| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human epidermal growth factor receptor 2 (HER2)-positive Early Breast Cancer. |
Receptor del factor de crecimiento epidérmico humano 2 (HER2) -
positivo temprano cáncer de mama |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive breast cancer refers to breast cancer that is positive for the HER2 protein, which promotes the growth of cancer cells |
El cáncer de mama HER2 positivo se refiere al cáncer de mama que es
positivo para la proteína HER2, que promueve el crecimiento de las
células cancerosas |
|
| 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 | 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) |
|
| 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 demonstrate the non-inferiority of the Cycle 7 (pre-dose Cycle 8) serum pertuzumab Ctrough of pertuzumab subcutaneous (SC) within the fixed-dose combination (FDC) compared with Perjeta IV (intravenous). |
D-emostrar la no inferioridad de la Cmín sérica que se alcanza en el ciclo 7 (antes de la dosis del ciclo 8) con el pertuzumab SC de la CDF en
comparación con Perjeta IV. |
|
| E.2.2 | Secondary objectives of the trial |
• To demonstrate the non-inferiority of the Cycle 7 (pre-dose Cycle 8) serum trastuzumab Ctrough of trastuzumab SC within the FDC compared with Herceptin IV
• To evaluate the efficacy of the SC FDC of pertuzumab and trastuzumab + chemotherapy compared with Perjeta IV and Herceptin IV + chemotherapy based on total pathological complete response
• To evaluate the efficacy of the SC FDC of pertuzumab and trastuzumab + chemotherapy compared with Perjeta IV and Herceptin IV + chemotherapy based on invasive disease-free survival ( including and excluding second primary non-breast cancer), event free survival (including and excluding second primary non-breast cancer), distant recurrence-free interval and overall survival
• To evaluate the safety of the SC FDC of pertuzumab and trastuzumab compared with Perjeta IV and Herceptin IV |
-Demostrar la no inferioridad de la Cmín sérica que se alcanza en el ciclo 7 (antes de la dosis del ciclo 8) con el trastuzumab SC de la CDF en comparación con Herceptin IV.
-Evaluar la eficacia de la CDF SC de pertuzumab y trastuzumab +
quimioterapia en comparación con Perjeta IV y Herceptin IV +
quimioterapia basada en bpCR
-Evaluar la eficacia de SC FDC de pertuzumab y trastuzumab +
quimioterapia en comparación con Perjeta IV y Herceptin IV +
quimioterapia basada en la supervivencia libre de enfermedad invasiva
(que incluye y excluye el segundo cáncer primario distinto del de mama), supervivencia libre de eventos (que incluye y excluye el segundo cáncer primario no mamario), intervalo distante sin recidiva y
supervivencia global
-Evaluar la seguridad de SC FDC de pertuzumab y trastuzumab en
comparación con Perjeta IV y Herceptin IV |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Ability to comply with the study protocol, in the investigator’s judgment
- Female and male patients with Stage II - IIIC (T2-T4, N0-N3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer
- Primary tumor > 2 cm in diameter, or node-positive
- HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material
- Hormone receptor status of the primary tumor, centrally confirmed
- Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy
- Availability of formalin-fixed, paraffin-embedded tumor tissue block for central confirmation of HER2 and hormone receptor status and additional biomarker research
- Baseline left ventricular ejection fraction (LVEF) >= 55% measured by echocardiogram or multiple-gated acquisition scan
- For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent or use one highly effective non-hormonal contraceptive method with a failure rate of < 1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy
- For men: men must remain abstinent or use a condom with a spermicidal product during the treatment
period and for 7 months after the last dose of HER2-targeted therapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period
- A negative serum pregnancy test must be available prior to randomization for WOCBP, unless they have undergone surgical sterilization
- No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment |
-Edad >= 18 años
--Capacidad para cumplir el protocolo del estudio, a criterio del
nvestigador
-Mujeres y varones con cáncer de mama invasivo en estadio II- IIIC (T2-T4, N0-N3, M0), localmente avanzado, inflamatorio o en estadío inicial,unilateral y confirmado histológicamente
-Diámetro del tumor primario > 2 cm o adenopatías positivas
-Cáncer de mama HER2-positivo confirmado por un laboratorio central
antes de la inclusión en el estudio. La positividad de HER2 se
determinará a partir del material de biopsia de mama
-Estado de los receptores hormonales del tumor primario, confirmado
centralmente
-Compromiso del paciente de someterse a una mastectomía o a una
cirugía conservadora de mama después del tratamiento neoadyuvante
-Disponibilidad de un bloque de tejido tumoral fijado en formol e incluido en parafina (FFPE) para confirmación central del estado de HER2 y de los receptores hormonales y evaluaciones de biomarcadores adicionales
-FEVI ³55% en el momento basal, determinado mediante
ecocardiograma o angiografía radioisotópica
-En las mujeres en edad fértil sexualmente activas: compromiso de
practicar abstinencia sexual (abstenerse de mantener relaciones
heterosexuales) o de utilizar un método anticonceptivo no hormonal muy eficaz que tenga una tasa anual de fallos <1%, o dos métodos
anticonceptivos no hormonales eficaces, durante el período de
tratamiento y hasta 7 meses después de la última dosis de tratamiento anti-HER2.
