[Principles and practice of clinical phase I studies]

There is clear evidence that the epidemiologic importance of malignant diseases will continue to rise in the future. This creates the ethical obligation to further intensify the search for improved systemic treatment options. This review is focussed on principles and practices of phase I trials. The trial methodology outlined here is not only used for first-in-human doses of new chemical entities but also for the investigation of new treatment schedules and combinations. The primary endpoints as well as preclinical requirements are addressed. Although for formal reasons antitumor activity cannot be an endpoint in phase I studies the careful observation and documentation of potential anticancer efficacy is of utmost importance in these early clinical trials. Signals of antitumor activity may serve as important guidance for subsequent clinical development plans. Inclusion criteria, dose escalation schemes, and the importance of the concept of the maximum tolerable dose (MTD) are addressed together with ethical principles of exposure to novel chemical agents.