Sarah Zohar1, Matthieu Resche-Rigon, Sylvie Chevret. 1. INSERM U717, Département de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, Paris 7 University, France. sarah.zohar@univ-paris-diderot.fr
Abstract
BACKGROUND: The Continual Reassessment Method typically is presented as the method of choice for the purpose of dose-finding based on a toxicity scale in phase I clinical trials. However, this adaptive statistical approach also can be applied easily to dose-finding experiments in phase II trials. PURPOSE: To provide a case study from a real clinical trial to illustrate the use of the Continual Reassessment Method in the context of phase II dose finding. METHODS: The Continual Reassessment Method was used to model the dose-failure relationship in order to estimate the minimal effective dose. This approach was retrospectively used to determine the minimal effective dose of granulocyte colony-stimulating factor for peripheral blood stem cell collection in allografted patients following chemotherapy. RESULTS: After the inclusion of 25 patients, the minimal effective dose was estimated to be the third dose level tested in the study. LIMITATIONS: The main limitation of the Continual Reassessment Method, which is not specific to the method but to the dose-finding setting, is that the empirical choice of the dose range can be either under or over-estimated. The method requires a calibration study prior to trial onset. CONCLUSIONS: Assuming that a dose-effect relationship is monotonically increasing, the use of the Continual Reassessment Method in phase II dose-finding studies allows the estimation of the minimum effective dose for further studies. Modeling the dose-failure relationship allows the direct use of available software developed for the Continual Reassessment Method in the context of phase I clinical trials.
BACKGROUND: The Continual Reassessment Method typically is presented as the method of choice for the purpose of dose-finding based on a toxicity scale in phase I clinical trials. However, this adaptive statistical approach also can be applied easily to dose-finding experiments in phase II trials. PURPOSE: To provide a case study from a real clinical trial to illustrate the use of the Continual Reassessment Method in the context of phase II dose finding. METHODS: The Continual Reassessment Method was used to model the dose-failure relationship in order to estimate the minimal effective dose. This approach was retrospectively used to determine the minimal effective dose of granulocyte colony-stimulating factor for peripheral blood stem cell collection in allografted patients following chemotherapy. RESULTS: After the inclusion of 25 patients, the minimal effective dose was estimated to be the third dose level tested in the study. LIMITATIONS: The main limitation of the Continual Reassessment Method, which is not specific to the method but to the dose-finding setting, is that the empirical choice of the dose range can be either under or over-estimated. The method requires a calibration study prior to trial onset. CONCLUSIONS: Assuming that a dose-effect relationship is monotonically increasing, the use of the Continual Reassessment Method in phase II dose-finding studies allows the estimation of the minimum effective dose for further studies. Modeling the dose-failure relationship allows the direct use of available software developed for the Continual Reassessment Method in the context of phase I clinical trials.
Authors: Andy P Grieve; Shien-Chung Chow; John Curram; Stephen Dawe; Lutz O Harnisch; Noreen R Henig; Hsien Ming J Hung; D Dunbar Ivy; Steven M Kawut; Mohammad H Rahbar; Shen Xiao; Martin R Wilkins Journal: Pulm Circ Date: 2013-01 Impact factor: 3.017