Phase I clinical trials: adapting methodology to face new challenges.
BACKGROUND: The conventional phase I clinical trial stands as a bridge between the laboratory and the clinic in the development of novel anticancer agents. The purpose of the phase I study is primarily to determine toxicity and to define the maximum tolerated dose of the drug in man. It is assumed for this purpose that dose-response curves for toxicity and efficacy are parallel or, simply expressed, the more pain, the more gain. Novel antineoplastic drugs are being developed that are mechanistically remote from conventional cytotoxic drugs, which have DNA as their predominant target; some of these new agents have, at least in vitro, bell-shaped dose-response curves. CONCLUSION: It is essential that flexible clinical trial methodologies are developed to accommodate new drugs and that attempts are made, when possible, to incorporate pharmacodynamic endpoints in addition to toxicological endpoints.