Using the continual reassessment method to estimate the minimum effective dose in phase II dose-finding studies: a case study

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.