Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152).
Invest New Drugs
; 30(4): 1519-30, 2012 Aug.
Article
em En
| MEDLINE
| ID: mdl-21626115
ABSTRACT
INTRODUCTION:
Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib.METHODS:
Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials.RESULTS:
The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial.DISCUSSION:
The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal.CONCLUSION:
Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Organofosfatos
/
Quinazolinas
/
Ensaios Clínicos Fase I como Assunto
/
Modelos Biológicos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Holanda