Two-stage model-based design of cancer phase i dose escalation trials: Evaluation using the phase i program of barasertib (AZD1152)

Ron J. Keizer, Anthe S. Zandvliet, Jos H. Beijnen, Jan H.M. Schellens, Alwin D.R. Huitema

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

8 Citaten (Scopus)


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 modelbased trial design in Phase I programs with novel anticancer 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.

Originele taal-2Engels
Pagina's (van-tot)1519-1530
Aantal pagina's12
TijdschriftInvestigational New Drugs
Nummer van het tijdschrift4
StatusGepubliceerd - aug. 2012
Extern gepubliceerdJa


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