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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/17055

Title: A randomized phase I Bayesian dose escalation design for the combination of anti-cancer drugs
Authors: Dejardin, David
LESAFFRE, Emmanuel
Hamberg, Paul
Verweij, Jaap
Issue Date: 2014
Publisher: WILEY-BLACKWELL
Citation: PHARMACEUTICAL STATISTICS, 13 (3), p. 196-207
Abstract: Nowadays, treatment regimens for cancer often involve a combination of drugs. The determination of the doses of each of the combined drugs in phase I dose escalation studies poses methodological challenges. The most common phase I design, the classic 3+3' design, has been criticized for poorly estimating the maximum tolerated dose (MTD) and for treating too many subjects at doses below the MTD. In addition, the classic 3+3' is not able to address the challenges posed by combinations of drugs. Here, we assume that a control drug (commonly used and well-studied) is administered at a fixed dose in combination with a new agent (the experimental drug) of which the appropriate dose has to be determined. We propose a randomized design in which subjects are assigned to the control or to the combination of the control and experimental. The MTD is determined using a model-based Bayesian technique based on the difference of probability of dose limiting toxicities (DLT) between the control and the combination arm. We show, through a simulation study, that this approach provides better and more accurate estimates of the MTD. We argue that this approach may differentiate between an extreme high probability of DLT observed from the control and a high probability of DLT of the combination. We also report on a fictive (simulation) analysis based on published data of a phase I trial of ifosfamide combined with sunitinib.Copyright (c) 2014 John Wiley & Sons, Ltd.
Notes: [Dejardin, David; Lesaffre, Emmanuel] KULeuven, Interuniv Inst Biostat & Stat Bioinformat, Louvain, Belgium. [Dejardin, David; Lesaffre, Emmanuel] Univ Hasselt, Diepenbeek, Belgium. [Lesaffre, Emmanuel] Erasmus MC, Dept Biostat, Rotterdam, Netherlands. [Hamberg, Paul; Verweij, Jaap] St Franciscus Gasthuis, Dept Internal Med, Rotterdam, Netherlands. [Hamberg, Paul; Verweij, Jaap] Erasmus MC Daniel den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands.
URI: http://hdl.handle.net/1942/17055
DOI: 10.1002/pst.1618
ISI #: 000336481900006
ISSN: 1539-1604
Category: A1
Type: Journal Contribution
Validation: ecoom, 2015
Appears in Collections: Research publications

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