-Varones: compromiso de practicar la abstinencia sexual o de utilizar
preservativo combinado con con un producto espermicida durante el
periodo de tratamiento y hasta al menos 7 meses después de la última
dosis del tratamiento anti-HER2 para evitar exponer al embrión.L os
varones deberán abstenerse de donar semen durante este mismo
período.
-Antes de la randomización debe estar disponible un resultado negativo en la prueba de embarazo en suero para WOCBP, a menos que se haya sometido a una esterilización quirúrgica
-Ausencia de intervención de cirugía mayor no relacionada con el cáncer de mama en los 28 días previos a la aleatorización o de necesidad prevista de cirugía mayor durante el curso del tratamiento del estudio |
|
| E.4 | Principal exclusion criteria |
- Stage IV breast cancer
- Patients with a history of invasive breast cancer
- Patients with a history of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin
- Patients who have received any previous systemic therapy for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer
- Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in situ if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast
- Patients with high-risk for breast cancer who have received chemo preventative drugs in the past are not allowed to enter the study
- Patients with multi-centric breast cancer, unless all tumors are HER2-positive
- Patients with bilateral breast cancer
- Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes
- Axillary lymph node dissection prior to initiation of neoadjuvant therapy
- Sentinel lymph node biopsy prior to neoadjuvant therapy
- Treatment with any investigational drug within 28 days prior to randomization
- Serious cardiac illness or medical conditions
- Inadequate bone marrow function, renal function or impaired liver function
- Current severe, uncontrolled systemic disease that may interfere with planned treatment
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study
- Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis
- Concurrent, serious, uncontrolled infections, or known infection with HIV
- Known hypersensitivity to study drugs, excipients, and/or murine proteins
- Current chronic daily treatment with corticosteroids
- History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
- History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome |
-Pacientes com antecedentes de cáncer de mama invasivo.
-Pacientes con antecedentes de cáncer distinto del de mama
concomitante o previamente tratado, con la excepción de 1) cáncer de
piel distinto del melanoma y 2) carcinomas in situ, incluyendo de cuello uterino, colon y piel, tratados correctamente.
-Pacientes que hayan recibido previamente cualquier tratamiento
sistémico para el tratamiento o la prevención del cáncer de mama, o
radioterapia para tratamiento del cáncer.
-Pacientes que tenga antecedentes de carcinoma ductal in situ (CDIS) o carcinoma lobulillar in situ (CLIS) para el que hayan recibido tratamiento sistémico o radioterapia de la mama homolateral.
-No pueden participar en el estudio aquellos pacientes con alto riesgo de padecer cáncer de mama que hayan recibido fármacos de quimioterapia preventiva en el pasado
-Pacientes con cáncer de mama multicéntrico (múltiples tumores con
afectación de más de un cuadrante), a menos que todos los tumores
sean HER2 positivos.
--Pacientes con cáncer de mama bilateral
-Pacientes que se hayan sometido a una biopsia por escisión del tumor
primario y/o de ganglios linfáticos axilares.
-Disección de ganglios linfáticos axilares antes de empezar el
tratamiento neoadyuvante
-Biopsia de ganglio linfático centinela antes de empezar el tratamiento
neoadyuvante
-Tratamiento con un fármaco experimental en los 28 días previos a la
aleatorización.
-Cardiopatías o trastornos médicos graves incluyendo
-Función inadecuada de la médula ósea,función renal
inadecuada,Insuficiencia hepática.
-Enfermedad sistémica en curso no controlada, grave, que pueda
interferir en el tratamiento previsto
-Embarazo o lactancia, o intención de quedarse embarazada durante el estudio o en los 7 meses siguientes a la última dosis del tratamiento
anti-HER2.
-Cualquier enfermedad grave o anomalía de los valores de laboratorio
que, a criterio del investigador, impida la participación segura del
paciente y la realización del estudio
-Hepatopatía activa conocida, por ejemplo, infección de hepatitis viral
activa,enfermedades hepáticas autoinmunes o colangitis esclerosante
-Infecciones conocidas concomitantes graves, no controladas, o
infección conocida por VIH.
-Hipersensibilidad conocida a los fármacos del estudio, sus excipientes
y/o a proteínas murinas
-Tratamiento diario crónico actual con corticosteroides
-Antecedentes de otra neoplasia maligna en los 5 años previos a la
selección, excepto carcinoma in situ de cuello uterino, carcinoma de piel distinto del melanoma o cáncer de útero en estadio I, debidamente tratados
-Antecedentes de arritmias ventriculares o factores de riesgo de arritmia ventricular, como cardiopatía estructural (p. ej., disfunción sistólica del ventrículo izquierdo, hipertrofia del ventrículo izquierdo),
coronariopatía, anomalías electrolíticas clínicamente significativas o
antecedentes familiares de muerte súbita inexplicada o síndrome del
intervalo QT largo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Serum pertuzumab Ctrough during Cycle 7 (pre-dose Cycle 8). |
| 1. Cmín sérica de pertuzumab en el ciclo 7 (es decir, antes de la dosis del ciclo 8) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Pre-dose at Cycle 8 |
| Pre-dosis en el ciclo 8 |
|
| E.5.2 | Secondary end point(s) |
1. Serum trastuzumab Ctrough during Cycle 7 (pre-dose Cycle 8)
2. Total pathological complete response (ypT0/isypN0)
3. Invasive disease-free survival (including and excluding second primary non-breast cancer)
4. Event free survival (including and excluding second primary non-breast cancer)
5. Distant recurrence-free interval
6. Overall survival
7. Incidence and severity of adverse events and serious adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version4 (NCI CTCAE v4)
8. Laboratory test abnormalities according to NCI CTCAE v4
9. Incidence of a symptomatic ejection fraction decrease (“Heart failure”) of New York Heart Association (NYHA) Class III or IV and a drop in LVEF of at least 10-percentage points from baseline and to below 50%
10. Cardiac death
11. Incidence of an asymptomatic or mildly symptomatic left ventricular systolic dysfunction of NYHA Class II, defined as an LVEF decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% |
1.Cmín sérica de trastuzumab durante el ciclo 7 (antes de la dosis del
ciclo 8)
2.TpCR, definida como la erradicación de la enfermedad invasiva en
mama y axila (es decir, ypT0/isypN0
3. Supervivencia libre de enfermedad invasiva (que incluye y excluye los segundos cánceres primarios distintos del de mama
4.iDFS, incluyendo el segundo cáncer primario distinto del de mama,
5.Intervalo distante sin recurrencia
6.Supervivencia global
7. Incidencia y gravedad de acontecimientos adversos y AAG,
determinando la gravedad según los criterios CTCAE del NCI, v4
8. Anomalías en los valores de laboratorio según los criterios CTCAE del NCI, v4.
9. Incidencia de una disminución sintomática de la fracción de eyección ("Insuficiencia cardíaca") de clase III o IV de la NYHA y una disminución de la FEVI de al menos el 10% con respecto al valor basal y por debajo del 50%.
10. Muerte de origen cardíaco
11 Incidencia de una disminución sistólica del ventrículo izquierdo
asintomática o levemente sintomática de clase II de la NYHA y una
disminución de la FEVI de al menos el 10% con respecto al valor basal y por debajo del 50%. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Pre-dose at Cycle 8
2-11. Up to 5.5 years |
1. Pre-dosis en el ciclo 8
2-11. Hasta 5.5 años |
|
| 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 | No |
| 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) | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Brazil |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| Turkey |
| 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
|
| LPLV |
| Última visita del último paciente |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
Print
