| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive advanced breast cancer |
| Cáncer de mama avanzado HER2 positivo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced breast cancer that is distinguished from other breast cancer types by stage and the presence of molecules that respond to certain treatments |
| Cáncer de mama avanzado que se diferencia de otros tipos de cáncer de mama por el estadío y presencia de moléculas que responden a ciertos tratamientos. |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Safety run-in Part 1:
To confirm the recommended dose of alpelisib in combination with trastuzumab and pertuzumab for Part 2
Double-blind, randomized, placebo-controlled Part 2:
To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs PFS compared to placebo in combination with trastuzumab and pertuzumab in adult patients with HER2-positive advanced breast cancer with a PIK3CA mutation |
Parte 1 de preinclusión de seguridad:
Confirmar la dosis recomendada de alpelisib en combinación con trastuzumab y pertuzumab para la parte 2
Parte 2 aleatorizada, con doble ciego y controlada con placebo:
Determinar si el tratamiento con alpelisib combinado con trastuzumab y pertuzumab prolonga la PFS en comparación con placebo combinado con trastuzumab y pertuzumab en pacientes adultos con cáncer de mama avanzado HER2 positivo con una mutación de PIK3CA |
|
| E.2.2 | Secondary objectives of the trial |
Safety run-in Part 1:
- To determine the safety and tolerability of alpelisib in combination with trastuzumab and pertuzumab
- To characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Double-blind, randomized, placebo-controlled Part 2:
- To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs OS in adult patients with HER2-positive advanced breast cancer with a PIK3CA mutation
- To assess safety and tolerability
- To assess additional efficacy parameters
- To characterize exposure of alpelisib in combination with trastuzumab and pertuzumab
- To evaluate PROs of alpelisib in combination with trastuzumab and pertuzumab
- To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib
- To evaluate alpelisib in combination with trastuzumab and pertuzumab with respect to time to deterioration of ECOG performance status |
Parte 1 de preinclusión de seguridad
- Determinar la seguridad y tolerabilidad de alpelisib en combinación con trastuzumab y pertuzumab.
- Caracterizar la exposición de alpelisib cuando se administre en combinación con trastuzumab y pertuzumab.
Parte 2 aleatorizada con doble ciego y controlada con placebo:
- Determinar si el tratamiento con alpelisib combinado con trastuzumab y pertuzumab prolonga la OS en pacientes adultos con cáncer de mama avanzado HER2 positivo con una mutación de PIK3CA.
- Evaluar la seguridad y la tolerabilidad.
- Evaluar parámetros adicionales de eficacia.
- Caracterizar la exposición de alpelisib en combinación con trastuzumab y pertuzumab.
- Evaluar los resultados comunicados por el paciente de alpelisib combinado con trastuzumab y pertuzumab
- Evaluar la asociación entre el estado de mutación de PIK3CA medido en ADNtc en la basal y la PFS después del tratamiento con alpelisib.
Falta de espacio. Para más información, referir al Protocolo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subject has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally not amenable to surgery t or metastatic).
- Subject has received pre-study induction therapy with up to and including 6 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. A minimum of 4 cycles of taxane is permitted if discontinuation was due to toxicity
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Subject has adequate bone marrow and organ function
- Applies only to Part 2: Subject has a PIK3CA mutation(s) present in tumor tissue prior to enrollment, as determined by a Novartis designated central laboratory. |
Sujetos con cáncer de mama HER2 positivo histológicamente confirmado en estadio avanzado (locorregionalmente no susceptible de cirugía o metastásico).
- Sujetos que hayan recibido terapia de inducción previa al estudio con un máximo de 6 ciclos (incluidos) de un taxano (docetaxel, paclitaxel o nab-paclitaxel) más trastuzumab y pertuzumab. Está permitido un mínimo de 4 ciclos de taxano si la discontinuación se ha debido a toxicidad.
- Sujetos con un estado funcional del ECOG de 0 o 1.
- Sujetos con una función adecuada de la médula ósea y los órganos.
- Solo aplica a la parte 2: Sujetos con una o varias mutaciones de PIK3CA presentes en el tejido tumoral antes de su inclusión, según un laboratorio central designado por Novartis. |
|
| E.4 | Principal exclusion criteria |
- Subject with inflammatory breast cancer at screening.
- Subject with evidence of disease progression during the pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2)
- Subject with an established diagnosis of diabetes mellitus type I or not controlled type II based on FPG and HbA1c (see inclusion criteria 7).
- Subject has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
- Subject has clinically significant, uncontrolled heart disease and/or recent cardiac events
- Subject has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN).
- Subject has currently documented pneumonitis/interstitial lung disease |
- Sujetos con cáncer inflamatorio de mama en la selección.
- Sujetos con signos de progresión de la enfermedad durante la terapia de inducción previa al estudio y antes de la primera dosis de alpelisib (o alpelisib/placebo de alpelisib en la parte 2).
- Sujetos con un diagnóstico establecido de diabetes mellitus tipo I o tipo II no controlada basándose en glucosa plasmática en ayunas (GPA) y HbA1c (véase el criterio de inclusión n.º 7).
- Sujetos con antecedentes de pancreatitis aguda en el plazo de 1 año antes de la selección o antecedentes de pancreatitis crónica.
- Sujetos con una enfermedad cardíaca no controlada, clínicamente significativa o acontecimientos cardíacos
- Sujetos con antecedentes de síndrome de Steven-Johnson (SJS), eritema multiforme (EM), necrólisis epidérmica tóxica (NET) o reacción a fármaco con eosinofilia y síndrome sistémico (DRESS).
- Sujetos con neumonitis/enfermedad pulmonar intersticial actualmente documentada. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Safety-run in
- Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab
Part 2: Double-blind, randomized, placebo-controlled
- PFS based on local investigator assessment and using RECIST 1.1 criteria, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause |
Parte 1: Pre-Inclusión de seguridad
- Incidencia de DLTs durante las primeras 6 semanas de tratamiento para cada nivel de dosis asociados a la administración de alpelisib en combinación con trastuzumab y pertuzumab
Parte 2 aleatorizada, con doble ciego y controlada con placebo
- PFS basado en la evaluación del investigador local mediante criterios RECIST 1.1, definido como el tiempo desde la randomización hasta la primera evidencia documentada de progresión o muerte por cualquier motivo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: 6 weeks
Part 2: up to approximately 38 months |
Parte 1: 6 semanas
Parte 2: hasta aproximadamente 38 meses |
|
| E.5.2 | Secondary end point(s) |
Part 1:
- Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria including changes in laboratory values, vital signs, liver assessments and cardiac assessments
- Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components
- Summary statistics of alpelisib concentrations by timepoint and dose level
Part 2:
- OS, as defined as the time from date of randomization to date of death due to any cause |
Parte 1:
- Seguridad: Incidencia, tipo y severidad de los efectos adversos según criterios CTCAE versión 4.03 incluyendo cambios en valores de laboratorio, constantes vitales, evaluaciones hepáticas y cardíacas.
- Tolerabilidad: interrupciones de dosis, intensidad de la dosis y duración de la exposición para todos los componentes del fármaco.
- Resumen estadístico de las concentraciones de alpelisib por tiempo y nivel de dosis.
Parte 2:
- Supervivencia global, definida como el tiempo desde la randomización hasta la fecha de la muerte por cualquier motivo. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: up to approximately 38 months
Part 2: up to approximately 70 months |
Parte 1: hasta aproximadamente 38 meses
Parte 2: hasta aproximadamente 70 meses |
|
| 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 | Yes |
| 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 | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 146 |
| 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 |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Colombia |
| Czech Republic |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Lebanon |
| Malaysia |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| 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
|
| Study completion is defined as when the last subject finishes their safety and efficacy follow-up periods (as applicable) and any repeat assessments associated with these visits have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
| La finalización del estudio se define desde cuando el último sujeto finalice su periodo de seguimiento de eficacia y seguridad (si aplica) y cualquier repetición de las evaluaciones asociadas con estas visitas se haya documentado y supervisado adecuadamente por el investigador o, en el caso de la decisión de una terminación prematura del estudio, la fecha de la decisión. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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