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

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.