A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors.
Invest New Drugs
; 31(4): 974-85, 2013 Aug.
Article
en En
| MEDLINE
| ID: mdl-23377661
ABSTRACT
PURPOSE:
Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.) panobinostat administered on different dosing schedules in patients with advanced solid tumors or lymphoma. Secondary objective was to characterize safety and tolerability, pharmacokinetic profiles, and activities of the i.v. formulation.METHODS:
i.v. panobinostat was administered at escalating doses on a daily (days 1-3 and 8-10 of a 21-day cycle; days 1-3 and 15-17 of a 28-day cycle) or weekly (days 1, 8, and 15 of a 28-day cycle; days 1 and 8 of a 21-day cycle) schedule, and safety and tolerability were monitored. Serial blood samples were collected following dosing for pharmacokinetic and pharmacodynamic analyses.RESULTS:
The MTD for the daily administration schedule was 7.2 g/m(2), whereas the MTD for the weekly schedule was 20.0 mg/m(2). In addition to fatigue and cardiac arrhythmias, including prolonged QTcF, DLTs associated with the study drug were principally due to myelosuppressive effects. Maximum concentrations and bioavailability of i.v. panobinostat increased dose-proportionally across all doses evaluated.CONCLUSIONS:
Based on the results of this study and others, the i.v. formulation of panobinostat was well tolerated in many patients, but concerns remain regarding its potential suitability outside the study setting due to potential electrocardiogram abnormalities. Therefore, further development will focus on the panobinostat oral formulation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácidos Hidroxámicos
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Indoles
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Linfoma
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Antineoplásicos
Tipo de estudio:
Risk_factors_studies
Límite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Invest New Drugs
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos