| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated invasive breast carcinoma eligible for primary definitive surgery (Stage I-IIIA) |
| Carcinoma de mama invasivo, inicial, y apto para la cirugía definitiva (Fase I-IIIA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early stage HER2+ breast cancer |
| Cancer de mama HER2+ estadio inicial |
|
| 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 | 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 evaluate the ability of the PAM50 HER2-enriched (HER2-E) subtype to predict pathological complete response in the breast (pCRB) to dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, at the time of surgery. |
| Evaluar la capacidad del subtipo HER2-E determinado con la plataforma PAM50 para predecir la respuesta patológica completa a nivel de la mama (RpCM) en el momento de la cirugía, tras el bloqueo dual del HER2 con lapatinib y trastuzumab (+/- terapia hormonal). |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the ability of the PAM50 HER2-E to predict pCR in the breast and axilla to dual HER2 blockade with lapatinib and trastuzumab, +/- endocrine therapy (ET), at the time of surgery.
-To evaluate the ability of the PAM50 HER2-E to predict residual cancer burden in the breast to dual HER2 blockade with lapatinib and trastuzumab, +/- ET, at the time of surgery.
-To evaluate if the hormone receptor (HR)?positive, PAM50 non-Luminal A/B (combined) subtypes benefit from dual HER2 blockade + ET, as measured by the changes in the % of Ki67-positive cells from Day 0 to Day 14 of treatment.
-To identify gene expression changes from Day 0 to Day 14 after dual HER2 blockade.
-To evaluate if the correlation to the PAM50 HER2-E centroid, as a continuous variable, predicts pCR and/or RCB in the breast to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery. |
-Evaluar la capacidad del subtipo HER2-E determinado mediante PAM50 para predecir la RpCMA en el momento de la cirugía, tras el bloqueo dual del HER2 con lapatinib y trastuzumab (+/- terapia hormonal).
-Evaluar la capacidad del subtipo HER2-E determinado mediante PAM50 para predecir la carga tumoral residual (CTR, 0-I vs. II-III) en el momento de la cirugía, tras el bloqueo dual del HER2 con lapatinib y trastuzumab (+/- terapia hormonal).
-Evaluar si los subtipos no-Luminal A/B según PAM50/HR+ (combinados) se benefician del bloqueo dual del HER2 más terapia hormonal, de acuerdo con los cambios en el porcentaje de células positivas para Ki67 entre el día 0 y el día 14.
-Identificar los cambios en la expresión génica entre el día 0 y el día 14 tras el bloqueo dual del HER2.
-Evaluar si la correlación con el centroide del HER2-E según PAM50 (como variable continua) predice la RpCM y/o la CTR atribuibles al bloqueo dual del HER2 con lapatinib y trastuzumab, en el momento de la cirugía. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures
-Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)
-Histologically confirmed invasive breast carcinoma, with all of the following characteristics:
a.Primary tumor >=1cm in largest diameter
b.cN0-2
c.No evidence of distant metastasis (M0)
-HER2-positive invasive breast cancer, centrally determined and defined by CAP guidelines as:
* 3+ overexpression by IHC (uniform, intense membrane staining of >30% of invasive tumor cells)
or
* 2+ or 3+ (in 30% or less neoplastic cells) overexpression by IHC and HER2 gene amplification by in situ hybridization (ISH >6 HER2 gene copies per nucleus, or a ISH ratio [HER2 gene copies to chromosome 17 signals] of >2.2)
-Female patients
-Age >=18 years
-ECOG Performance Status of 0 or 1
-Adequate organ function defined as:
*Absolute neutrophil count (ANC) >=1.5 x 109/L
*Hemoglobin (Hgb) >=10 g/dL
*Platelets >100 000 /mm3
*Creatinine <=1.6 mg/dL
*ALT and AST <=2.5 x ULN
*Alkaline phosphatase ?5 ULN
*Total bilirubin <=1.5 mg/dL
-Baseline LVEF ?50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
-Negative ?-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after the last dose of investigational product
-Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. |
1.Consentimiento informado por escrito para todos los procedimientos del estudio, de acuerdo con los requerimientos legales locales, antes de iniciar cualquier procedimiento específico del protocolo
2.Carcinoma de mama invasivo no tratado, elegible para cirugía definitiva primaria (estadios I-IIIa)
3.Carcinoma de mama invasivo confirmado histológicamente, con todas las características siguientes:
a.Tumor primario ?1cm en su diámetro mayor
b.cN0-2
c.Sin evidencias de metástasis a distancia (M0)
4.CM invasivo HER2+, definido por las guías del CAP como:
a.sobreexpresión 3+ por IHQ (tinción uniforme e intensa de la membrana de >30% de las células tumorales invasivas)
o
b.sobreexpresión 2+ o 3+ (en un 30% o menos de las células neoplásicas) por IHQ y amplificación génica de HER2 por hibridación in situ (ISH; >6 copias del gen HER2 por núcleo, o un cociente entre las pruebas de ISH [copias del gen HER2 respecto a señales en el cromosoma 17] >2,2)
5.Pacientes mujeres
6.Edad ?18 años
7.Estado funcional del ECOG de 0 ó 1
8.Función orgánica adecuada, definida por:
a.Recuento absoluto de neutrófilos (RAN) ?1,5 x 109/l
b.Hemoglobina (Hg) ?10 g/dl
c.Plaquetas >100.000/mm3
d.Creatinina ?1,6 mg/dl
e.ALT y AST ?2,5 x LSN,
f.Fosfatasa alcalina ?5 LSN
g.Bilirrubina total ?1,5 mg/dl
9.Fracción de eyección del ventrículo izquierdo (FEVI) basal ?50%, determinada mediante ecocardiograma (ECO) o ventriculografía isotópica (MUGA).
