E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase 2 (IDH2) mutation |
Tratamiento de pacientes mayores de 60 años con leucemia mieloide aguda (LMA) recidivante o resistente al tratamiento de segunda o tercera línea y con mutación del gen de la isocitrato deshidrogenasa 2 (IDH2). |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of subjects 60 years or older with AML that does not respond to or that came back after 2 or 3 different AML therapies and that presents a mutation on isocitrate dehydrogenase 2 (IDH2) |
Tratamiento de pacientes mayores de 60 años con LMA recidivante o resistente a 2 o 3 tratamientos para la LMA diferentes y que presenten mutación de la isocitrato deshidrogenasa 2 (IDH2). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 | 10060558 |
E.1.2 | Term | Acute myeloid leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To determine the primary efficacy, measured as overall survival (OS), of AG-221 compared with conventional care regimens (CCRs) in subjects 60 years or older with AML refractory to or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation |
Analizar la eficacia principal, determinada por la supervivencia global (SG), de AG-221 en comparación con los regímenes de tratamiento habituales (RTH) en pacientes mayores de 60 años con LMA recidivante o resistente al tratamiento de segunda o tercera línea y con mutación de IDH2. |
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E.2.2 | Secondary objectives of the trial |
-To determine the supporting efficacy of AG-221 compared with CCRs -To determine the safety and tolerability of AG-221 compared with CCRs -To determine the effect of AG-221 compared with CCRs on Health-related Quality-of-Life |
- Determinar la eficacia complementaria de AG-221 en comparación con los RTH. - Determinar la seguridad y tolerabilidad de AG-221 en comparación con los RTH. - Determinar el efecto de AG-221 sobre la calidad de vida relacionada con la salud (CVDRS) en comparación con los RTH. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is ? 60 years of age at the time of signing the ICF 2. Subject has primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO classification 3. Subject has received second- or third-line/regimen of AML therapy 4. Subject has the following disease status: a. Refractory to or relapsed after second- or third-line/regimen of intensive therapy for AML (eg, the ?7 + 3? regimen): at least 5% leukemic blasts in bone marrow; or b. Refractory to or relapsed after second- or third-line low-intensity AML therapy (eg, LDAC, azacitidine or decitabine): at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles 5. Subject is eligible for and willing to receive the pre-selected CCR treatment option, according to the investigator's assessment 6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 7. Subject has IDH2 gene mutations tested centrally (using the ?investigational use only? PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral blood 8. Subject has adequate organ function defined as: - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ? 3 x upper limit of normal (ULN), unless considered due to leukemic organ involvement, following review by the Medical Monitor; and - Serum total bilirubin ? 1.5 x ULN, unless considered due to Gilbert?s syndrome (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review by the Medical Monitor; and - Creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation: (140 - Age)x(weight in kg)x(0.85 if female)/72xserum creatinine |
1. Edad mínima de 60 años en el momento de firmar el DCI. 2. LMA primaria (es decir, de novo) o secundaria (progresión de un SMD o una neoplasia mieloproliferativa [NMP], o debida a un tratamiento previo) conforme a la clasificación de la OMS. 3. Haber recibido un régimen de segunda o tercera línea para el tratamiento de la LMA. 4. Uno de los estados de enfermedad siguientes: a. Resistencia o recidiva tras un régimen de segunda o tercera línea de tratamiento intensivo para la LMA (por ejemplo, el régimen "7 + 3"): al menos un 5 % de blastos leucémicos en la médula ósea. b. Resistencia o recidiva tras un régimen de segunda o tercera línea de tratamiento de baja intensidad para la LMA (por ejemplo, LDAC, azacitidina o decitabina): al menos un 5 % de blastos leucémicos en la médula ósea después de al menos dos ciclos de tratamiento. 5. Cumplir los requisitos para recibir la opción de RTH elegida conforme a la evaluación del investigador, y estar dispuesto a ello. 6. Estado funcional de 0, 1 ó 2 según el Eastern Cooperative Oncology Group (ECOG). 7. Haberse realizado un análisis centralizado de las mutaciones de IDH2 (mediante el análisis de PCR RealTime IDH2 de Abbott, "de uso exclusivamente experimental") en muestras de aspirado de médula ósea y sangre periférica que confirme la positividad en el aspirado de médula ósea y/o en sangre periférica. 8. Función orgánica adecuada, definida como: - Aspartato aminotransferasa (AST)/transaminasa glutámicooxaloacética sérica (SGOT)/ y alanina aminotransferasa (ALT)/transaminasa glutámico-pirúvica sérica (SGPT) ? 3 veces el límite superior de la normalidad (LSN), a menos que se considere debido a una afectación orgánica de la leucemia, previa evaluación por parte del monitor médico; y Bilirrubina total en suero ? 1,5 veces el LSN, a menos que se considere debido a un síndrome de Gilbert (por ejemplo, mutación de UGT1A1) o una afectación orgánica de la leucemia, previa evaluación por parte del monitor médico; y - Aclaramiento de creatinina 30 ml/min calculado según la ecuación de filtración glomerular de Cockcroft-Gault: (140 ? edad) x (peso en kg) x (0,85 en las mujeres)/72 x creatinina sérica. |
