Méthodologie des essais de phase précoce en cancérologie : évolution des schémas et apport de la pharmacologie

In cancer research, the objectives of phase 1 studies are the estimation of the toxicity to define the Maximal Tolerated Dose and the Recommended Dose as well as the study of the pharmacology of the tested molecule. The evolution of anticancer treatments, the pharmacology and the progress of the biostatistics modified the methodological approach of these studies. We can include these studies under the generic name of early-phase clinical trial represented by: - phase 1 studies, - phase 0 studies, to study very prematurely molecules, - phase 1/2 studies which bring to light the dose maximizing the efficacy under restrictive toxicity conditions. The objective of our work is in a first part, to review the methodological evolution and the contribution of the pharmacology in the early-phase clinical trial in cancer research. We show that the methodology of the early-phase clinical trial evolved with the therapeutic innovations. We present the various traditional designs still very used nowadays. The evolution of these designs by the use of adapted statistical models, by the better use of the pharmacology or to answer the specific methodological requirements of the targeted therapies. We also describe the recent approaches as the phase 0 trial or the hybrid phase 1/2 trial. To finish by designs of molecules combination, the complexity of which is far from being resolved. The second part of this work illustrates these theoretical considerations by a series of studies of early-phase clinical trial published previously by our team or in the course of development. Six studies are presented. They seem to be representative of a part of design exposed in the theoretical part.