10.En las mujeres premenopáusicas con capacidad reproductiva (biológicamente fértiles) y en aquellas cuya menopausia se haya producido con una anterioridad menor a 12 meses: prueba de embarazo de ?-HCG (en suero) negativa. Todas las pacientes biológicamente fértiles deberán estar de acuerdo en utilizar un método anticonceptivo fiable y comprometerse a emplearlo desde las 2 semanas previas a la administración de la primera dosis del producto en investigación hasta 28 días después de haber recibido la última dosis del mismo.
11.Ausencia de anomalías psicológicas, familiares, sociológicas o geográficas que potencialmente puedan dificultar el cumplimiento del protocolo del estudio y la pauta de seguimiento. Estas anomalías deberán ser discutidas con la paciente antes de su inclusión en el estudio. |
|
| E.4 | Principal exclusion criteria |
-Stage III inoperable breast cancer (e.g. T4 tumors and/or N3)
-Patients with locally advanced disease, or patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment
-Prior chemotherapy, radiotherapy, or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy
-Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years
-Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
-Concurrent congestive heart failure or LVEF <50%
-Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (<6 months before enrollment), unstable angina pectoris, myocardial infarction ?6 months before enrollment, uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or high-risk uncontrolled arrhythmias
-Uncontrolled diabetes mellitus, active peptic ulcer disease, or uncontrolled epilepsy
-Active uncontrolled infection at the time of enrollment
-History of significant co-morbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent
-Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment
-Patients who are pregnant or breast-feeding
-Women of child bearing potential who are unable or unwilling to use contraceptive measures
-Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee
-Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
-Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy other than the trial therapies)
-Concomitant use of CYP3A4 inhibitors or inducers |
1.Cáncer de mama inoperable en estadio III (p.ej., tumores T4 y/o N3)
2.Pacientes con enfermedad localmente avanzada, o aquellas en quienes se considere apropiada la quimioterapia de primera línea con taxanos y antraciclinas como tratamiento neoadyuvante óptimo
3.Quimioterapia, radioterapia o cirugía previas para el cáncer de mama invasivo, a excepción de la resección de tumor en la mama contralateral y a condición de que la paciente no haya recibido previamente radio o quimioterapia adyuvantes
4.Pacientes con una segunda neoplasia activa simultánea, a excepción del cáncer de piel distinto del melanoma tratado satisfactoriamente, del melanoma in situ o del carcinoma in situ de cérvix. Las pacientes con otras neoplasias malignas no mamarias deberán haber permanecido sin enfermedad durante 5 años como mínimo
5.Presencia o sospecha de reacción de hipersensibilidad a cualquier fármaco en investigación o compuesto terapéutico, o a sus excipientes
6.Insuficiencia cardiaca congestiva concomitante o FEVI <50%
7.Enfermedades cardiovasculares clínicamente significativas (es decir, activas): accidente vascular cerebral (<6 meses previamente a la inclusión), angina inestable, infarto de miocardio ?6 meses antes de la inclusión, hipertensión no controlada (presión sistólica >150 mmHg y/o diastólica >100 mmHg) y arritmias de alto riesgo no controladas
8.Diabetes mellitus no controlada, úlcera péptica activa o epilepsia no controlada
9.Infecciones activas no controladas presentes en el momento de la inclusión
10.Antecedentes de comorbilidades significativas que, a juicio del investigador, puedan interferir con la ejecución del estudio, la evaluación de la respuesta o el consentimiento informado
11.Uso de cualquier fármaco en investigación o participación en otro ensayo clínico terapéutico de forma simultánea o durante los 30 días anteriores a la inclusión
12.Pacientes gestantes o en período de lactancia
13.Mujeres con capacidad de concebir que no puedan o no deseen emplear métodos anticonceptivos
14.Incapacidad o rechazo a cumplir con el protocolo del estudio o a colaborar plenamente con el investigador o el profesional que él designe
15.Síndrome de malabsorción, patologías que afecten de forma significativa a la función gastrointestinal o resección gástrica o del intestino delgado. Las pacientes con colitis ulcerosa también quedarán excluidas del estudio
16.Tratamiento antineoplásico neoadyuvante simultáneo (quimioterapia, radioterapia, inmunoterapia o terapias biológicas, exceptuando los tratamientos del ensayo)
17.Tratamiento simultáneo con inhibidores o inductores del CYP3A4 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Comparison between the PAM50 HER2-enriched versus non HER2-enriched cases to achieve pCRB from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery. |
| Comparación entre los casos de PAM50 HER2-enriquecido y PAM50 HER2-no enriquecido para evaluar pCR en la mama tras el bloqueo dual HER2 con lapatinib y trastuzumab en el momento de la cirugia. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the surgery |
| Despues de la cirugia |
|
| E.5.2 | Secondary end point(s) |
| -Comparison between the PAM50 HER2-enriched versus non HER2-enriched cases to achieve pCR in the breast and axilla from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery. |
| Comparación entre los casos de PAM50 HER2-enriquecido y PAM50 HER2-no enriquecido para evaluar pCR en la mama y la axila tras el bloqueo dual HER2 con lapatinib y trastuzumab en el momento de la cirugia. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the surgery |
| Despues de la cirugia |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Placlitaxel será administrado a las pacientes tras la progresión confirmada por US en la semana 7. |
| Paclitaxel will be administered to all patients who have confirmed progression by US at week 7. |
|
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| Last Visit Last Patient |
| Ultima Visita Ultimo Paciente |
|
| 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 | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
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