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- Ensayo clínico NCT00691938
LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)
A Phase I/II Study of LBH589 Plus Decitabine for Patients Age ≥ 60 Years With High Risk MDS or AML
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
To address the need for less toxic, more effective treatments for older patients with advanced MDS and AML, the purpose of this Phase 1-2 single institution study is to evaluate the safety and efficacy of LBH 589 and decitabine administered in combination.
Decitabine is an epigenetic modifier of gene expression that has been shown to be well-tolerated in this population at the dose schedule proposed in this study, with reasonable efficacy. Although its precise mechanism of action is incompletely understood, it is postulated to work by reactivating the expression of key tumor suppressor genes silenced in tumor cells by reversing a pattern of hypermethylation of promotor elements.
LBH389 is likewise an epigenetic modifier that inhibits the deacetylation of both histones and non-histone proteins, including HSP90 and p53. Although clinical experience with LBH589 in AML is limited, aberrant histone deacetylase activity has been previously shown to play a significant role in the pathogenesis of AML. The addition of LBH589 to a decitabine regimen of previously established efficacy and tolerability will allow us to evaluate the hypothesis that two epigenetic modifiers that are believed to work through distinct mechanisms of action may act together to improve the responses of patients treated with decitabine alone, without significant additional toxicity.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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Missouri
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St. Louis, Missouri, Estados Unidos, 63110
- Washington University
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- AML (except t(15;17), inv(16) or t(8;21) and variants) or high risk MDS (IPSS Int-2 or High) diagnosed according to WHO criteria (see Appendix 1)
- Age ≥ 60 years old
- Not a candidate for allogeneic stem cell transplantation within next 12 weeks
- Ability to provide written informed consent, obtained prior to participation in the study and any related procedures being performed
- Patients must meet the following laboratory criteria:
- Serum albumin ≥ 3 g/dL
- Aspartate aminotransferase (AST)/SGOT and alanine aminotransferase (ALT)/SGPT ≤ 2.5 x upper limit of normal (ULN) ) or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement
- Serum bilirubin ≤ 1.5 x ULN
- Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min
- Serum potassium ≥ lower limit of normal (LLN)
- Serum phosphorus ≥ LLN
- Serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ LLN
- Serum magnesium ≥ LLN, thyroid stimulating hormone (TSH) and free thyroxine (T4) within normal limits (WNL) (patients may be on thyroid hormone replacement)
- Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional normal.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
Exclusion Criteria:
- Prior treatment for MDS / AML with Histone deacetylase (HDAC) inhibitor or hypomethylating agent (e.g., Decitabine, azacitidine etc.)
- Active central nervous system (CNS) involvement with MDS/AML
- Impaired cardiac function including any one of the following:
- Screening electrocardiogram (ECG) with a QTc > 450 msec confirmed by central laboratory prior to enrollment to the study
- Patients with congenital long QT syndrome
- History of sustained ventricular tachycardia
- Any history of ventricular fibrillation or torsades de pointes
- Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible.
- Patients with a myocardial infarction or unstable angina within 6 months of study entry
- Congestive heart failure (NY Heart Association class III or IV)
- Right bundle branch block and left anterior hemiblock (bifasicular block)
- Uncontrolled hypertension
- Concomitant use of drugs with a risk of causing torsades de pointes
- Patients with unresolved diarrhea > CTCAE grade 1
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589
- Other concurrent severe and/or uncontrolled medical conditions
- Patients who have received chemotherapy or any investigational drug < 2 weeks or hydroxyurea < 48 hours prior to starting study drug or who have not recovered from side effects of such therapy.
- Concomitant use of any anti-cancer therapy or radiation therapy
- Male patients whose sexual partners are women of child bearing potential (WOCBP) not using effective birth control
- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
- Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
- Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment
- Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
- Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: No aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Level 1
LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Level 2
LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Level 3
LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Level 4
LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Level 5
LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Level 5B
LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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Experimental: Phase II
LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was Level 5B. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle. |
Otros nombres:
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
---|---|---|
Phase I: Maximum Tolerated Dose (MTD) of LBH589 When Given in Combination With Decitabine
Periodo de tiempo: Completion of Phase I enrollment for MTD (approximately 26 months)
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Completion of Phase I enrollment for MTD (approximately 26 months)
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Phase II: Overall Rate of Morphologic Complete Remission (CR) + Cytogenetic Complete Remission (CRc) + Morphologic Complete Remission With Incomplete Blood Count Recovery (CRi)
Periodo de tiempo: Up to 12 months
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Up to 12 months
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
---|---|---|
Rate of Cytogenetic Complete Remission (CRc)
Periodo de tiempo: Up to 12 months
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Cytogenetic complete remission (CRc).
A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.
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Up to 12 months
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Changes in Quality of Life Scores as Measured by the Function Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4
Periodo de tiempo: Up to approximately 12 months after start of treatment
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-The FACT-Leu consists of a 27-item compilation of general questions divided into four primary quality of life domains: physical well-being, social/family well being, emotional well-being, and functional well-being along with a 17 item subscale developed specifically for patients with leukemia.
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Up to approximately 12 months after start of treatment
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Time to Response
Periodo de tiempo: Up to 12 months
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Time to response is defined as the date of the first dose of study drug to the date that all criteria for CR or CRi are fulfilled.
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Up to 12 months
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Safety and Tolerability of Regimen as Measured by the Rate of the Most Common Adverse Events Experienced
Periodo de tiempo: Up to 13 months after start of treatment
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Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.
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Up to 13 months after start of treatment
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Remission Duration
Periodo de tiempo: Completion of follow-up (median follow-up was 58 months)
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Defined as the first date that all criteria for CR, CRi or HI are fulfilled to the date of treatment failure, relapse from CR, or death due to any cause.
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Completion of follow-up (median follow-up was 58 months)
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Progression-free Survival
Periodo de tiempo: Completion of follow-up (median follow-up was 58 months)
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Completion of follow-up (median follow-up was 58 months)
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Event-free Survival
Periodo de tiempo: Completion of follow-up (median follow-up was 58 months)
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Event-free survival is defined as the interval from the date of first dose of study drug to date of treatment failure, relapse from CR, or death due to any cause.
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Completion of follow-up (median follow-up was 58 months)
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Overall Survival
Periodo de tiempo: Completion of follow-up (median follow-up was 58 months)
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Overall survival is defined as the date of first dose of study drug to the date of death from any cause.
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Completion of follow-up (median follow-up was 58 months)
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Rates of Morphologic Complete Remission With Incomplete Count Recovery (CRi)
Periodo de tiempo: Up to 12 months
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Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (< 1,000/μL) or thrombocytopenia (< 100,000/μL).
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Up to 12 months
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Rate of Hematologic Improvement.
Periodo de tiempo: Up to 12 months
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-Hematologic improvement (HI). Includes the following categories:
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Up to 12 months
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Geoffrey Uy, M.D., Washington Univerisity
Publicaciones y enlaces útiles
Publicaciones Generales
- Cashen, A., G. J. Schiller, et al. (2006). Phase II Study of Low-Dose Decitabine for the Front-Line Treatment of Older Patients with Acute Myeloid Leukemia (AML). ASH Annual Meeting Abstracts 108(11): 1984.
- Uy GL, Duncavage EJ, Chang GS, Jacoby MA, Miller CA, Shao J, Heath S, Elliott K, Reineck T, Fulton RS, Fronick CC, O'Laughlin M, Ganel L, Abboud CN, Cashen AF, DiPersio JF, Wilson RK, Link DC, Welch JS, Ley TJ, Graubert TA, Westervelt P, Walter MJ. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia. 2017 Apr;31(4):872-881. doi: 10.1038/leu.2016.282. Epub 2016 Oct 14.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Procesos Patológicos
- Neoplasias por tipo histológico
- Neoplasias
- Enfermedad
- Enfermedades de la médula ósea
- Enfermedades hematológicas
- Condiciones precancerosas
- Síndrome
- Síndromes mielodisplásicos
- Leucemia
- Leucemia Mieloide
- Leucemia Mieloide Aguda
- Preleucemia
- Mecanismos moleculares de acción farmacológica
- Inhibidores de enzimas
- Antimetabolitos, Antineoplásicos
- Antimetabolitos
- Agentes antineoplásicos
- Inhibidores de histona desacetilasa
- Decitabina
- Panobinostat
Otros números de identificación del estudio
- 08-0172 / 201012979
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .