| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary breast cancer, ER or PgR positive, or triple negative and HER-2 negative, larger than 2 cm in diameter. |
| Cáncer de mama primario, ER o PgR positivo, o triple negativo y HER-2 negativo, de más de 2 cm de diámetro. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary breast cancer, more than 2 cm in diameter, belonging to specific molecular types. |
| Cáncer de mama primario, de más de 2 cm de diámetro, pertenecientes a determinados tipos moleculares. |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
| 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 | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069196 |
| E.1.2 | Term | Cytostatic chemotherapy |
| E.1.2 | System Organ Class | 100000004865 |
|
| 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 and compare the rate of complete response or pCR (according NSABP guidelines) at the time of surgery in patients with luminal A o B and triple negative (non-Her2/Erb 2 overexpressing and/or amplified) operable breast cancer randomized to standard neoadyuvant chemotherapy (NAC) based in antracyclines versus customized NAC according levels of BRCA1 and ERCC1 mRNA (measured by quantitative RT-PCR). |
| Evaluar y comparar la tasa de respuesta completa o pCR (conforme a las directrices NSABP) en el momento de la cirugía, en pacientes con cáncer de mama operable de tipo luminar A o B y triple negativo (sin sobre-expresión y/o amplificación de HER2/Erb2) randomizados y tratados alternativamente con quimioterapia neoadyuvante estándar con antraciclinas, en relación con una terapia individualizada conforme a los niveles de expresión de mRNA de ERCC1 y BRCA1 (medidos mediante RT-PCR cuantitativa). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the objective response rate (partial plus complete) among the two arms at definitive surgery.
To compare the percent of patients with node-negative disease at surgery among the two treatments arms.
To compare the rate of conversion to breast conserving surgery among the two treatments arms.
To compare the rate of conversion to breast surgery of patients with non-operable breast cancer among the two arms.
To compare disease free survival (DFS) and overall survival (OS).
To identify the molecular characteristics of responding tumors by inmunohistochemical, FISH genomic and proteomic analysis. |
Comparar la tasa de respuesta objetivo (parcial y completa) entre los dos brazos de tratamiento en la cirugía definitiva.
Comparar el porcentaje de pacientes con enfermedad nodo negativo en la cirugía entre los dos brazos de tratamiento.
Comparar la tasa de conversión a cirugía de conservación del seno, entre los dos brazos de tratamiento.
Comparar la tasa de conversión a cirugía de mama de los pacientes con cáncer de mama no operable, entre los dos brazos de tratamiento.
Comparar la supervivencia libre de enfermedad (DFS) y la supervivencia global.
Identificar las características moleculares de los tumores sensibles a la terapia, mediante análisis inmunohistoquímico, utilizando tecnologías de hibridación fluorescente in-situ (FISH) en genómica y proteómica. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Female gender
Age ? 18 years
Performance Status- ECOG: 0-1
Histologically confirmed invasive breast cancer
Primary tumor greater than 2 cm diameter
Any N (0-3)
No evidence of metastasis (M0), HER-2/ERBb2 negative.
Known hormone receptors status.
Haematopoietic status: Absolute neutrophil count ? 1.5 x 109/L; Platelet count ? 100 x 109/L; Hemoglobin at least 9 g/dl)
Hepatic status: Serum total bilirubin ? 1.5 x upper limit of normal (ULN), in the case of known Gilbert?s syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed;AST and ALT ? 2.5 times ULN; Alkaline phosphatase ? 2.5 times ULN)
Renal status: Creatinine ? 1.5 mg/dl or Cl CR > 60 ml/m
For women of childbearing potential Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization.
Signed informed consent form (ICF). |
Mujeres mayores de edad (? 18 años).
Carcinoma de mama invasivo confirmado histológicamente.
Tumor primario mayor de 2 cm de diámetro, con cualquier afectación ganglionar (N0-N3), sin evidencias de metástasis (M0) y HER-2/ERBb2 negativo.
Estado conocido de receptores hormonales.
Estado funcional ECOG de 0 a 1 (según la ECOG).
Estado hematopoyético: Neutrófilos totales ? 1.5 x 109/L; Plaquetas ? 100 x 109/L; Hemoglobina mínima 9 g/dl.
Función hepática: Bilirrubina sérica total ? 1.5 x límite superior normal (LSN), en caso de Síndrome e Gilbert confirmado, se permite un nivel mayor de bilirrubina (< 2 x LSN); AST y ALT ? 2.5 veces LSN; Fosfatasa alcalina ? 2.5 veces LSN.
Función renal: Creatinina ? 1.5 mg/dl; Aclaramiento de Creatinina > 60 ml/m. Para mujeres en edad fértil test de embarazo en suero negativo, realizado en las 2 semanas previas, preferentemente 7 días antes, a la randomización.
Aceptación del consentimiento informado. |
|
| E.4 | Principal exclusion criteria |
Received any prior treatment for primary invasive breast cancer.
Previous (less than 10 years) or current history of malignant neoplasms, except for curatively treated: Basal and squamous cell carcinoma of the skin;Carcinoma in situ of the cervix.
Diagnosis of inflammatory breast cancer.
Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction uncontrolled hypertension (? 180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen.
Left Ventricular Eyection Fraction of < 50% measured by echocardiography or MUGA.
Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject?s safety.
Unresolved or unstable, serious adverse events from prior administration of another investigational drug.
Active or uncontrolled infection.
Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF.
Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies).
Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial.