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E.4 | Principal exclusion criteria |
1. Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype 2. Subject has AML secondary to chronic myelogenous leukemia 3. Subject has received a targeted agent against an IDH2 mutation 4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis in subjects with white blood cell (WBC) counts> 30 x 10^9/L (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine) 5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment 6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoing skin GVHD is permitted. 7. Subject has persistent, clinically significant non-hematologic toxicities from prior therapies 8. Subject has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening. |
1. Leucemia promeliocítica aguda presunta o confirmada por la morfología, el inmunofenotipo, el análisis molecular o el cariotipo 2. LMA secundaria a una leucemia mielógena crónica 3. Haber recibido un fármaco dirigido contra la IDH2 mutada. 4. Haber recibido tratamiento antineoplásico sistémico o radioterapia menos de 14 días antes del comienzo del tratamiento del estudio. Se permite la administración de hidroxiurea antes de empezar el tratamiento del estudio para controlar la leucocitosis en pacientes con cifras de leucocitos > 30 x 109/l (sin embargo, no debe administrarse en las 72 horas previas y posteriores a la administración de azacitidina). 5. Haber recibido fármacos no citototóxicos o experimentales menos de 14 días o 5 semividas antes del comienzo del tratamiento del estudio, lo que suponga más tiempo 6. Haberse sometido a un TCPH en los 60 días anteriores al comienzo del tratamiento del estudio, estar en tratamiento inmunodepresor posterior al TCPH en el momento de la selección o presentar una enfermedad del injerto contra el huésped (EICH) de importancia clínica. Se permite el tratamiento con esteroides orales en dosis estables después de un TCPH o con esteroides tópicos para la EICH cutánea. 7. Toxicidad no hematológica persistente y de importancia clínica debida a tratamientos anteriores. 8. Leucemia del sistema nervioso central (SNC) presunta o confirmada. Durante la selección se hará un análisis del líquido cefalorraquídeo únicamente si se sospecha afectación del SNC. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival |
Supervivencia Global |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to death due to any cause (up to approximately 28 months) |
Tiempo transcurrido desde la aleatorización hasta la fecha de muerte por cualquier causa (Aproximadamente 28 meses). |
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E.5.2 | Secondary end point(s) |
1.Overall response rate 2.Event-free survival 3.Duration of response 4.Time to response 5.Treatment mortality at 30 and 60 days 6.One-year survival 7.Overall remission rate 8.Complete remission rate 9.Hematologic improvement rate 10.Rate of HSCT 11.Time to treatment failure 12.Safety and tolerability 13.HRQoL |
1. Tasa de respuesta global 2. Supervivencia sin acontecimientos 3. Duración de la respuesta 4. Tiempo hasta la respuesta 5. Mortalidad del tratamiento a los 30 y 60 días 6. Supervivencia a un año 7. Tasa de remisión global 8. Tasa de remisión completa 9. Tasa de mejoría hematológica 10. Tasa de TCPH 11. Tiempotranscurrido hasta el fracaso del tratamiento 12. Seguridad y tolerabilidad 13. CVRS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.up to approximately 28 months 2.up to approximately 28 months 3.up to approximately 28 months 4.up to approximately 28 months 5.At 30 and 60 days after treatment start 6.up to approximately 28 months 7.up to approximately 28 months 8.up to approximately 28 months 9.up to approximately 28 months 10.up to approximately 28 months 11.up to approximately 28 months 12.up to approximately 28 months 13.up to approximately 28 months |
1. Hasta aproximadamente 28 meses 2. Hasta aproximadamente 28 meses 3. Hasta aproximadamente 28 meses 4. Hasta aproximadamente 28 meses 5. En los días 30 y 60 despues del comienzo del tratamiento. 6. Hasta aproximadamente 28 meses 7. Hasta aproximadamente 28 meses 8. Hasta aproximadamente 28 meses 9. Hasta aproximadamente 28 meses 10. Hasta aproximadamente 28 meses 11. Hasta aproximadamente 28 meses 12. Hasta aproximadamente 28 meses 13. Hasta aproximadamente 28 meses |
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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 | 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 | 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 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 74 |
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 |
Brazil |
Canada |
Denmark |
France |
Germany |
Italy |
Japan |
Korea, Republic of |
Russian Federation |
Spain |
United Kingdom |
United States |
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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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The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
El fin del estudio está definido como la fecha de la última visita del último sujeto en completar el seguimiento de post-tratamiento, o la fecha de recogida del último punto de datos del último paciente que se requiera para un análisis primario, secundario y / o análisis exploratorio, como está especificado previamente en el protocolo, lo que suceda más tarde. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |