E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with operable HER2-positive primary breast cancer |
Pacientes con cáncer de mama primario HER2-positivo operable |
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E.1.1.1 | Medical condition in easily understood language |
Newly diagnosed with primary breast cancer that is HER2-positive |
Diagnóstico reciente de cáncer de mama primario HER2-positivo |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
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 compare invasive disease-free survival (IDFS) in patients with HER2-positive breast cancer randomized to chemotherapy plus one year of trastuzumab plus placebo or chemotherapy plus one year of trastuzumab plus pertuzumab. |
Comparar la supervivencia libre de enfermedad invasiva (SLEI) en pacientes con cáncer de mama HER2-positivo randomizados para recibir quimioterapia más tratamiento con trastuzumab y placebo durante un año o quimioterapia más tratamiento con trastuzumab y pertuzumab durante un año. |
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E.2.2 | Secondary objectives of the trial |
To compare invasive disease-free survival including second non-breast cancers, disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), cardiac safety, overall safety and health-related quality of life (HRQL) in the two treatment arms. |
Comparar la supervivencia libre de enfermedad invasiva, incluyendo los segundos tumores que no sean de mama, la supervivencia libre de enfermedad (SLE), supervivencia global (SG), intervalo libre de recurrencia (ILR), intervalo libre de recurrencia a distancia (ILRD), seguridad cardíaca, seguridad general y calidad de vida relacionada con la salud (CVRS) en los dos grupos de tratamiento |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A subset of patients will participate in a substudy as detailed in a separate protocol. Full title: A pharmacokinetic substudy in association with the phase III, randomized, multicenter, doubleblind, placebo-controlled trial APHINITY (BIG 4-11/BO25126/TOC4939G) to evaluate pharmacokinetics and potential drug-drug interactions in patients with early breast cancer. Protocol identifiers: BIG 4-11 / BO25126 / TOC4939G (PK substudy 1) Protocol date: 2011-06-20 Please refer to the substudy protocol for further information. |
Un subgrupo de pacientes participarán en los subestudios de farmacocinética y de interacciones farmacológicas que se describen detalladamente en protocolos independientes. |
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E.3 | Principal inclusion criteria |
- Adult patients. >/= 18 years of age - Non-metastatic primary invasive HER2-positive carcinoma of the breast that is adequately excised, and that is either node-positive (except T0) or node-negative but with presence of at least one risk factor as defined by the protocol - Eastern Cooperative Oncology Group (ECOG) performance status </=1 - The interval between definitive surgery for breast cancer and randomization must be at least 3 weeks but no more than 7 weeks and the patient must be willing and able to start treatment within 1 week of randomization - Known hormone receptor status (estrogen receptor and progesterone receptor) - Baseline LVEF >/= 55% - Women of childbearing potential and male participants with partners of childbearing potential must agree to use effective contraception (as defined by the protocol) by the patient and/or partner for the duration of the study treatment and for at least 6 months after the last dose of study drug |
- Edad >/=18 años. - Presentar carcinoma de mama primario invasivo no metastásico y operable y que es o bien enfermedad ganglionar positiva (excepto T0) o enfermedad ganglionar negativa pero con presencia de al menos un factor de riesgo según se define en el protocolo. - Estado funcional del Eastern Cooperative Oncology Group (ECOG) >/= 1. - El intervalo entre la cirugía definitiva del cáncer de mama y la randomización debe ser de un mínimo de 3 y un máximo de 7 semanas y el paciente debe estar dispuesto y ser capaz de iniciar el tratamiento en la semana siguiente a la randomización. - Estado del receptor hormonal conocido (receptor de estrógenos y receptor de progesterona). - FEVI basal >/= 55% - Las mujeres potencialmente fértiles y los varones participantes en el estudio cuyas parejas sean potencialmente fértiles deben comprometerse a utilizar medidas anticonceptivas eficaces (como se define en el protocolo) durante el tratamiento del estudio y, como mínimo, hasta 6 meses después de administrar la última dosis del tratamiento del estudio. |
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E.4 | Principal exclusion criteria |
- History of any prior (ipsi- and/or contralateral) invasive breast cancer - History of non-breast malignancies within the 5 years prior to study entry, except for carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin - Any "clinical" T4 tumor as defined by TNM, including inflammatory breast cancer - Any previous systemic chemotherapy for cancer or radiotherapy for cancer - Prior use of anti-HER2 therapy for any reason or other prior biologic or immunotherapy for cancer - Concurrent anti-cancer treatment in another investigational trial - Serious cardiac or cardiovascular disease or condition - Pregnant or lactating women |
- Antecedentes de carcinoma de mama invasivo (ipsi y/o contralateral) - Antecedentes de neoplasias que no sean de mama en los 5 años previos a la inclusión en el estudio*, excepto las siguientes: carcinoma in situ de cervix, carcinoma in situ de colon, melanoma in situ y carcinoma de piel basocelular y escamocelular. - Cualquier tumor T4 ?clínico?, de acuerdo con la definición TNM, incluyendo carcinoma inflamatorio de la mama. - Tratamiento previo para el cáncer con cualquier tipo de quimioterapia o radioterapia. - Uso previo de agentes anti-HER2 por cualquier motivo, o de otros agentes biológicos o inmunoterapia para el cáncer. - Tratamiento concomitante para el cáncer en otro ensayo clínico. - Enfermedades o afecciones cardíacas graves - Mujeres embarazadas o en período de lactancia |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the trial is Invasive Disease-Free Survival (IDFS). It is a composite endpoint which is defined as the time from randomization until the date of the first occurrence of one of the following events: ? Ipsilateral invasive breast tumor recurrence (ie, an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ? Ipsilateral local-regional invasive breast cancer recurrence (ie, an invasive breast cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast); ? Distant recurrence (ie, evidence of breast cancer in any anatomic site ? other than the two abovementioned sites ? that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); ? Contralateral invasive breast cancer; ? Death attributable to any cause including breast cancer, non-breast cancer or unknown cause (but cause of death should be specified if at all possible). |
La variable principal del ensayo supervivencia libre de enfermedad invasiva SLEI se define como el tiempo transcurrido desde la randomización hasta la fecha en la que se manifiesta por primera vez uno de los acontecimientos siguientes: - Recurrencia del tumor invasivo en la mama ipsilateral (es decir, tumor de mama invasivo que afecta al mismo parénquima mamario que la lesión primaria original); - Recurrencia locorregional del tumor invasivo en la mama ipsilateral (es decir, tumor de mama que invade la axila, ganglios linfáticos regionales, pared torácica y/o piel de la mama ipsilateral); - Recurrencia a distancia (es decir, evidencia de cáncer de mama en cualquier localización anatómica, excepto en las dos que se han mencionado anteriormente, confirmado histológicamente o diagnosticado clínicamente como cáncer de mama invasivo recurrente); - Cáncer de mama contralateral invasivo; - Muerte atribuible a cualquier causa, incluyendo cáncer de mama, otro tipo de cáncer o por causas desconocidas (aunque se debe especificar la causa de la muerte, si es posible). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will take place when approximately 379 IDFS events have occurred. |
. El análisis final se realizará cuando se hayan producido aproximadamente 379 acontecimientos de SLEI. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of the present trial include OS (overall survival), DFS (disease-free survival), IDFS (invasive disease-free survival) including second primary non-breast cancer, RFI (recurrence-free interval) and DRFI (distant recurrence-free interval). Additionally, cardiac and overall safety, as well as quality of life will be evaluated. |
Las variables secundarias de este ensayo incluyen SG (supervivencia global), SLE (supervivencia libre de enfermedad, SLEI (supervivencia libre de enfermedad invasiva) incluyendo los segundos cánceres primarios que no son de mama, ILR (intervalo libre de recurrencia) y , ILRD (intervalo libre de recurrencia a distancia). Adicionalmente serán evaluadas la seguridad cardiaca y global así como calidad de vida. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary variables will be analyzed in a similar manner as the primary endpoint to compare the two treatment arms, estimate 3-year event rates (5-year event rates for OS). An event driven OS analysis is planned when 640 deaths have occurred, estimated to be around nine and a half years after last patient randomized. Assuming the primary analysis for IDFS occurs after 379 events then the first OS analysis will be made available at this time (estimated to be 4 to 5 years after the first patient is randomized). Two subsequent interim analyses of OS will be performed approximately 2.5 and 5 years later, with the final event-driven OS analysis defined above. |
Se analizarán de manera similar a la variable principal para comparar los dos grupos de tratamiento, la estimación de los índices de acontecimientos a 3 años (a 5 años, para la SG). Está previsto realizar un análisis de la SG orientado por los acontecimientos cuando se hayan producido 640 muertes. Asumiendo que el análisis principal de la SLEI tenga lugar después de que se hayan producido 379 acontecimientos, los resultados del primer análisis de la SG estarían disponibles en ese momento (lo cual se prevé que suceda entre 4 y 5 años después de la randomización del primer paciente). Aproximadamente 2,5 y 5 años después, se realizarán dos análisis intermedios de la SG, así como el análisis final de la SG orientado por los acontecimientos que se ha definido anteriormente. |
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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 | 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 | 40 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 288 |
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 |
European Union |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
Croatia |
El Salvador |
Guatemala |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Mexico |
New Zealand |
Panama |
Peru |
Philippines |
Russian Federation |
South Africa |
Switzerland |
Taiwan |
Thailand |
Ukraine |
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
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The study will formally end approximately 10 years from the date the last patient is randomized into the study providing the study objectives have been met by this time. This may or may not coincide with the time of the event-driven Overall Survival analysis, depending on the event rate. |
El estudio terminará formalmente aproximadamente 10 años después de la fecha de la randomización del último paciente en el estudio, siempre que se hayan cumplido los objetivos del estudio en ese momento. Esto puede coincidir o no con la fecha del análisis de la SG orientado por los acontecimientos, dependiendo de la tasa de acontecimientos. |
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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 | 12 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 12 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |