E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory acute myeloid leukemia. |
Leucemia mieloide aguda en recaída o refractaria |
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E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia (AML) is a type of cancer that starts in the blood-forming cells of the bone marrow, characterised by an over-production of immature white blood cells. |
La leucemia mieloide aguda (LMA) es un tipo de cancer que comienza en las células precursoras de sangre de la medula espinal, caracterizado por una sobreproducción de globulos blancos inmaduros |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Within the TP53 wild-type population: ? To compare overall survival (OS) in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. |
En la población con TP53 no mutado: ? Comparar la supervivencia global (SG) entre los pacientes con leucemia mieloide aguda (LMA) en recaída o refractaria que hayan sido aleatorizados a recibir idasanutlin en combinación con citarabina y los que lo hayan sido a recibir citarabina y placebo. |
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E.2.2 | Secondary objectives of the trial |
Within the all-patient population ? To compare OS in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. Within the all-patient population and the TP53 wild-type population ? To compare - the proportions of complete remission (CR), and CR with incomplete platelet count recovery (CRp) between treatment arms - the proportions of overall remissions (CR, CRp, CR with incomplete blood count recovery [Cri]) between treatment arms - event-free survival (EFS) and leukemia-free survival (LFS) between treatment arms - the proportions of allogeneic hematopoietic stem cell transplant (HSCT) following response between treatment arms - the differences in disease and treatment related symptoms and health related quality of life ? To assess the safety between treatment arms ? To characterize the pharmacokinetics of both idasanutlin and cytarabine. |
Población de todos los pacientes ? Comparar la SG de los pacientes con LMA en recaída o refractaria entre los grupos de tratamiento En la población de todos los pacientes y la población con TP53 no mutado ? Comparar -Las proporciones de remisiones completas (RC) y remisiones completas con recuperaciones incompletas del recuento de plaquetas (RCp) entre los grupos de tratamiento. - Las proporciones de remisiones globales (RC, RCp, RC con recuperación incompleta del hemograma [RCi]) entre los grupos de tratamiento. -La supervivencia sin eventos (SSE) y sin leucemia (SSL) entre los grupos de tratamiento. - Las proporciones de alotrasplantes de células madre hematopoyéticas (alo- TCMH) tras la respuesta entre los grupos de tratamiento. -Las diferencias en cuanto a sintomas relacionados con el tratamiento y enfermedad y la calidad de vida relacionada con salud ? Para evaluar la seguridad entre los brazos de tratamiento ? Determinar la farmacocinética de idasanutlin y citarabina |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >=18 years - Documented/confirmed 1st/2nd refractory/relapsed AML using World Health Organization classification, except acute promyelocytic leukemia - No more than 2 prior induction regimens (excl. prior HSCT) and one must have included cytarabine with an anthracycline (or anthracenedione) - Eastern Cooperative Oncology Group performance status of 0 to 1 - Patient should be a potential candidate for allogeneic HSCT - Adequate hepatic and renal function. |
-Edad ? 18 años. -Primera o segunda LMA refractaria o en recaída documentada o confirmada según la clasificación de la Organización Mundial de la Salud, excepto leucemia promielocítica aguda. -No más de dos pautas de inducción previas (excluido un TCMH previo), una de las cuales tendrá que haber incluido citarabina con una antraciclina (o antracenodiona). -Estado funcional del Eastern Cooperative Oncology Group de 0 o 1 -El paciente ha de ser un posible candidato a recibir un alo-TCMH. · Función hepática y renal adecuada |
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E.4 | Principal exclusion criteria |
- Patients with CR1 duration of >1 year AND age <60 years - Patients with AML with myelodysplasia related changes, or AML that has developed as a consequence of an AHD - AML secondary to any prior chemotherapy unrelated to leukemia - Patients who have received more than two prior cytarabine containing induction regimens for AML - Patients who have relapsed within 90 days after therapy with intermediate-dose cytosine arabinoside (IDAC) or high-dose cytosine arabinoside (HiDAC) containing regimens - Patients who have received allogeneic HSCT within 90 days prior to randomization - Patients who have received immunosuppressive therapy for graft versus host disease (G versus HD) within 2 weeks prior to study start - Prior treatment with a Murine Double Minute 2 (MDM2) antagonist - Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy - Patients with a history of other malignancy within 5 years prior to screening - Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study - Pregnant or breastfeeding patients. |
-Pacientes con una duración de la RC1 > 1 año Y una edad < 60 años. -Pacientes con LMA con cambios relacionados con mielodisplasia o LMA que se ha desarrollado como consecuencia de un trastorno hematológico previo (THP) -LMA secundaria a cualquier quimioterapia previa no relacionada con la leucemia. -Pacientes que hayan recibido más de dos pautas de inducción previas con citarabina para tratar la LMA. -Pacientes que hayan presentado recaída en los 90 días siguientes al tratamiento con pautas que contengan IDAC o HiDAC. -Pacientes que hayan recibido un alo-TCMH en los 90 días previos a la aleatorización. -Pacientes que hayan recibido tratamiento inmunodepresor por una enfermedad del injerto contra el huésped (EICH) en las 2 semanas previas al comienzo del estudio. -Tratamiento previo con un antagonista de MDM2. -Pacientes que hayan recibido cualquier otro fármaco o tratamiento en investigación o comercializado administrado con intención de tratar su neoplasia maligna -Pacientes con antecedentes de otra neoplasia maligna en los 5 años previos a la selección -Pacientes que presenten trastornos médicos graves o incontrolados u otros trastornos que pudieran afectar a su participación en el estudio -Pacientes embarazadas o en período de lactancia. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (OS) in TP53 wild-type population. |
Supervivencia Global (SG) en la población con TP53 no mutado |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Interim analysis, after 120 patients enrolled - primary analysis, approximately 4.5 years after study start. |
-Analisis intermedio, después de 120 pacientes randomizados -Analisis primario, aproximadamente 4,5 años después del comienzo del estudio |
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E.5.2 | Secondary end point(s) |
1. OS in the all-patient population 2. CR and CRp proportions at the end of induction in the TP53 wild-type population 3. Overall remission rate (ORR) (CR, CRp and CRi) proportion at the end of induction in the TP53 wild-type population 4. EFS in the TP53 wild-type population 5. LFS in the TP53 wild-type population 6. Proportion of HSCT in the TP53 wild-type population 7. CR and CRp proportions at the end of induction in the overall population 8. ORR (CR, CRp and CRi) proportion at the end of induction in the overall population 9. EFS in the overall population 10. LFS in the overall population 11. Proportion of HSCT in the overall population. |
1-SG en la población global 2- Proporciones de RC y RCp al final del tratamiento de inducción en la población con TP53 no mutado 3-Proporción de TRG (RC, RCp y RCi) al final del tratamiento de inducción en la población con TP53 no mutado. 4-SSE en la población con TP53 no mutado. 5-SSL en la población con TP53 no mutado. 6-Proporción de TCMH en la población con TP53 no mutado. 7-Proporciones de RC y RCp al final del tratamiento de inducción en la población global 8-Proporción de TRG (RC, RCp y RCi) al final del tratamiento de inducción en la población global. 9-SSE en la población global. 10-SSL en la población global. 11-Proporción de TCMH en la población global. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Interim analysis, after 120 patients enrolled - primary analysis, approximately 4.5 years after study start. |
-Analisis intermedio, después de 120 pacientes randomizados -Analisis primario, aproximadamente 4,5 años después del comienzo del 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 | 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) | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 |
Canada |
Finland |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Netherlands |
New Zealand |
Norway |
Russian Federation |
Spain |
Switzerland |
Taiwan |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |