NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies.
Invest New Drugs
; 31(6): 1522-9, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24072436
ABSTRACT
PURPOSE:
AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS ANDMETHODS:
Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D).RESULTS:
35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months).CONCLUSION:
In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ureia
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Benzimidazóis
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Inibidores de Proteínas Quinases
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Neoplasias
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Antineoplásicos
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article