E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive, operable, locally advanced or inflammatory early breast cancer. |
Cáncer de mama precoz HER2 positivo, operable, localmente avanzado o inflamatorio. |
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E.1.1.1 | Medical condition in easily understood language |
Breast Cancer. |
Cáncer de mama |
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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 compare the pathological complete response (pCR) rate between chemotherapy, trastuzumab plus pertuzumab (Arm A) and trastuzumab emtansine plus pertuzumab (Arm B) using local evaluation. |
Comparar la tasa de RCp entre quimioterapia, trastuzumab + pertuzumab (Brazo A) y trastuzumab emtansina + pertuzumab (Brazo B), en base a la evaluación local. |
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E.2.2 | Secondary objectives of the trial |
To evaluate event-free survival (EFS), invasive disease-free survival (IDFS), overall survival (OS) and rate of breast-conserving surgery across treatment arms. |
Evaluar la SLE, la SLEI, la SG y el porcentaje de cirugía conservadora de la mama entre los brazos de tratamiento |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- age > = 18 years - Histologically confirmed invasive breast cancer with a primary tumor size of > 2 cm - HER2-positive breast cancer - Patients with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) if all sampled lesions are centrally confirmed as HER2-positive - Stage at presentation: cT2-cT4, cN0-cN3, cM0 - Known hormone receptor status of the primary tumor - Patient agreement to undergo mastectomy or breastconserving surgery after neoadjuvant therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 -Adequate hematologic, renal and liver funciton - Baseline LVEF ? 55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) -Negative serum pregnancy rest for premenopausal women, and for women who have experienced menopause onset < 12 months prior to first dose of therapy -Documentation of hepatitis B virus and hepatitis C virus serology is required - Effective contraception as defined by protocol. |
- Edad < ó = 18 años - Carcinoma de mama infiltrante confirmado histológicamente, con tumor primario de tamaño ? 2 cm - Cáncer de mama HER2 positivo - Pacientes que presenten tumores multifocales (más de un tumor localizado en el mismo cuadrante que el tumor primario), siempre y cuando la valoración central confirme que todas las lesiones analizadas son HER2 positivas - Estadio al diagnóstico: cT2?cT4, cN0?cN3, cM0 - Conocimiento del estado de los receptores hormonales del tumor primario - Acuerdo del paciente para someterse a una mastectomía o cirugía conservadora de la mama tras el tratamiento neoadyuvante. - Estado funcional ECOG de 0 ó 1. - Función hematológica, renal y hepática adecuada. - FEVI basal > ó = 55%, determinada mediante ecocardiograma (ECO) o ventriculografía isotópica (MUGA). - Prueba de embarazo en suero negativa para las mujeres premenopáusicas y las mujeres que hayan iniciado la menopausia < 12 meses antes de la primera administración de la terapia del estudio - Serología documentada del virus de la hepatitis B (VHB) y virus de la hepatitis C. - Métodos anticonceptivos de acuerdo al protocolo. |
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E.4 | Principal exclusion criteria |
- Stage IV (metastatic) breast cancer - Patients who have received prior anti-cancer therapy for breast cancer except those patients with a history of breast lobular carcinoma in situ (LCIS) that was surgically managed or ductal carcinoma in situ (DCIS) treated exclusively with mastectomy. In case of prior history of LCIS/DCIS, >5 years must have passed from surgery until diagnosis of current breast cancer - Patients with multicentric (multiple tumors involving more than 1 quadrant) or bilateral breast cancer - Patients who have undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes - Axillary lymph node dissection or positive sentinel lymph node prior to start of neoadjuvant therapy. - History of concurrent or previous non-breast malignancies except for appropriately treated (1) nonmelanoma skin cancer and (2) in situ carcinomas, including cervix, colon, and skin. A patient with previous invasive non-breast cancer is eligible provided he/she has been disease-free for more than 5 years - Treatment with any investigational drug within 28 days prior to randomization - Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade > or = 2 peripheral neuropathy - Cardiopulmonary dysfunction as defined by the protocol - Any significant concurrent medical or surgical conditions or findings that would jeopardize the patient's safety or ability to complete the study - Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to randomization - Known hypersensitivity to study drugs, excipients and/or murine proteins - Concurrent, serious, uncontrolled infections or known infection with HIV - Any known active liver disease, e.g. due to HBC, HCV, autoimmune hepatic disorders, or sclerosing cholangitis - Pregnancy or breastfeeding. |
- Cáncer de mama en estadio IV (metastásico) - Pacientes que hayan recibido tratamiento antineoplásico previo para el cáncer de mama, excepto aquellos pacientes con antecedentes de CLIS de mama tratado quirúrgicamente o CDIS tratado únicamente mediante mastectomía. En caso de antecedentes de CLIS/CDIS, deberán haber transcurrido > 5 años desde la cirugía hasta el diagnóstico del cáncer de mama actual - Pacientes con cáncer de mama multicéntrico (múltiples tumores en más de un cuadrante) - Pacientes sometidos a biopsia incisional y/o excisional del tumor primario y/o de los ganglios axilares - Disección de ganglios axilares o ganglio centinela positivo previa al inicio del tratamiento neoadyuvante - Antecedentes de neoplasias malignas no mamarias concurrentes o previas, excepto (1) el cáncer cutáneo no melanoma y/o (2) los carcinomas in situ de cérvix, colon y piel adecuadamente tratados. Los pacientes con un cáncer infiltrante no mamario previo serán elegibles siempre y cuando hayan estado libres de enfermedad durante más de 5 años - Tratamiento con cualquier medicamento en investigación dentro de los 28 días anteriores a la aleatorización - Neuropatía periférica de grado > ó = 2 según la versión actual (v4.03) de los NCI CTCAE - Patología cardiopulmonar definida según protocolo - Presencia de enfermedad sistémica severa y no controlada que pueda interferir con el tratamiento planeado - Cirugía mayor no relacionada con el cáncer de mama o lesión traumática importante dentro de los 28 días anteriores a la aleatorización - Hipersensibilidad conocida a los fármacos del estudio, sus excipientes y/o las proteínas murinas - Infecciones concurrentes graves y no controladas, o infección conocida por VIH - Hepatopatía activa conocida (p. ej., debida al VHB, VHC, una enfermedad hepática autoinmune o una colangitis esclerosante) - Mujer actualmente embarazada y/o en periodo de lactancia |
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E.5 End points |
E.5.1 | Primary end point(s) |
Local evaluation of pathological complete response (pCR). |
Evaluación local de la respuesta completa patológica RCp. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 21 months |
Aproximadamente 21 meses |
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E.5.2 | Secondary end point(s) |
1. Event-free survival (EFS) 2. Invasive disease-free survival (IDFS) 3. Overall survival (OS) 4. Breast-conserving surgery rate 5. Incidence of adverse events 6. Incidence of hepatic events 7. Incidence of cardiac events 8. Health related quality of life as assessed by the European organization for reasearch and treatment of cancer (EORTC) quality of life questionnaire (QLQ) C30/BR23 9. Observed drug serum concentrations 10. Incidence of anti-therapeutic antibodies. |
1. Supervivencia libre de evento (SLE) 2. Supervivencia libre de enfermedad infiltrante (SLEI) 3. Supervivencia global (SG) 4. Porcentaje de cirugía conservadora de la mama 5. Incidencia de acontecimientos adversos 6. Incidencia de acontecimientos hepáticos 7. Incidencia de acontecimientos cardiacos 8. Calidad de vida relacionada con la salud que se medirán utilizando el EORTC y el módulo modificado para el cáncer de mama QLQ-BR23 9. Concentraciones séricas observadas de los medicamentos 10. Incidencia de anticuerpos anti-fármaco |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. -7. Approximately 36 months 8. Up to 36 months 9. Up to 20 months 10. Up to 20 months. |
1-7. Aproximadamente 36 meses 8. Hasta 36 meses 9. Hasta 20 meses 10. Hasta 20 meses |
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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 | 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 | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
Belgium |
Canada |
France |
Ireland |
Italy |
Germany |
Korea, Republic of |
Spain |
Russian Federation |
Taiwan |
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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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 | 45 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 45 |