Known immediate or delayed hypersensitivity reaction, idiosyncrasy or contraindication to drugs chemically related to any of the study treatments or their excipients.
Pregnant or lactating women.
Refusal to use contraception throughout the study (surgical sterilization, barrier methods associated with spermicidal gels or total abstinence). Use of hormonal contraceptives is not allowed.
Patient unable to comply with study procedures. |
Pacientes que hayan sido tratados previamente para cáncer de mama invasivo primario.
Historia médica previa (menos de 10 años) o actual de neoplasias malignas, exceptuando cáncer de piel basocelular y escamocelular, o carcinoma in situ de cérvix uterino, cuando éstos hayan sido sometidos a tratamiento curativo.
Diagnóstico confirmado de cáncer de mama inflamatorio.
Historia médica conocida de angina sintomática no controlada, arritmias de relevancia clínica, insuficiencia cardiaca congestiva, infarto de miocardio transmural, hipertensión no controlada (? 180/110), diabetes mellitus inestable, disnea nocturna o terapia crónica con oxígeno.
Fracción de eyección del ventrículo izquierdo inferior al 50%, medida mediante ecocardiografía o Ventriculografía isotópica (MUGA).
Enfermedades concurrentes o afecciones que puedan hacer inapropiada la participación del sujeto, o desórdenes médicos graves que puedan interferir con la seguridad del paciente.
Efectos adversos graves no resueltos ocurridos como consecuencia de la administración previa de otros medicamentos en investigación.
Infección activa o no controlada.
Demencia o estados mentales alterados, o cualquier otra condición psiquiátrica que dificulte la comprensión y firma del documento de consentimiento informado.
Terapia antineoplásica neoadyuvante concurrente (quimioterapia, radioterapia, inmunoterapia, terapia biológica u otras terapias anticancerosas diferentes al régimen terapéutico en estudio).
Tratamiento concurrente con otro MI o participación simultánea en otro ensayo clínico terapéutico.
Reacciones de hipersensibilidad inmediata o retardada conocidas, idiosincrasias o contraindicaciones a medicamentos químicamente relacionados a cualquiera de los fármacos en estudio o sus excipientes.
ujeres embarazadas o en periodo de lactancia.
Negativa al uso de métodos anticonceptivos durante todo el estudio (esterilización quirúrgica, métodos de barrera asociados a geles espermicidas o abstinencia total). No se permite el uso de anticonceptivos hormonales orales, inyectables o implantes.
Paciente incapaz de cumplir con los requisitos del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pathological Complete Response (pCR) is the primary endpoint.
Surgical breast and axillary node resection specimens will be evaluated for pathologic tumour response according to NSABP guidelines. Patients will be considered in pCR if there is no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. |
La Respuesta patológica completa (pCR) es la variable principal.
Respuesta patológica completa (pCR) del tumor, que se evaluará conforme a las directrices NSABP, a partir de muestras de la resección quirúrgica de los ganglios axilares. Los pacientes se considerarán pCR si no hay evidencias de carcinoma infiltrante, o solo hay carcinoma in situ en la pieza resecada. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumour pCR will be assessed at baseline and after definitive surgery. |
| La pCR del tumor será evaluada al inicio, y después de la cirugía definitiva. |
|
| E.5.2 | Secondary end point(s) |
Feasibility and type of surgery as indicated by surgeon prior to study treatment. It will be recorded for each patient enrolled at baseline as well as after neoadjuvant treatment period.
Percentage of patients with negative axillary nodes at the time of definitive surgery, in both treatment arms.
Complete and partial tumor response at the time of surgery. Tumoral response will be assessed by clinical examination and by breast tumor imaging with mammography, ultrasound or MRI, according to the facilities at each site.Overall response (OR) will be assessed using the WHO criteria.
Disease free survival (DFS), defined as the time from definitive surgery until disease recurrence.
Overall survival (OS), defined as the time from completion of surgery to death from any cause.
Identification of molecular characteristics of tumors that are sensitive to therapy, using immunohistochemical analysis of tumor samples (biopsies and resection), as well as in-situ fluorescent hybridization techniques (FISH) in genomics and proteomics. |
Factibilidad y tipo de cirugía, según lo indicado por el cirujano. Ésta se registrará para cada paciente antes de iniciar el tratamiento del estudio, y una vez finalizado.
Respuesta tumoral completa y parcial en el momento de realizar la cirugía. La respuesta tumoral será evaluada mediante examen clínico e imagen del tumor de mama mediante mamografía, ultrasonografía o MRI, según las facilidades en cada centro. La respuesta global será evaluada mediante los criterios de la OMS.
Porcentaje de pacientes con ganglios axilares negativos en la cirugía, en ambos brazos de tratamiento.
Tasa de supervivencia libre de la enfermedad, definida desde la cirugía definitiva hasta la recurrencia de la enfermedad.
Supervivencia global, definida como el tiempo desde la finalización de la cirugía hasta la muerte por cualquier causa.
Características moleculares de los tumores sensibles a la terapia, analizadas mediante análisis inmunohistoquímico de las muestras de tumor (biopsias y resección), utilizando tecnologías de hibridación fluorescente in-situ (FISH) en genómica y proteómica. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Each secondary endpoint will be evaluated according to the timepoints set out in the protocol. |
| Cada variable secundaria será evaluada según el esquema temporal previsto en el protocolo. |
|
| 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 | 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 | 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) | 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 | 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 | 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 | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
| LVLS |
| Ultima 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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