A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200.
Ann Oncol
; 26(5): 973-981, 2015 May.
Article
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| MEDLINE
| ID: mdl-25632070
ABSTRACT
BACKGROUND:
A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS ANDMETHODS:
SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods.RESULTS:
Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity.CONCLUSION:
This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL NCT01112384.Palabras clave
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Sarcoma
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Translocación Genética
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Bencimidazoles
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Biomarcadores de Tumor
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Histona Desacetilasa 2
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Inhibidores de Histona Desacetilasas
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Recurrencia Local de Neoplasia
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Antineoplásicos
Tipo de estudio:
Clinical_trials
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Risk_factors_studies
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
País/Región como asunto:
America do norte
Idioma:
En
Revista:
Ann Oncol
Asunto de la revista:
NEOPLASIAS
Año:
2015
Tipo del documento:
Article