| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive primary breast cancer |
| Cáncer de mama precoz HER2-positivo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer |
| Cáncer de mama |
|
| 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 | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 assess the overall safety and tolerability of subcutaneous (SC) trastuzumab in HER2-positive early breast cancer (EBC) patients with assisted administration using a conventional syringe and needle (vial formulation) and with assisted administration with or without self-administration using a single-use injection device (SID). |
| El objetivo principal de este estudio es valorar la tolerabilidad y seguridad global de trastuzumab administrado por vía subcutánea (SC) en pacientes con cáncer de mama precoz (CMP) HER2-positivo con administración asistida con aguja y jeringuilla convencional (formulación en vial) y con administración asistida con o sin auto-administración utilizando un dispositivo de inyección monouso (DIM). |
|
| E.2.2 | Secondary objectives of the trial |
? Efficacy (both cohorts):
- disease-free survival (DFS)
- overall survival (OS)
? Patient satisfaction with trastuzumab SC administration using the SID (patients in Cohort B who went on to self-administration of the study drug). |
Los objetivos secundarios de este estudio consisten en evaluar los valores siguientes:
?Eficacia (ambas cohortes):
-Supervivencia libre de enfermedad (SLE)
-Supervivencia global (SG)
?Satisfacción del paciente con la administración de trastuzumab SC utilizando el DIM (pacientes de la Cohorte B que prosiguen con la auto-administración del fármaco del estudio). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent approved by the reviewing independent Ethics Committee
2. Female or male aged 18 years or above
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Histologically confirmed early invasive HER2-positive carcinoma of the breast with no evidence of residual, locally recurrent or metastatic disease and defined as clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for adjuvant treatment with trastuzumab.
Note: Patients treated without neoadjuvant or adjuvant chemotherapy, such as patients with low risk node negative tumours ? 1.0 cm, elderly patients (>65 years of age) or patients with HER2-positive EBC but denying chemotherapy, will also be eligible to participate in the study, but their enrolment will be limited to approximately 10% of the total study population.
5. HER2-positive EBC, defined as IHC 3+, or FISH/CISH positive, as determined in a local laboratory that is experienced/certified in HER2-expression testing using an accurate and validated assay.
6. Screening left ventricular ejection fraction (LVEF) ? 55% as measured by echocardiography, Multi Gated Acquisition (MUGA) scan or Magnetic Resonance Imaging (MRI) per local practice.
7. Agreement to use an adequate, non-hormonal means of contraception by women of childbearing potential (defined as pre-menopausal and not surgically sterilized or < 1 year after the onset of menopause) and by male participants with partners of childbearing potential only. Examples of adequate contraceptive measures are an intra-uterine device, a barrier method (condoms, diaphragm) in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not acceptable for females participating in the study.
8. Intact skin at site of SC injection on the thigh. |
1.Habrán firmado el formulario de consentimiento informado por escrito aprobado por el Comité Ético de Investigación Clínica correspondiente.
2.Pacientes de ambos sexos de 18 años o mayores
3.Grado de actividad Eastern Cooperative Oncology Group (ECOG) 0 ó 1
4.Carcinoma de mama histológicamente confirmado en fase precoz invasivo HER2-positivo sin pruebas de enfermedad residual metastásica o localmente recurrente, y definido como en estadio clínico I (T1, N0, M0) a IIIC (cualquier T, N3, M0) que sea idóneo para el tratamiento adyuvante con trastuzumab.
Nota: Los pacientes tratados sin quimioterapia neoadyuvante o adyuvante, tal como los pacientes con tumores sin afectación ganglionar de bajo riesgo ? 1,0 cm, pacientes ancianos (>65 años de edad) o pacientes con CMP HER2-positivo pero que rehúsan el uso de quimioterapia, también podrán participar en el estudio, pero se limitará su inclusión aproximadamente al 10% de la población total del estudio.
5.CMP HER2-positivo, definido como IHC 3+, o FISH/CISH positivo, determinado en un laboratorio local aprobado / con experiencia en las pruebas de expresión HER2 utilizando un análisis validado y exacto.
6.Fracción de eyección ventricular izquierda (FEVI) ? 55% determinado por ecocardiografía, angiografía sincronizada multinuclear (Multi Gated Acquisition, MUGA) o resonancia magnética nuclear (RMN) de acuerdo con la práctica local.
7.Aceptación del uso de métodos anticonceptivos no hormonales adecuados por las mujeres en edad fértil (definidas como pre-menopáusicas y no esterilizadas por cirugía o < 1 año después del inicio de la menopausia) y por los participantes masculinos con parejas en edad fértil. Ejemplos de métodos anticonceptivos adecuados son el dispositivo intrauterino, un método de barrera (preservativos, diafragma) asociados con gel espermicida, o abstinencia total. No son aceptables los anticonceptivos hormonales orales, inyectables o de implante en las mujeres participantes en el estudio.
8.Piel intacta en la zona de la inyección SC en el muslo. |
|
| E.4 | Principal exclusion criteria |
Cancer Related Criteria
1. Previous neoadjuvant or adjuvant breast cancer treatment with an approved or investigational anti-HER2 agent
2. History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively treated carcinoma in situ of the cervix or basal cell carcinoma, and patients with other curatively-treated malignancies who have been disease-free for at least 5 years, are eligible.
3. Past history of ductal carcinoma in situ (DCIS) and/or lobular carcinoma in situ (LCIS) that has been treated with any systemic therapy OR with radiation therapy to the ipsilateral breast where invasive cancer subsequently develops. Patients who had their DCIS/LCIS treated with surgery only are allowed to enter the study.
4. Metastatic disease
Haematological, Biochemical and Organ Function Related Criteria
5. Inadequate bone marrow function (as indicated by any of the following):
? Total white blood cell count < 2,500 / mm3 (<2.5 x 109/L)
? Absolute neutrophil count < 1,500 / mm3 (< 1.5 x 109/L)
? Platelets < 100,000 / mm3 (< 100 x 109/L)
? Haemoglobin < 10 g/dL
6. Impaired hepatic function (as indicated by any of the following):
? Serum total bilirubin > 1.5 x upper limit of normal (ULN)
? Alanine amino transferase and/or aspartate amino transferase > 1.25 x ULN
? Alkaline phosphatase > 2.5 x ULN
7. Impaired renal function: serum creatinine > 1.5 x ULN
Other Study Drug Related Exclusion Criteria
8. Serious cardiac illness or medical conditions including but not confined to:
? History of documented heart failure or systolic dysfunction (LVEF < 50%)
? High-risk uncontrolled arrhythmias such as atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV) block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
? Angina pectoris requiring anti-anginal medication
? Clinically significant valvular heart disease
? Evidence of transmural infarction on electrocardiogram (ECG)
? Poorly controlled hypertension, or history of hypertensive crisis or hypertensive encephalopathy
9. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness
10. Prior maximum cumulative dose of doxorubicin >360 mg/m2 or maximum cumulative dose of epirubicin >720 mg/m2 or equivalent
11. Known hypersensitivity to trastuzumab, murine proteins, or excipients, or to the adhesive of the SC device
12. History of severe allergic or immunological reactions, e.g. difficult to control asthma
General Exclusion Criteria
13. Pregnancy or lactation
14. Unable or unwilling to comply with the requirements of the protocol as assessed by the investigator
15. Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment, including hormonal therapy, bisphosphonate therapy and immunotherapy, within 28 days prior to the first dose of study treatment
16. Major surgical procedure or significant traumatic injury within 28 days prior to the first dose of study treatment or anticipated need for major surgery during the course of study treatment. Patients must be free of any clinically significant sequalae of prior surgery before they can receive their first dose of study treatment.
17. More than 12 weeks between the end of the last chemotherapy cycle and the first dose of study treatment, in case these treatments are initiated sequentially. This criterion does not apply to patients who are starting trastuzumab SC without previous or concurrent chemotherapy or concurrently with chemotherapy.
18. Current chronic daily treatment with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids
19. Current peripheral neuropathy of grade 3 or greater per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. |
Criterios relacionados con el cáncer
1.Tratamiento para el cáncer de mama adyuvante o neoadyuvante previo con un fármaco aprobado o en investigación anti-HER2.
2.Antecedentes de otra neoplasia que pueda afectar el cumplimiento del protocolo o interpretación de los resultados. Pueden incluirse los pacientes con carcinoma in situ de cérvix o basocelular con tratamiento curativo, y los que sufren otras neoplasias con tratamiento curativo que han estado libres de enfermedad durante al menos 5 años.
3.Antecedentes de carcinoma ductal in situ (ductal carcinoma in situ, DCIS) y/o carcinoma lobular in situ (LCIS) que se les ha sometido a tratamiento general o bien radioterapia en la mama homolateral en que aparece posteriormente el cáncer de mama invasivo.
Sólo se permite la inclusión en el estudio de los pacientes que tienen su DCIS/LCIS tratado con cirugía.
4.Enfermedad metastásica
Criterios relacionados con la función orgánica, bioquímica y hematológica
5.Función deficiente de la médula ósea (indicado por uno de los criterios siguientes):
?Recuento total de leucocitos < 2.500 / mm3 (<2,5 x 109/L)
?Recuento absoluto de neutrófilos < 1.500 / mm3 (< 1,5 x 109/L)
?Plaquetas < 100.000 / mm3 (< 100 x 109/L)
?Hemoglobina < 10 g/dL
6.Deterioro de la función hepática (indicado por uno de los criterios siguientes):
?Bilirrubina sérica total > 1,5 x límite normal superior (LNS)
?Alanina aminotransferasa y/o aspartato aminotransferasa > 1,25 x LNS
?Fosfatasa alcalina > 2,5 x LNS
7.Deterioro de la función renal: creatinina sérica > 1,5 x LNS
Otros criterios de exclusión relacionados con el fármaco del estudio
8.Cardiopatía grave o enfermedades tales como:
?Antecedentes de insuficiencia cardiaca documentada o disfunción sistólica (FEVI < 50%)
?Arritmias de alto riesgo no controladas tales como taquicardia auricular con una frecuencia cardiaca > 100/min en reposo, arritmia ventricular significativa (taquicardia ventricular) o bloqueo auriculoventricular de alto grado (AV) (bloqueo AV de segundo grado Tipo 2 [Mobitz 2] o bloqueo AV de tercer grado)
?Angina de pecho que requiere medicación antianginosa.
?Valvulopatía clínicamente significativa.
?Pruebas de infarto transparietal en el electrocardiograma (ECG)
?Hipertensión mal controlada, o antecedentes de crisis hipertensiva o encefalopatía hipertensiva.
9.Otras enfermedades graves concomitantes que pueden interferir con el tratamiento previsto, tal como enfermedades/afecciones pulmonares severas.
10.Dosis acumulada máxima previa de doxorubicina >360 mg/m2 o dosis máxima acumulada de epirubicina >720 mg/m2 o equivalente.
11.Hipersensibilidad conocida a trastuzumab, proteínas murinas, o excipientes, o al adhesivo del dispositivo SC.
12.Antecedentes de reacciones inmunológicas o alérgicas severas, ej. Dificultad para controlar el asma.
Criterios generales de exclusión
13.Embarazo o lactancia
14.Incapacidad o falta de deseo de cumplir con los requisitos del protocolo, de acuerdo con la valoración por el investigador.
15.Inclusión simultánea en otro estudio clínico en que se utilice un tratamiento antitumoral en investigación, tal como tratamiento hormonal, tratamiento con bisfosfonato e inmuno terapia, en los 28 días previos a la primera administración del tratamiento del estudio.
16.Procedimiento quirúrgico mayor o lesión traumática significativa en los 28 días previos a la primera administración del tratamiento del estudio o necesidad prevista de cirugía mayor durante el curso del tratamiento del estudio. Los pacientes no deben tener secuelas clínicamente significativas de cirugía previa antes de que puedan recibir su primera administración del tratamiento del estudio.
17.Más de 12 semanas entre el final del último ciclo de quimioterapia y la primera administración del tratamiento del estudio, en caso de que los tratamientos se inicien secuencialmente. Este criterio no se aplica en pacientes que comienzan trastuzumab SC sin quimioterapia previa o concomitante, o con quimioterapia en curso.
18.Tratamiento diario crónico en curso con corticoesteroides (dosis equivalente o superior a 10 mg/día de metilprednisolona), con exclusión de los esteroides inhalados.
19.Neuropatía periférica en curso de grado 3 o superior de acuerdo con los National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) versión 4.0. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety endpoints are the primary objectives in this study and will include: all AEs, Grade ?3 AEs, SAEs, AEs leading to premature discontinuation of study treatment, AEs causing interruption of trastuzumab SC, cardiac AEs, CHF-related SAEs, premature withdrawals from study and study medication, exposure to treatment, laboratory parameters, LVEF, vital signs, ECG, weight, and ECOG performance status. |
| En este estudio los objetivos principales son las variables de valoración de seguridad, e incluirán: todos los AA, AA Grado ?3, AAG, AA que conducen a la retirada prematura del tratamiento del estudio, los AA que causan la interrupción de trastuzumab SC, AA cardíacos, AAG relacionados con la ICC, retiradas prematuras del estudio y medicación del estudio, exposición al tratamiento, variables de laboratorio, FEVI, constantes vitales, ECG, peso, y grado de actividad ECOG. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the safety endpoints will take place when all patients have received 18 cycles of trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks after their last dose of study treatment). |
| Los análisis principales de las variables de valoración de seguridad tendrán lugar cuando todos los pacientes hayan recibido 18 ciclos de trastuzumab SC y hayan completado las valoraciones de seguimiento de seguridad (4 semanas después de su última administración del tratamiento del estudio). |
|
| E.5.2 | Secondary end point(s) |
| Secondary efficacy endpoints include DFS, OS (both cohorts) and patients? satisfaction with trastuzumab SC administration using the SID (Cohort B patients who went on to self administration only). |
| Las variables secundarias de valoración de eficacia incluyen SLE, SG (ambas cohortes) y la satisfacción del paciente con la administración de trastuzumab SC utilizando el DIM (Sólo los pacientes de la Cohorte B que continúan con la autoadministración). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A preliminary analysis of DFS and OS will be undertaken at the time of the primary safety analysis, i.e. when all patients have received 18 cycles of trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks after their last dose of study treatment). The final analysis of OS and DFS will take place when the last patient has been followed up for at least 24 months after her/his last study treatment, or earlier, if one of the following is documented for all treated patients: withdrawal of consent, loss to follow-up or death. |
| Se realizará un análisis preliminar de SLE y SG en el momento del análisis principal de seguridad, es decir cuando todos los pacientes hayan recibido 18 ciclos de trastuzumab SC y hayan completado las valoraciones de seguimiento de seguridad (4 semanas después de la última administración del tratamiento del estudio). Los análisis finales de SG y SLE tendrán lugar cuando se haya sometido a seguimiento al último paciente durante al menos 24 meses después de su último tratamiento del estudio, o antes en caso de que se documente uno de los siguientes criterios en todos los pacientes tratados: retirada del consentimiento, pérdida de seguimiento o muerte. |
|
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Patient satisfaction and Medical Care Utilization |
|
| 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 | No |
| 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 | 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) | 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 300 |
| 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 |
| Albania |
| Algeria |
| Argentina |
| Australia |
| Bahrain |
| Bosnia and Herzegovina |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Dominican Republic |
| Ecuador |
| Egypt |
| El Salvador |
| Guatemala |
| Hong Kong |
| India |
| Indonesia |
| Korea, Republic of |
| Kuwait |
| Lebanon |
| Malaysia |
| Mexico |
| Moldova, Republic of |
| Montenegro |
| Morocco |
| New Zealand |
| Pakistan |
| Panama |
| Peru |
| Philippines |
| Qatar |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| Singapore |
| South Africa |
| Switzerland |
| Taiwan |
| Thailand |
| Trinidad and Tobago |
| Tunisia |
| Turkey |
| Ukraine |
| United Arab Emirates |
| Uruguay |
| Venezuela, Bolivarian Republic of |
| Vietnam |
|
| 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
|
| End of study is defined as the last patient last visit in the follow-up period. The study will end when all patients have been followed for at least 24 months after their last study treatment, or earlier, if one of the following is documented for all treated patients: withdrawal from the study, loss to follow up or death. |
| El final del estudio se define como la última visita del último paciente en el periodo de seguimiento. El estudio finalizará cuando se hayan sometido a seguimiento a todos los pacientes durante al menos 24 meses después de su último tratamiento del estudio, o antes en caso de que se documente uno de los siguientes criterios en todos los pacientes tratados: retirada del estudio, pérdida de seguimiento o muerte. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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