E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
WOMEN WITH ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE BREAST CANCER |
Mujeres con cancer de mama en estadio inicial con RE positivos y Her2 negativo |
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E.1.1.1 | Medical condition in easily understood language |
Early Breast cancer |
cancer de mama precoz |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070575 |
E.1.2 | Term | Estrogen receptor positive breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as measured by the following co-primary endpoints: -Tumor overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors (RECIST) in all enrolled patients and PIK3CA MT patients -pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled patients and PIK3CA MT patients |
El objetivo principal de este estudio es evaluar la eficacia de letrozol más GDC-0032 versus letrozol más placebo en mujeres con RE+/Her2- en cancer de mama en estadio precoz, determinado por los siguientes criterios coprincipales de valoración: -Tasa de respuesta objetiva global tumoral (TRO) mediante resonancia magnética (RM) de mama evaluada de forma central con los Criterios modificados de evaluación de la respuesta en tumores sólidos (RECIST) en todas las pacientes incluidas y en las pacientes con mutación (MT) del gen PIK3CA. - Tasa de respuesta patológica completa (RPC) en la mama y en la axila (ypT0/Tis ypN0) según evaluación local en todas las pacientes incluidas y en las pacientes con MT del gen PIK3CA. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives of this study are the following: -Tumor ORR, assessed by centrally assessed breast MRI via modified Response Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients -pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA WT patients |
Los objetivos secundarios de eficacia de este estudio son los siguientes: - Tasa de respuesta objetiva tumoral (TRO) evaluada mediante resonancia magnética (RM) de mama evaluada de forma central con los Criterios modificados de evaluación de la respuesta en tumores sólidos (RECIST) en las pacientes con PIK3CA de tipo salvaje (WT, wild type) -Tasa de RPC en la mama y en la axila (RPC ypT0/Tis ypN0 total) mediante evaluación local en las pacientes con PIK3CA de WT |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Histologically confirmed invasive breast carcinoma, with all of the following characteristics: - Primary tumor >= 2 cm in largest diameter (cT1-3) by MRI. In the case of a multifocal tumor (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be >= 2 cm and designated as the ?target? lesion for all subsequent tumor evaluations. - Stage I to operable Stage III breast cancer - Documentation confirming the absence of distant metastasis (M0) as determined by institutional practice (in patients where there may be a reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms). - ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition - Breast cancer eligible for primary surgery - Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable for PIK3CA mutation status by central histopathology laboratory - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Fasting glucose <=125 mg/dL - Adequate hematological, renal, and hepatic function, as follows: - Absolute neutrophil count >= 1500/?L - Platelets count >=100,000/?L |
- Carcinoma de mama invasivo confirmado histológicamente, con todas las características siguientes: - Tumor primario >= 2 cm de diámetro mayor (cT1-3) mediante una RM. En caso de un tumor multifocal (definido como la presencia de dos o más focos de cáncer en el mismo cuadrante de la mama), la lesión mayor debe ser >= 2 cm y se considerará la lesión objetivo para todas las evaluaciones tumorales posteriores. - Cáncer de mama en estadio I a estadio III operable - Documentación que confirme la ausencia de metástasis a distancia (M0), determinada según la práctica del centro (en pacientes en las que exista una sospecha razonable de enfermedad avanzada, p. ej., tumores grandes, ganglios linfáticos axilares positivos clínicamente, signos y síntomas). - Cáncer de mama positivo para ER y HER2-negativo, según el laboratorio local o la definición regional. - Cáncer de mama apto para cirugía primaria. - El tejido tumoral de una muestra FFIP obtenida mediante biopsia del tumor de mama primario debe estar confirmado como evaluable para el estado de mutación de PIK3CA mediante el laboratorio histopatológico central -Función hematológica,renal y hepática adecuada, según lo siguiente: - Recuento absoluto de neutrófilos >=1500/?l ? Cifra de plaquetas >= 100000/?l |
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E.4 | Principal exclusion criteria |
-Any prior treatment for primary invasive breast cancer -Patients with cT4 or cN3 stage breast tumors -Metastatic (Stage IV) breast cancer -Bilateral invasive breast cancer -Multicentric breast cancer (the presence of more than one tumor in different quadrants of the breast) -Patients who have undergone excisional biopsy of primary tumor and/or axillary lymph nodes. - Patients for whom upfront chemotherapy is clinically judged appropriate as optimal neoadjuvant treatment - Patients for whom immediate surgery is indicated. -Patients who have undergone sentinel lymph node biopsy prior to study treatment -Type 1 or 2 diabetes requiring antihyperglycemic medication -Inability or unwillingness to swallow pills -Malabsorption syndrome or other condition that would interfere with enteric absorption. - DLCO <60% of the predicted values (see Appendix 7 for calculations) |
-Cualquier tratamiento previo para cáncer de mama invasivo primario. - Pacientes con tumores de mama en estadio cT4 o cN3. - Cáncer de mama metastásico (estadio IV). - Cáncer de mama invasivo bilateral. - Cáncer de mama multicéntrico (presencia de más de un tumor en diferentes cuadrantes de la misma mama). - Pacientes en las que se haya realizado una biopsia escisional del tumor primario y/o de los ganglios linfáticos axilares. - Pacientes en las que se haya realizado una biopsia del ganglio linfático centinela antes del tratamiento del estudio. - Pacientes que requieran quimioterapia neoadyuvante según criterio clínico, como tratamiento neoadyuvante óptimo. - Pacientes que requieran una intervención quirúrgica inmediata. - Diabetes de tipo 1 o 2 que requiere medicación antihiperglucemiante. - Incapacidad o falta de disposición para tragar los comprimidos. - Síndrome de malabsorción u otras enfermedades que pudieran interferir en la absorción intestinal. - Valores de DLCO <60% de los previstos (véase el anexo 7 para los cálculos) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-primary endpoints: 1) Tumor ORR, assessed by modified RECIST criteria by breast MRI in all enrolled patients and PIK3CA MT patients 2) Rate of pCR in breast and axilla (total pCR) after completion of study drug in all enrolled patients and PIK3CA MT patients |
criterios coprincipales de valoración: - TRO del tumor mediante RM de la mama evaluada centralmente con los criterios RECIST modificados en todas las pacientes incluidas y en las pacientes con MT de PIK3CA. - Tasa de RPC en la mama y en la axila (RPC total), mediante tras completar el tratamiento de estudio en todas las pacientes incluidas y en las pacientes con MT de PIK3CA. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Tumor ORR evaluated prior to initiating study treatment (baseline) and after completion of study treatment (16 weeks) 2) pCR evaluated after completion of study treatment (16 weeks) |
1-TRO del tumor evaluado con antelación al inicio del tratamiento de estudio (Basal) y tras completar el mismo (16 semanas) 2- Tasa de RPC evaluada tras completar el tratamiento de estudio (16 semanas) |
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E.5.2 | Secondary end point(s) |
1) Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by breast MRI in PIK3CA WT patients 2) Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT patients The following will be performed in all enrolled patients and separated by PIK3CA mutation status: 3) ORR by clinical breast examination, mammography and breast ultrasound 4) Ki67 values at baseline, Week 3, and surgery 5) Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery 6) PEPI score 7) Change in enhancing tumor volume from baseline to surgery as measured by breast MRI 8) Evaluation of different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, ypNX (breast pCR). |
1- TRO del tumor tras completar el tratamiento de estudio, evaluada con los criterios RECIST modificados mediante RM de la mama en pacientes con PIK3CA WT 2-Tasa de RPC en mama y axila (RPC total) tras completar el tratamiento de estudio en pacientes con PIK3CA WT Los siguientes se evaluarán en todas las pacientes incluidas y por separado según el estado de mutación de PIK3CA: 3- TRO mediante examen clínico de la mama, mamografía y ecografía mamaria 4- niveles de Ki67 a nivel basal, semana 3 y momento de cirugia 5- Cambios en Ki67desde basal a semana 3, de basal a cirugia y de semana 3 a cirugia 6- Indice PEPI 7- cambios en el volumen tumoral desde el periodo basal hasta el momento de la cirugía determinados mediante RM de la mama. 8- Evaluar las diferentes definiciones de RPC, incluidas las siguientes: a) ypT0, ypN0 y b) yoT0/is, ypNX (RPC en la mama). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For secondary endpoints involving ORR and change in enhancing tumor volume, timepoints are prior to initiating study treatment and after completion of study treatment (16 weeks). For pCR and PEPI score, timepoint is completion of study treatment (16 weeks). For Ki67 analyses, timepoints are as listed with surgery occurring within 1 week of completion of the study treatment (16 weeks). |
Para los criterios secundarios de valoración correspondientes a TRO y cambios en el volumen tumoral, los tiempos son previos al inicio del tratamiento de estudio y tras completar el mismo (16 semanas ). Para analisis de Ki67, los tiempos vendrán dados cuando tenga lugar la cirugia dentro de 1 semana de plazo tras completar el tratamiento de estudio (16 semanas) |
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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 | Yes |
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 | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | 17 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 |
Australia |
Austria |
Belgium |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Poland |
Portugal |
Russian Federation |
Spain |
Switzerland |
Ukraine |
United Kingdom |
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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The end of the study is defined as the date when the last patient has her postsurgery visit. The total duration of the study is expected to be approximately 24 months for enrollment, plus 5.5 months after last patient in. |
El fin de estudio se define como la fecha de la visita postcirugia del último paciente. La duración total del estudio se prevee sea de aproximadamente de 24 meses para el reclutamiento, más 5,5 meses tras el ultimo paciente incluido. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 15 |