Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152)
2012 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 30, no 4, 1519-1530 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2012. Vol. 30, no 4, 1519-1530 p.
Barasertib, AZD1152, Oncology, Phase I, Modeling and simulation, Hematological toxicity
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-178072DOI: 10.1007/s10637-011-9694-5ISI: 000305955300026OAI: oai:DiVA.org:uu-178072DiVA: diva2:542161