E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HR+, HER2- early breast cancer |
Cáncer de mama primario HR+, HER2 negativo |
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E.1.1.1 | Medical condition in easily understood language |
Early Breast Cancer |
Cáncer de mama primario |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 estimate the difference in anti-proliferative activity of LEE011 600 mg QD and LEE011 400 mg QD in combination with letrozole from baseline to time of surgery (day15) as determined by cell cycle response rate 2.5 mg QD vs single agent letrozole 2.5 mg QD as measured by changes in Ki-67 levels |
Estimar la diferencia en la actividad antiproliferativa de LEE011 600 mg QD y LEE011 400 mg QD en combinación con letrozol 2,5 mg QD frente a letrozol 2,5 mg QD en monoterapia determinado por cambios en los niveles de ki67 desde la basal hasta el momento de la cirugía (día 15). |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of the combination of LEE011 + letrozole as measured by frequency and severity of AEs, laboratory abnormalities. To characterize the ECG effects of LEE011 at 400 mg and 600 mg QD in combination with letrozole 2. To assess pharmacodynamics markers related to the activity of LEE011 in breast cancer as measured by changes between baseline and posttreatment expression of markers such as- but not limited to- pRB and CDK1 3.To assess pharmacokinetics of LEE011 (and any relevant metabolites) and letrozole as measured by PK parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole. |
1. Evaluar la seguridad y tolerabilidad de la combinación de LEE011 + letrozol 2. Caracterizar los efectos del ECG de LEE011 (y cualquier metabolito relevante) a 400 mg y 600 mg QD en combinación con letrozol mediante comparación directa de intervalos de ECG y morfología durante el tratamiento comparado con una basal pretratamiento y por modelos PK-PD. 3. Evaluar los marcadores farmacodinámicos relacionados con la actividad de LEE011 en cáncer de mama. 4. Evaluar la farmacocinética de LEE011 (y cualquier metabolito relevante) y letrozol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is ? 18 years old at the time of informed consent, with newly diagnosed resectable breast cancer, who received no prior therapy for breast cancer. 2. Patient is postmenopausal. Postmenopausal status is defined either by: ? Prior bilateral oophorectomy ? Age ?60 ? Age <60 and amenorrhea for 12 or more months and FSH and estradiol in the postmenopausal range. 3. Patient has a histologically (and/or cytologically) confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory. 4. Patient has a grade II or grade III invasive breast cancer 5. Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization (respectively FISH/CISH/SISH) test is required) by local laboratory testing 6. Patient has at least one breast lesion with a diameter of ?1.5 cm by ultrasound. 7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 |
1. El consentimiento informado por escrito debe ser obtenido antes de realizar cualquier evaluación y siguiendo las normas locales. En el momento del consentimiento informado, la paciente sea ? 18 años de edad, con cáncer de mama resecable de nuevo diagnóstico, que no recibió terapia previa para el cáncer de mama. 2. La paciente es postmenopáusica. El estado de postmenopausia se define por cualquiera de los siguientes: ? Ooforectomía bilateral previa ? Edad ?60 ? Edad <60 y amenorrea durante 12 o más meses (en ausencia de quimioterapia, tamoxifeno, toremifeno, o supresión ovárica) y FSH y estradiol en el rango de la postmenopausia. 3. La paciente tiene un diagnostico confirmado histológicamente (y/o citológicamente) de cáncer de mama receptor de estrógeno positivo y/o receptor de progesterona positivo por el laboratorio local. 4. La paciente tiene un cáncer de mama invasivo de grado II o grado III. 5. La paciente tiene cáncer de mama HER2 negativo definido como prueba de hibridación in situ negativa o un estado IHC de 0, 1+ o 2+ (si IHC 2+, es obligatoria una prueba de hibridación in situ negativa (respectivamente FISH/CISH/SISH)) mediante análisis por el laboratorio local. 6. La paciente tiene al menos una lesión de mama con un diámetro ? 1,5 cm mediante ecografía. 7. La paciente tiene un estado de actividad del Grupo Oncológico Cooperativo del Este (ECOG) de 0 o 1. |
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E.4 | Principal exclusion criteria |
