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

AbstractINTRODUCTION:
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.
AuthorsRon J Keizer, Anthe S Zandvliet, Jos H Beijnen, Jan H M Schellens, Alwin D R Huitema
JournalInvestigational new drugs (Invest New Drugs) Vol. 30 Issue 4 Pg. 1519-30 (Aug 2012) ISSN: 1573-0646 [Electronic] United States
PMID21626115 (Publication Type: Evaluation Study, Journal Article)
Chemical References
  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • Antineoplastic Agents
  • Organophosphates
  • Quinazolines
Topics
  • Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
  • Clinical Trials, Phase I as Topic (methods)
  • Dose-Response Relationship, Drug
  • Humans
  • Leukocyte Count
  • Maximum Tolerated Dose
  • Models, Biological
  • Organophosphates (administration & dosage, pharmacokinetics, therapeutic use)
  • Quinazolines (administration & dosage, pharmacokinetics, therapeutic use)

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