ArticleInvestigational new drugs2012
Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152).
Article in Investigational new drugs, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
6 citing papers in PubMed.
- Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways.Molecules (Basel, Switzerland) · 2021Review
- On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology.Nature biomedical engineering · 2020Article
- Quercetin suppresses lung cancer growth by targeting Aurora B kinase.Cancer medicine · 2016Article
- The Aurora kinase inhibitors in cancer research and therapy.Journal of cancer research and clinical oncology · 2016Review
- Integrated Simulation Framework for Toxicity, Dose Intensity, Disease Progression, and Cost Effectiveness for Castration-Resistant Prostate Cancer Treatment With Eribulin.CPT: pharmacometrics & systems pharmacology · 2015Article
- Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.Carcinogenesis · 2012Article
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionModeling 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.
methodsData 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.
resultsThe 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.
conclusionApplication 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.
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