E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult female patients with HER2 negative breast cancer which is found to be inoperable locally advanced or metastatic disease |
Mujeres adultas con cáncer de mama HER2 negativo, que se considere enfermedad metastásica o localmente avanzada inoperable |
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E.1.1.1 | Medical condition in easily understood language |
Inoperable locally advanced breast cancer, Metastatic Breast Cancer (MBC) |
Cáncer de mama metastásico o localmente avanzado inoperable |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Phase Ib: to determine the MTD of BEZ235 in combination with paclitaxel
Phase II: to estimate the treatment effect of BEZ235/paclitaxel combination therapy versus paclitaxel alone |
Fase Ib: Determinar la MDT de la terapia de combinación de BEZ235 con paclitaxel.
Fase II: Calcular el efecto del tratamiento de la terapia de combinación de BEZ235/paclitaxel frente a paclitaxel en monoterapia. |
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E.2.2 | Secondary objectives of the trial |
Phase Ib: - to evaluate the safety of BEZ235 in combination with paclitaxel - to assess the preliminary efficacy of the study treatment
Phase II: - to estimate the treatment effect of BEZ235/paclitaxel combination therapy versus paclitaxel alone - to estimate/compare the effect of study treatment - to evaluate the safety and tolerability of the study treatment |
Fase Ib: - Evaluar la seguridad y la tolerabilidad de la terapia de combinación de BEZ235/paclitaxel - Evaluar la actividad de la terapia de combinación de BEZ235/paclitaxel.
Fase II: - Calcular el efecto del tratamiento de la terapia de combinación de BEZ235/paclitaxel frente a paclitaxel en monoterapia según el estado de activación de PI3K. - Calcular/ comparar el efecto del tratamiento de la terapia. - Evaluar la seguridad y la tolerabilidad de la terapia de combinación de BEZ235/paclitaxel frente a paclitaxel en monoterapia. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria applicable to Phase Ib and II: ? Patient is a female ? 18 years of age. ? Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer. ? Patient has radiological evidence of inoperable locally advanced or metastatic breast cancer. ? Patient has HER2 negative disease. ? Patient has adequate bone marrow and organ function.
Additional criteria for Phase II: ? Patient has a known PI3K status (activated or wildtype) based on results from a Novartis designated laboratory prior to start of treatment. ? Patient has recent radiological documentation of recurrent disease or newly diagnosed disease. ? Patient has at least one measurable lesion as per RECIST 1.1. |
Criterios de inclusión principales aplicables para la fase Ib y fase II ? Pacientes mujeres con ? 18 años de edad. ? La paciente deberá presentar diagnóstico citológicamente y/o histológicamente confirmado de cáncer de mama ? La paciente deberá presentar evidencia radiológica de cáncer de mama metastásico o localmente avanzado inoperable. ? La paciente deberá presentar enfermedad HER2 negativa. ? La paciente deberá presentar función orgánica y de la médula ósea adecuada.
Criterios de inclusión principales adicionales aplicables a la fase II ? Paciente con un estado de PI3K conocido (activado o wildtype) basado en los resultados de un laboratorio designado de Novartis antes de iniciar el tratamiento. ? Paciente con documentación radiológica reciente de enfermedad recurrente o de enfermedad recién diagnosticada. ? Pacientes con por lo menos una lesión medible según los RECIST 1.1 |
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E.4 | Principal exclusion criteria |
Exclusion criteria applicable for Phase Ib and II: ? Patient has received previous treatment with PI3K and/or mTOR pathway inhibitors. ? Patient has active uncontrolled or symptomatic central nervous system (CNS) metastases. ? Patient has received wide field radiotherapy or irradiation of ? 25% of the bone marrow ? 28 days or limited field radiation for palliation ? 14 days prior to starting study drug or has not recovered from side effects of such therapy. ? Patient has active cardiac disease or a history of cardiac dysfunction. ? Patient has a family history of congenital long or short QT, or known history of QT/QTc prolongation or Torsades de Pointes (TdP). ? Patient has inadequately controlled hypertension (i.e., SBP>180 mmHg or DBP>100mmHg). ? Patient has uncontrolled diabetes mellitus. ? Patient has impairment of GI function or GI disease that may significantly alter the absorption of BEZ235 and/ or paclitaxel.
Additional exclusion criterion for Phase II: ? Patient has received any prior chemotherapies for the inoperable locally advanced or metastatic disease.
Other protocol-defined inclusion/exclusion criteria may apply. |
Criterios de exclusión principales aplicables a la fase Ib y a la fase II ? Pacientes que hayan recibido tratamiento previo con inhibidores de la vía de señalización PI3K y/o mTOR. ? Pacientes con metástasis del sistema nervioso central (SNC) sintomáticas o incontroladas activas. ? Pacientes que hayan recibido radioterapia de campo extenso o irradiación de ? 25% de la médula ósea ? 28 días o radiación de campo limitado con carácter paliativo ? 14 días antes del inicio de la medicación del estudio o que no se hayan recuperado de los efectos secundarios de dicha terapia. ? Pacientes con enfermedad cardíaca activa o antecedentes de disfunción cardíaca. ? Pacientes con antecedentes familiares de QT corto o prolongado congénito, o antecedentes conocidos de prolongación del QT/QTc o de Torsades de Pointes (TdP). ? Pacientes con hipertensión insuficientemente controlada (es decir, PAS > 180 mmHg o PAD > 100 mmHg). ? Pacientes con diabetes mellitus incontrolada. ? Pacientes con deterioro de la función GI o enfermedad GI que pueda alterar significativamente la absorción de BEZ235 y/o paclitaxel.
Criterios de exclusión principales adicionales para la fase II ? Pacientes que hayan recibido cualquier quimioterapia previa para la enfermedad metastásica o localmente avanzada inoperable. Otros criterios de inclusión/exclusión definidos por protocolo pueden aplicarse. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase Ib: DLTs (the first cycle) at each dose level
Phase II: progression free survival according to local radiological assessment |
Fase I: Incidencia de TLDs en el primer ciclo, en cada nivel de dosis.
Fase II: Supervivencia libre de progresión (SLP) según la evaluación radiológica local. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: after ~1 month treatment
Phase II: throughout the study |
Fase Ib: Después de ~1 mes de tratamiento.
Fase II: Durante todo el estudio. |
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E.5.2 | Secondary end point(s) |
Phase Ib: - frequency and severity of Adverse Events, abnormal laboratory values, other safety data as appropriate - Progression Free Survival (PFS), Overall Response Rate (ORR), Clinical Benefit Rate
Phase II: - Progression free survival in PI3K subgroups according to local radiological assessment - Progression free survival (PFS) according to independent central radiological assessment, Clinical Benefit Rate, Time to Response, Duration of Response, Median Overall Survival, Overall Response Rate - frequency and severity of Adverse Events, abnormal laboratory values, other safety data as appropriate |
Fase Ib: - Frecuencia y severidad de acontecimientos adversos y otros datos de seguridad, cuando se considere apropiado. - Supervivencia libre de progresión (SLP), tasa de respuesta global (TRG), tasa de beneficio clínico.
Fase II: - SLP en los subgrupos de Pi3K según la evaluación radiológica local. - SLP según la evaluación radiológica central independiente ? Tasa de beneficio clínico ? Tiempo hasta la respuesta ? Duración de la respuesta ? Supervivencia global media ? Tasa de respuesta global ? Frecuencia y severidad de acontecimientos adversos y otros datos de seguridad, cuando se considere apropiado |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: - 30-35 days after treatment discontinuation - throughout the study
Phase II: - throughout the study - throughout the study - 30-35 days after treatment discontinuation |
Fase Ib: - 30-35 días después de la interrupción del tratamiento. - Durante todo el estudio.
Fase II: - Durante todo el estudio. - Durante todo el estudio. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
dose escalation in combination with paclitaxel |
escalado de dosis en combinación con Paclitaxel |
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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 | 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
Belgium |
Brazil |
France |
Germany |
Hong Kong |
Italy |
Korea, Republic of |
Russian Federation |
Singapore |
Spain |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
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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
|
Phase Ib will end when all patients have discontinued treatment or at least 1 year after the last patient was included in phase Ib of the study. Phase II of the study will end when all patients have discontinued treatment or at least 1 year after the last patient was included in phase II of the study. The study will be considered as closed when the phase Ib as well as the phase II parts have ended. |
La Fase Ib finalizará cuando todos los pacientes discontinúen el tratamiento o al menos 1 año después de que fuese incluido último paciente en la fase Ib del estudio. La fase II del estudio finalizará cuando todos los pacientes discontinuén el tratamiento o al menos 1 año después de que fuese incluido último paciente en la fase II del estudio. El estudio será considerado como cerrado cuando la fase Ib así como la fase II se hayan terminado. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |