E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with Ph+ chronic phase CML that have been treated with Imatinib for at least 2 years, are in CCyR, but have not achieved MR4.0 at study entry. |
Los pacientes elegibles son adultos con un diagnóstico confirmado de LMC en fase crónica, Ph+ y/o BCR-ABL+ que hayan sido tratados con imatinib de primera línea durante 2 años de calendario o más y presenten RCC. Los pacientes no deberán haber alcanzado ?RM4.0 al inicio del estudio, evaluado por un laboratorio local. |
|
E.1.1.1 | Medical condition in easily understood language |
Adult patients with CML who have been treated with imatinib (Glivec) for at least two years and who have not achieved a certain level of molecular response at study entry. |
Pacientes adultos con Leucemia Mieloide Crónica que han sido tratados con imatinib (Glivec)durante al menos dos años y que no han alcanzado un cierto nivel de respuesta molecular al inicio del estudio |
|
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 | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054352 |
E.1.2 | Term | Chronic phase chronic myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the optimal duration of consolidation treatment with nilotinib 300 mg BID in order that patients remain in treatment free remission (?MR4.0) without molecular relapse 12 months after cessation of nilotinib. |
Evaluar la duración optima del tratamiento de consolidación con 300 mg de nilotinib BID para aquellos pacientes que continúen en remisión libre de tratamiento (?RM4.0) sin recaída molecular, 12 meses después de entrar en la fase de RLT. |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate the proportion of patients who are eligible to suspend nilotinib therapy by achieving and maintaining a sustained ?MR4.0 for at least 12 months during consolidation treatment with nilotinib 300 mg BID. - To assess the kinetics of the molecular response in patients during induction/consolidation treatment with nilotinib 300 mg BID. - To assess the kinetics of the molecular response in patients during the TFR phase of the study in the two treatment arms. - To assess the progression-free survival (PFS) rate during the TFR phase of the study in the two treatment arms. - To assess treatment-free survival (TFS) during the TFR phase of the study in the two treatment arms. - To assess the overall survival (OS) rate during the TFR phase of the study in the two treatment arms. - To assess the safety profile of nilotinib during the induction/consolidation treatment phase, the TFR phase, and during the treatment re-initiation phase. |
?Evaluar el porcentaje de pacientes que sean elegibles para suspender la terapia con nilotinib alcanzando y manteniendo la ?RM4.0 prolongada durante los últimos 12 meses durante el tratam.de consolidación con 300mg BID de nilotinib ?Evaluar la cinética de la resp.molecular de los pacientes durante el tratam.de inducción/consolidación con 300mg BID de nilotinib ?Evaluar la cinética de la resp.molecular en pacientes durante la fase de remisión libre de tratamiento(RLT) con 300mg BID de nilotinib ?Evaluar la cinética de la resp.molecular en pacientes durante la fase de remisión libre de tratamiento(RLT) en ambos brazos ?Evaluar la tasa de supervivencia libre de progresión (SLP)durante la fase de RLT del estudio en ambos brazos. ?Evaluar la tasa de supervivencia libre de tratamiento(SLT) durante la fase de RLT del estudio en ambos brazos ?Calcular la tasa de supervivencia global (SG) durante la fase de RLT del estudio en ambos brazos. ?Evaluar el perfil de seguridad de nilotinib. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
?Confirmed diagnosis of chronic phase Ph+ CML ?Previous first-line treatment with imatinib for a minimum of 2 years; ?Patient in complete cytogenetic response;
Additional inclusion criteria as per protocol apply. |
?Pacientes hombres o mujeres, con edad ? 18 años ?Estado funcional del ECOG de 0-2; ?Diagnóstico confirmado de LMC BCR-ABL+ y/o Ph+ en fase crónica ?Tratamiento previo de primera línea con imatinib durante un mínimo de 2 años ?Evidencia de tránscritos BCR-ABL típicos que sean susceptibles a PCR-RQ estandarizada ?Paciente en RCC |
|
E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
?Previous achievement of MR4.0 at study entry; ?Previous treatment with other target cells inhibitors other than imatinib; ?Patients with any history of detectable atypical Leukemia transcripts or patients with detectable atypical leukemia transcripts at screening; ?Previous anticancer agents for Chronic myeloid leukemia other than imatinib except for cytoreduction; ?Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol; ?History of other active malignancies within the 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively; ?Patients who have not recovered from prior surgery; ?Treatment with other investigational agents within 4 weeks of Day 1; ?Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
Additional exclusion criteria as per protocol apply. |
?Que hayan alcanzado ?RM4.0 en el inicio del estudio; ?Tratamiento previo con inhibidores de BCR-ABL que no sean imatinib ?Pacientes con cualquier antecedente de tránscritos BCR-ABL atípicos detectables o pacientes con tránscritos BCR-ABL atípicos detectables en la selección; ?Agentes antineoplásicos previos para LMC (incluyendo interferón) que no sea imatinib, excepto para citorreducción después del diagnóstico de LMC ?Segunda fase crónica conocida de LMC después de progresión previa a FA/CB ?Diabetes mellitus insuficientemente controlada (definida como HbA1c > 8%) ?Deterioro de la función cardíaca; ?Enfermedad clínica concurrente incontrolada y/o severa que, a criterio del investigador, pudiese causar riesgos de seguridad inaceptables o comprometer el cumplimiento con el protocolo; ?Antecedentes de pancreatitis aguda dentro de los 12 meses de entrar en el estudio o antecedentes clínicos previos de pancreatitis crónica; ?Presencia conocida de una alteración hemorrágica adquirida o congénita significativa no relacionada con el cáncer; ?Antecedentes de otra enfermedad maligna activa dentro de los 5 años antes de entrar en el estudio con la excepción de cáncer cutáneo de células basales concomitante o previo y carcinoma previo in situ tratado curativamente; ?Pacientes que no se han recuperado de la cirugía previa; ?Tratamiento con otro agente en investigación dentro de las 4 semanas de la visita de selección; ?Pacientes que reciban terapia activamente con inhibidores y/o inductores potentes de CYP3A4 o medicaciones con potencial para prolongar el intervalo QT que no puedan ser suspendidos o cambiados por una medicación distinta antes de iniciar la medicación del estudio; ?Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de la medicación del estudio; |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the number of patients who remain in treatment free remission (?MR4.0) ,without molecular relapse, at the end of 12 months in the TFR phase of the study, in the nilotinib 12 months consolidation treatment arm (arm 1) versus the nilotinib 24 months consolidation treatment arm (arm 2). |
El número de pacientes que continúen en remisión libre de tratamiento (?RM4.0), sin recaída molecular, al final de los 12 meses de la fase de RLT del estudio, en el grupo de tratamiento de consolidación de 12 meses con nilotinib frente al brazo de tratamiento de consolidación de 24 meses con nilotinib. La recaída molecular durante la RLT se define como la pérdida de RMM o la pérdida confirmada de RM4.0 (definida con 3 análisis consecutivos inferiores a RM4.0 evaluado en 3 visitas consecutivas según el calendario de visitas de la fase de RLT) (véase Apartado 10.4.1). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months after treatment cessation |
12 meses después de la interrupción del tratamiento. |
|
E.5.2 | Secondary end point(s) |
- The proportion of patients who have achieved a sustained ?MR4.0 (defined as having 4 out of 5 quarterly assessments of ?MR4.0 by a EUTOS standardized laboratory over the last 12 months and the last assessment before randomization is at least MR4.0) during the consolidation treatment phase of the study. - The proportion of patients who achieve MR4.0 or MR4.5 on the study at selected time points during the induction/consolidation phase of the study. - The proportion of patients who maintain in MR4.0 or MR4.5 on the study at selected time points during the TFR phase in each one of the two treatment arms - PFS defined as progression to AP/BP or death, where the "failure" event is the earliest occurrence of either of these events; Kaplan-Meier (KM) estimation of PFS is measured from the date of start of the nilotinib TFR phase to the date of the earliest failure event. Patients not known to have recurred or died on or before the cut-off date for the KM analysis will have their PFS interval censored at the earlier of the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who are still on study, and at the date of last contact for patients who are in follow-up. - TFS is defined as lack of any of the following events: loss of MMR, confirmed loss of MR4.0, re-start of nilotinib treatment, progression to AP/BP, or death from any cause;KM estimation of TFS, which is measured from the date of the start of the nilotinib TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4.0, re-start of nilotinib treatment, progression to AP/BP, or death from any cause. - Overall survival is defined as the time from start of the TFR phase to the time of death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study, and at the date of last contact for patients who are in follow-up. - Descriptive statistics on adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the study |
El porcentaje de pacientes que hayan alcanzado una ?RM4.0 prolongada (definido como tener 4 de las 5 evaluaciones trimestrales de ?RM4.0 por un laboratorio estandarizado EUTOS durante los últimos 12 meses y la última evaluación antes de la aleatorización que sea por lo menos RM4.0) durante la fase de tratamiento de consolidación del estudio. El porcentaje de pacientes que alcancen RM4.0 o RM4.5 en el estudio, en los periodos de tiempo seleccionados (cada 3 meses hasta el mes 24 o hasta el mes 36 dependiendo del brazo aleatorizado) durante la fase de inducción/consolidación del estudio |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
see under secondary endpoints |
Ver criterios de valoración secundarios. |
|
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 | No |
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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
evaluation of treatment free remission rate |
Evaluación del tratamiento de tasa de remisión libre. |
|
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 | No |
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) | 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 | 50 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 301 |
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
|
LPLV |
El estudio continuará hasta que el último paciente que fue elegible para aleatorización haya completado 5 años desde el inicio del estudio o haya sido retirado del estudio. Por lo tanto, la duración máxima total del estudio es de 5 años para cada paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |