E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IB-IIIA non-small cell lung carcinoma, with a centrally confirmed, common sensitising EGFR mutations (Ex19del and L858R either alone or in combination with other EGFR mutations), following complete tumour resection with or without adjuvant chemotherapy |
Carcinoma de pulmón no microcítico en Estadio IB-IIIA, con las mutaciones sensibilizantes del EGFR más comunes (Ex19del y L858R ya sea sola o en combinación con otras mutaciones del EGFR), confirmadas de manera centralizada, tras la resección completa del tumor, con o sin quimioterapia adyuvante |
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E.1.1.1 | Medical condition in easily understood language |
Specific type of lung cancer called "non-small cell lung cancer" (NSCLC) stage IB-IIIA with EGFR mutations positive |
Tipo específico de cancer de pulmón llamado "cáncer de pulmón no microcítico" (CPNM) estadio IB-IIIA con mutaciones EGFR positivas |
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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 | 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) |
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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 | 10029517 |
E.1.2 | Term | Non-small cell lung cancer stage I |
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 | 10029518 |
E.1.2 | Term | Non-small cell lung cancer stage II |
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 assess the efficacy of AZD9291 compared to placebo as measured by disease free survival (DFS) |
Evaluar la eficacia de AZD9291 en comparación con placebo mediante la medición de la supervivencia sin enfermedad (SSE) |
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E.2.2 | Secondary objectives of the trial |
1) To further assess the efficacy of AZD9291 compared with placebo by assessment of DFS rate at 2 years, 3 years and 5 years, of OS and OS rate at 5 years 2) To assess the effect of AZD9291 compared with placebo on health-related quality of life (HRQoL) by assessment of patient health-related quality of life and symptoms (HRQoL) using SF-36 questionnaire (version 2) 3) To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) by assessment of PK exposure parameters derived from plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550. 4) To assess the safety and tolerability profile of AZD9291 compared with placebo by assessment of number and severity of adverse events, clinical chemistry, haematology, urinalysis, vital signs, physical examination, body weight, digital electrocardiogram (ECG), left Ventricular Ejection Fraction (LVEF), World Health Organization (WHO) Performance Status and Ophthalmologic assessment |
1) Evaluar adicionalmente la eficacia del tratamiento con AZD9291 en comparación con placebo mediante evaluación de la SSE a los 2, 3 y 5 años, de la Supervivencia global (SG) y SG a los 5 años. 2) Evaluar el efecto de AZD9291 en comparación con placebo sobre la calidad de vida relacionada con la salud (HRQoL) mediante la medición del HRQoL de los pacientes a través del cuestionario SF-36 (version 2) 3) Caracterizar la farmacocinética (FC) de AZD9291 y sus metabolitos (AZ5104 y AZ7550) mediante evaluación de los parámetros de exposición derivados de las concentraciones plasmáticas de AZD9291 y sus metabolitos AZ5104 y AZ7550. 4) Evaluar el perfil de seguridad y de tolerabilidad del tratamiento con AZD9291 en comparación con placebo mediante la evaluación del número y gravedad de acontecimientos adversos, bioquímica sérica, hematología, análisis de orina, constantes vitales, exploración física, peso corporal, ECG digital , FEVI, Estado funcional de la OMS, y Estudio oftalmológico |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, aged at least 18 years. 2. Histologically confirmed diagnosis of primary non small lung cancer (NSCLC) on predominantly non-squamous histology 3. MRI or CT scan of the brain must be done prior to surgery as it is considered standard of care. 4. Patients must be classified post-operatively as Stage IB, II or IIIA on the basis of pathologic criteria. 5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. 6. Complete surgical resection of the primary NSCLC is mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. 7. Complete recovery from surgery and standard post-operative therapy (if applicable) at the time of randomization. 8. World Health Organization Performance Status of 0 to 1. 9. Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-child-bearing potential. |
1. Hombre o mujer, de como mínimo 18 años de edad. 2. Diagnóstico, confirmado histológicamente, de cáncer de pulmón no microcítico (CPNM) primario de histología predominantemente no epidermoide 3. Antes de la cirugía deberá haberse practicado una RM o un TAC de cerebro, al tratarse de una práctica habitual. 4. Posoperatoriamente, los pacientes deberán clasificarse como en estadio IB, II o IIIA según criterios anatomopatológicos. 5. Confirmación por el laboratorio central de que el tumor es portador de una de las 2 mutaciones más frecuentes del EGFR que se sabe que se asocian a sensibilidad de la tirosina cinasa del EGFR (Ex19del, L858R), ya sea sola o en combinación con otras mutaciones del EGFR, incluida la mutación T790M. 6. Es imprescindible la resección quirúrgica completa del CPNM primario. Al término de la cirugía deberá haberse resecado toda la enfermedad macroscópica. Todos los márgenes quirúrgicos de la resección deben estar libres de enfermedad. 7. En ocasión de la aleatorización, recuperación completa de la cirugía y del tratamiento posoperatorio estándar (si procede). 8. Estado funcional de la OMS 0 o 1. 9. Las pacientes de sexo femenino deberán utilizar medidas anticonceptivas adecuadas, no podrán estar practicando la lactancia natural y deberán presentar un resultado negativo en una prueba de embarazo antes de la primera dosis del fármaco del estudio; o las pacientes de sexo femenino debén presentar evidencia de carecer de potencial procreativo. |
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E.4 | Principal exclusion criteria |
1. Treatment with any of the following: - Pre-operative or post-operative or planned radiation therapy for the current lung cancer - Pre-operative (neo-adjuvant) platinum based or other chemotherapy - Any prior anticancer therapy - Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time - Major surgery (including primary tumour surgery, excluding placement of vascular access within 4 weeks of the first dose of study drug - Patients currently receiving medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 and potent inducers of CYP3A4 - Treatment with an investigational drug within five half-lives of the compound or any of its related material. 2. Patients who have had only segmentectomies or wedge resections 3. History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumours curatively treated with no evidence of disease for > 5 years following the end of treatment. 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291. 6. Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value. - Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG. - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval. 7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 8. Inadequate bone marrow reserve or organ-function. |
1. Cualquiera de los siguientes tratamientos: - Radioterapia preoperatoria o postoperatoria o programada para el cáncer de pulmón actual - Quimioterapia preoperatoria (neoadyuvante) basada en el platino o en otro fármaco - Cualquier tratamiento antineoplásico previo - Tratamiento previo neoadyuvante o adyuvante con un inhibidor de la tirosina cinasa del EGFR - Cirugía mayor (incluida la cirugía del tumor primario y excluida la colocación de un acceso vascular) en el plazo de las 4 semanas anteriores a la primera dosis del fármaco del estudio. - Pacientes que estén recibiendo actualmente medicamentos o suplementos de herbolario conocidos como potentes inhibidores de citocromo P450 (CIP)3A4 y potentes inductores de CYP3A4 - Tratamiento con un fármaco en fase de investigación sin haber transcurrido cinco semividas de dicho producto o de cualquier material relacionado, si se conoce. 2. Pacientes sometidos solamente a segmentectomía o resección en cuña 3. Antecedentes de otro proceso maligno, excepto: cáncer cutáneo de tipo no melanoma tratado adecuadamente, cáncer in situ tratado curativamente u otros tumores sólidos tratados curativamente y sin evidencia de enfermedad durante> 5 años después del fin del tratamiento. 4. Toda evidencia de enfermedad sistémica severa o no controlada lo que incluye la hipertensión no controlada y las diátesis hemorrágicas activas; o infección activa, tal como hepatitis B, hepatitis C y virus de la inmunodeficiencia humana (VIH). 5. Náuseas y vómitos resistentes al tratamiento, enfermedades gastrointestinales crónicas, incapacidad de deglutir el producto formulado o resección intestinal importante previa que pueda impedir la absorción adecuada de AZD9291. 6. Cualquiera de los siguientes criterios cardíacos: - Valor medio del intervalo QT corregido (QTc) en reposo >470 ms, obtenido a partir de 3 ECG, utilizando el valor del QTcF calculado por el electrocardiógrafo del centro en la selección. - Cualquier factor que aumente el riesgo de prolongación del QTc o de arritmias, o muerte súbita inexplicada en un familiar de primer grado menor de 40 años, o cualquier medicamento concomitante que se sabe que prolonga el intervalo QT. 7. Antecedentes médicos de neumopatía intersticial (NPI), NPI de origen farmacológico, neumonitis por radiación que haya precisado tratamiento con corticoides, o cualquier evidencia de NPI clínicamente activa 8. Reserva de médula ósea o función orgánica inadecuadas. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease free survival (DFS) using investigator assessments |
Supervivencia sin enfermedad (SSE) según evaluación del Investigador |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline and from randomization until recurrence |
En el momento basal y desde la aleatorización hasta recurrencia. |
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E.5.2 | Secondary end point(s) |
1) Assessment of Disease free survival (DFS) rate at 2 years, 3 years and 5 years 2) Analysis of Overall Survival (OS) 3) Assessment of Overall Survival (OS) rate at 5 years 4) Assessing of patient health-related quality of life and symptoms (HRQoL) using SF-36 questionnaire (version 2, standard) 5) PK exposure parameters derived from plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550. Pharmacokinetics data from this study will be analysed using a population PK approach and may also form part of a pooled analysis with other AZD9291 studies; results from these analyses will be reported separately from the CSR 6) Safety and tolerability endpoints assessed by number and severity of adverse events, clinical chemistry, haematology, urinalysis, vital signs, physical examination, body weight, digital electrocardiogram (ECG), left Ventricular Ejection Fraction (LVEF), World Health Organization (WHO) Performance Status and Ophthalmologic assessment |
1) Evaluación de la SSE a los 2, 3 y 5 años 2) Supervivencia global (SG) 3) SG a los 5 años. 4) Evaluación de la calidad de vida relacionada con la salud (HRQoL) usando el cuestionario SF-36 (versión 2) 5) parámetros de exposición derivados de las concentraciones plasmáticas de AZD9291 y sus metabolitos AZ5104 y AZ7550. Los datos de FC de este estudio se analizarán mediante una estrategia de FC poblacional y podrán analizarse conjuntamente con los de otros estudios con AZD9291; los resultados de estos análisis se comunicarán por separado del Clinical Study Report (CSR). 6) Perfil de seguridad y de tolerabilidad mediante la evaluación del número y gravedad de acontecimientos adversos, bioquímica sérica, hematología, análisis de orina, constantes vitales, exploración física, peso corporal, ECG digital , FEVI, Estado funcional de la OMS, y Estudio oftalmológico |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the trial |
A lo largo del estudio |
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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 | Yes |
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 | Yes |
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 | 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 | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 82 |
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 |
Belgium |
Brazil |
Canada |
China |
France |
Germany |
Hong Kong |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Thailand |
Turkey |
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 last visit of the last patient undergoing the study |
Última visita del ultimo paciente en el estudio |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 11 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |