyuvante previa para el CPNM.
Exposición previa a quimioterapia sistémica y a inhibidores de la ALK.
-Sensibilidad conocida a cualquier componente de los fármacos del estudio a los que se pueda aleatorizar al paciente. Esto incluye, pero no está limitado sólo a pacientes que tengan intolerancia a la galactosa, deficiencia congénita de lactasa, o malabsorción de glucosa-galactosa.
-Neoplasias malignas distintas del CPNM en los 5 años anteriores a la inclusión, excepto carcinoma basocelular de la piel tratado de forma curativa, cáncer gastrointestinal (GI) en estadio inicial extirpado por endoscopia, carcinoma in situ de cuello uterino, carcinoma ductal in situ, carcinoma papilar de tiroides o cualquier cáncer curado siempre que se considere que no afectará a la SSE ni a la SG del CPNM actual.
-Cualquier trastorno digestivo que pueda afectar a la absorción de los medicamentos orales, como el síndrome de malabsorción o una resección intestinal extensa
-Hepatopatía caracterizada ALT y AST >= 3 X LSN o alteración de la función excretora o de síntesis u otros trastornos indicativos de hepatopatía descompensada, como coagulopatía, encefalopatía hepática, hipoalbuminemia, ascitis, hemorragia por varices esofágicas, Hepatitis vírica aguda, autoinmunitaria activa, alcohólica u otros tipos de hepatitis aguda.
-Solo en los pacientes japoneses que participen en la recogida de muestras FC seriadas/intensivas: administración de inhibidores o inductores potentes del CYP450 3A en los 14 días anteriores a la primera dosis del tratamiento del estudio y durante el tratamiento con alectinib hasta la semana 3
-Cualquier criterio de exclusión basado en las fichas técnicas locales del régimen de quimioterapia.
-Pacientes con bradicardia sintomática.
-Antecedentes de trasplante de órganos.
-Positividad conocida para el VIH o enfermedades asociadas al sida.
-Cualquier enfermedad o trastorno concomitante de importancia clínica que pueda interferir con la realización del estudio o con la absorción de los medicamentos por vía oral o que pueda entrañar un riesgo inaceptable para los pacientes que participen en este estudio, en opinión del investigador principal.
-Cualquier circunstancia psicológica, familiar, sociológica o geográfica que pueda dificultar el cumplimiento de los requisitos del protocolo del estudio y/o los procedimientos de seguimiento; estas circunstancias se deben comentar con el paciente antes de su incorporación al ensayo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease-free survival |
| Supervivencia libre de enfermedad |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 12 weeks for the first 2 years, every 24 weeks during Years 3 to 5 and annually thereafter until disease recurrence |
| Cada 12 semanas en los dos primeros años, cada 24 semanas entre los años 3 y 5 y después anualmente hasta la recurrencia de la enfermedad |
|
| E.5.2 | Secondary end point(s) |
1.Overall survival
2.Incidence of adverse events, with severity determined through use of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
3.Incidence of abnormal laboratory findings
4.Changes in vital signs and electrocardiograms
5.Plasma concentrations of alectinib and its major metabolite(s) at specified timepoints for alectinib arm |
1. Supervivencia global
2. Incidencia de acontecimientos adversos, con determinación de la intensidad conforme a los criterios CTCAE del NCI, versión 4.0.
3. Incidencia de Valores analíticos de seguridad.
4. Cambios en los signos vitales y electrocardiogramas
5. Concentraciones plasmáticas de alectinib y sus principal(es) metabolito(s) en los momentos especificados. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Every 6 months after disease recurrence (in survival follow-up period)
2-4. During study treatment period and at safety follow-up visit (28 days after last dose of study drug)
5. At baseline and at Weeks 3, 6, 9, 12, 24, 36, 48, 60, 72, 84, and 96 |
1. Cada 6 meses después de la recurrencia de la enfermedad (en el periodo de supervivencia de seguimiento)
2-4. Durante el periodo de tratamiento del estudio y en la visita de seguimiento de seguridad (28 días después de la ultima dosis del fármaco del estudio)
5. En basal y en las semanas 3, 6, 9, 12, 24, 36, 48, 60, 72, 84, y 96 |
|
| 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 | Yes |
| 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 | 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Bosnia and Herzegovina |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Kazakhstan |
| Korea, Republic of |
| Latvia |
| Macedonia, the former Yugoslav Republic of |
| New Zealand |
| Poland |
| Portugal |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The study will formally end once the final survival follow-up analysis has been completed. |
| El estudio terminará formalmente una vez que el análisis final de la supervivencia en seguimiento se haya completado |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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 |
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