1. Patient has received any prior therapy for breast cancer. 2. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. 3. Patient has active cardiac disease or a history of cardiac dysfunction including any of the following: ? History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry ? History of documented congestive heart failure (New York Heart Association functional classification III-IV) ? Documented cardiomyopathy ? Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) ? History of ventricular, supraventricular, nodal arrhythmias, or any other cardiac arrhythmias, Long QT Syndrome or conduction abnormality in the previous 12 months. ? Family history of QTc prolongation or of unexplainable sudden death at <50 years of age. ? On screening 12 lead ECG, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec. ? Systolic blood pressure >160 mmHg or <90 mmHg. 4. Patient is currently receiving any of the following medications (see Appendix 1 for details): ? That are known strong inducers or inhibitors of CYP3A4. ? That have a narrow therapeutic window and are predominantly metabolized through CYP3A4. ? That have a known risk to prolong the QT interval or induce Torsades de Pointes. |
1. La paciente ha recibido alguna terapia previa para el cáncer de mama. 2. La paciente tiene un cáncer concomitante o un cáncer en los 3 años de la aleatorización, a excepción del cáncer cutáneo no melanoma, carcinoma basal o de células escamosas, adecuadamente tratado, o cáncer de cervix resecado curativamente. 3. La paciente tiene enfermedad cardiaca activa o antecedentes de disfunción cardiaca incluyendo cualquiera de los siguientes: ? Historia de angina pectoris, pericarditis sintomática, o infarto de miocardio en los 12 meses previos a la entrada en el estudio. ? Historia de insuficiencia cardiaca congestiva documentada (clasificación funcional III-IV de la Asociación del Corazón de Nueva York) ? Cardiomiopatía documentada. ? La paciente tiene una Fracción de Eyección Ventricular Izquierda (FEVI) < 50% determinada mediante ventriculografía isotópica (MUGA) o ecocardiograma (ECO) ? Historia de arritmia ventricular, supraventricular, nodal, o cualquier otra arritmia cardiaca, síndrome QT largo o anomalía de conducción en los 12 meses previos. ? Historia familiar de prolongación del QTc o de muerte súbita inexplicable a edad < 50 años ? En el ECG de 12 derivaciones de la selección, cualquiera de los siguientes parámetros: bradicardia (frecuencia cardiaca < 50 en reposo), taquicardia (frecuencia cardiaca > 90 en reposo), intervalo PR > 220 mseg, intervalo QRS > 109 mseg, o QTcF > 450 mseg ? Presión arterial sistólica >160 mmHg o <90 mmHg. 4. La paciente está actualmente recibiendo alguna de las medicaciones siguientes: ? Que sean inductores o inhibidores fuertes conocidos de CYP3A4 ? Que tengan un margen terapéutico estrecho y sean metabolizados predominantemente por CYP3A4 ? Que tengan un riesgo conocido de prolongar el intervalo QT o inducir Torsades de Pointes |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cell cycle response rate defined by proportion of patients with natural logarithm of Ki-67 levels (expressed as percentage of baseline values) of less than 1 at the time of surgery |
Tasa de respuesta del ciclo celular definido por la proporción de pacientes con logaritmo natural de niveles de ki67 (expresados como porcentaje de valores basales) de menos de 1 en el momento de la cirugía |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Difference from baseline to time of surgery in levels of Ki-67 |
Diferencia entre el inicio y el tiempo de la cirugía en los niveles de Ki-67 |
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E.5.2 | Secondary end point(s) |
1. Frequency and severity of AEs, laboratoryabnormalities 2. Time matched, placebo corrected, change from baseline in QTc and other cardiac intervals, changes in ECG morphology, and correlation between the QTc interval change from baseline and plasma concentrations of LEE011 and/or any relevant metabolites 3. Changes between baseline and post-treatment expression of markers such as- but not limited to- pRB and CDK1 4. PK parameters, including but not limited to, Cmax, Tmax, AUClast for LEE011 (and any relevant metabolites) and letrozole. |
1-Frecuencia y severidad de AAs, anomalías de laboratorio. 2-Tiempo exacto, corregido para placebo, del cambio desde la basal en QTc y otros intervalos cardiacos, cambios en la morfología del ECG, y correlación entre el cambio en el intervalo QTc desde la basal y concentraciones plasmáticas de LEE011 y/o cualquier metabolito relevante. 3-Cambios entre la expresión basal y post-tratamiento de marcadores como -pero sin limitarse a- pRb y CDK1. 4-Parámetros de PK, incluyendo pero no limitados a, Cmax, Tmax, AUClast para LEE011 (y cualquier metabolito relevante) y letrozol. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Frequency of AEs Day 0 -day 14 i.e Changes from baseline to day of surgery |
Frecuencia de Acontecimientos Adversos Día 0 ?día 14 p.e. cambios del basal al día de la cirugía |
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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 | No |
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 end of study is defined as the time point when data collection will stop and the final analysis of the study will occur. |
El final del estudio se define cuando la recopilación de datos se detiene y se obtiene el análisis final del 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 | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |