E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed/refractory or untreated acute leukemia |
recidivante / refractaria o leucemia aguda no tratada |
|
E.1.1.1 | Medical condition in easily understood language |
relapsed/refractory or untreated acute leukemia |
recidivante / refractaria o leucemia aguda no tratada |
|
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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000835 |
E.1.2 | Term | Acute leukemia |
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 |
To evaluate the rate of complete remission (CR) and complete remission with incomplete blood count recovery (CRi) on two different dosing schedules of LDE225 in acute leukemia |
Evaluar la tasa de remisión completa (RC) y de remisión completa con recuperación incompleta del recuento hemático (RCi) en dos posologías distintas de LDE225 en leucemia aguda |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the Overall Response Rate on two different dosing schedules of LDE225 in acute leukemia 2. To evaluate the safety and tolerability of two different dosing schedules of LDE225 in acute leukemia 3. To further characterize the pharmacokinetics of two different dosing schedules of LDE225 in acute leukemia |
1. Evaluar la tasa de respuesta global en dos posologías distintas de LDE225 en leucemia aguda 2. Evaluar la seguridad y tolerabilidad de dos posologías distintas de LDE225 en leucemia aguda 3. Caracterizar mejor la farmacocinética de dos posologías distintas de LDE225 en leucemia aguda. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female adult patients (?18 years). - Histological or cytological diagnosis of either relapsed or primary refractory non-M3 acute myeloid leukemia (AML); untreated AML in patients ? 65 years of age, if they are not candidates for standard induction chemotherapy; or relapsed or refractory non-T-cell acute lymphoblastic leukemia (ALL) - White blood cell count (WBC) ? 50 x 109/L. - Performance status corresponding to ECOG (WHO) score of 0, 1 or 2. - Adequate renal function - Adequate liver function - Serum CK ? 1.5 x ULN. - At least 2 weeks since end of last leukemia therapy.
Other protocol defined inclusion criteria may apply. |
- El consentimiento informado por escrito deberá obtenerse antes de cualquier procedimiento de selección - Pacientes hombres o mujeres adultos (18 años) - Diagnóstico histológico o citológico de:Leucemia mieloide aguda (LMA) no-M3 refractaria primaria o en recidiva, según la clasificación de la Organización Mundial de la Salud (OMS) (independientemente del número de regímenes previos) o de novo o secundaria [es decir, a síndrome mielodisplásico (SMD), neoplasma mieloproliferativo o quimioterapia previa para otra neoplasia] - LMA sin tratamiento previo en pacientes 65 años de edad, si no son candidatos para quimioterapia de inducción estándar - Leucemia linfoblástica aguda (LLA) no de célula T, refractaria o en recidiva, según la clasificación de la OMS. Pacientes con LLA cromosoma filadelfia positivo (Ph+) que hayan demostrado resistencia a terapia con inhibidor tirosina quinasa - Estado funcional que corresponda a la puntuación de 0, 1 ó 2 del ECOG (OMS) - Función renal adecuada, demostrado con: Creatinina sérica 1.5 x límite superior de normalidad (LSN) - Función hepática adecuada, demostrado con: Bilirrubina total 1.5 x rango de valores por encima del límite de normalidad (LSN), excepto que sea debido a elevación de la bilirrubina indirecta (es decir, síndrome de Gilbert o hemolisis). Alanina aminotransferasa sérica (ALT)/transaminasa pirúvico glutámico sérica (SGPT) 3 x LSN. Albúmina 2.0 g/dl. Fosfatasa alcalina (AP) 2.5 x LSN. CK sérica 1.5 LSN. - Por lo menos 2 semanas desde el final de la última terapia para la leucemia (excepto para hidroxiurea, que está permitida, si está clínicamente indicado, para disminuir la cifra de blastos, pero debería suspenderse después de 2 semanas de recibir la medicación del estudio, y corticosteroides, que están permitidos, pero deberían suspenderse cuando se inicie el tratamiento del estudio), recuperación a grado 1 de cualquier toxicidad no hematológica derivada del tratamiento previo (excluyendo alopecia de cualquier grado y neuropatía periférica de grado 2). Sólo se permitirán dosis estables orales bajas de corticosteroides ( 10 mg/día de prednisona o equivalente) durante el transcurso del estudio. |
|
E.4 | Principal exclusion criteria |
- Allogeneic SCT within the last 4 months and/or active GVHD, or autologous SCT within the last 4 weeks. - Active CNS leukemic involvement. - Major surgery within 2 weeks of initiation of study medication. - Concurrent uncontrolled medical conditions that may interfere or potentially affect the interpretation of the study. - Unable to take oral drugs, or lack of physical integrity of the upper gastrointestinal tract, or known malabsorption syndromes. - Patients with unresolved diarrhea > CTCAE grade 2. - Patients who have previously been treated with systemic LDE225 or with other Hh pathway inhibitors. - Patients who have neuromuscular disorders or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis - patients who are planning on embarking on new physical activities, such as strenuous exercise, that can result in significant increases in plasma CK levels while on study treatment. - Patient has history of cardiac dysfunction - patient has active cardiac disease - Use of other investigational drugs within 30 days or 5 half-lives of initiation of study medication, whichever is longer. - Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. - Patients are excluded if the use of warfarin is necessary and cannot be substituted - Pregnant or nursing (lactating) women - Patients who are not willing to apply highly effective contraception during the study and the defined duration after final dose of study treatment. - Known HIV positivity.
Other protocol defined exclusion criteria may apply. |
- SCT alogénico dentro de los últimos 4 meses y/o GVHD activa, o SCT autólogo dentro de las últimas 4 semanas - Afectación leucémica activa del SNC - Cirugía mayor dentro de las 2 semanas del inicio de la medicación del estudio - Condiciones médicas incontroladas concurrentes que puedan interferir o posiblemente influir en la interpretación del estudio - Incapacidad para tomar fármacos orales, o sin integridad física del tracto gastrointestinal superior o síndromes de mala absorción conocidos - Pacientes con diarrea no resuelta > grado 2 de los CTCAE - Pacientes que hayan sido tratados previamente con LDE225 sistémico o con otros inhibidores de la vía de señalización Hh - Pacientes que presenten alteraciones neuromusculares (es decir, miopatías inflamatorias, distrofia muscular, esclerosis lateral amiotrófica y atrofia muscular espinal) o que reciban tratamiento concomitante con fármacos que se conoce que causan rabdomiolisis, como inhibidores de la HMG CoA (estatinas), clofibrato y gemfibrozil. Puede utilizarse pravastatina si es necesario, con precaución adicional - Pacientes que tengan previsto iniciar nuevas actividades físicas, como ejercicio enérgico, que pueda producir aumentos significativos en los niveles de CK en plasma mientras reciban el tratamiento del estudio. La actividad muscular enérgica DEBERA evitarse dentro de la 1 semana de los análisis de sangre durante el estudio |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Rate of CR and CRi |
Tasa de RC y de RCi, según los criterios del grupo internacionalde trabajo (IWG) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
As defined in Table 3-1 and section 10.4.2 of the protocol. |
Tal como se define en la Tabla 3-1 y la sección 10.4.2 del protocolo. |
|
E.5.2 | Secondary end point(s) |
1. Overall Response Rate (ORR) 2. Safety (Adverse events, abnormal lab values, ECGs, SAEs etc.) 3. PK parameters: - Tmax, Cmax, Ctrough, and AUC0-8h for all patients - AUC0-24h, CL/F and Racc for 800 mg QD arm only |
1. Tasa de respuesta global (TRG), (tasa de RC, RCi o PR) según los criterios del IWG 2. Seguridad (acontecimientos adversos, alteraciones en los valores de laboratorio, ECGs, AAGs, etc) 3. Parámetros PK -Tmax, Cmax, Ctrough y AUC0-8h para todos los pacientes - AUC0-24h, CL/F y Racc, sólo para el grupo de 800 mg QD |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
As defined in Table 3-1 and sections 10.5., 10.5.2 and 10.5.3 of the protocol. |
Tal como se define en la Tabla 3-1 y las secciones 10.5. 10.5.3, 10.5.2 y del 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 | No |
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 | 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) | 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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
dos esquemas de tratamiento de LDE225 |
two treatment schedules of LDE225 |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
Belgium |
Canada |
France |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Russian Federation |
Spain |
Sweden |
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
|
LVLS |
Última 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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |