MODELS FOR EARLY CHEMOPREVENTION TRIALS IN BREAST-CANCER

The ideal model for phase I and II testing of potential breast cancer chemoprevention agents has yet to be delineated clearly. Phase I trial s are heterogeneous in their design. For a drug with minimal prior hum an exposure, classic phase I dose-range finding tests are performed fi rst in normal volunteers. A non-to-minimally toxic dose range is estab lished and pharmacokinetic and pharmacodynamic studies are performed. Once the dose range is established, later phase I trials seek to estab lish a nontoxic dose at which biochemical activity or surrogate endpoi nt biomarker (SEB) activity is modulated. Phase II trials are randomiz ed, double-blind efficacy trials in which modulation of previously val idated SEBs is used as the measure of response. Phase ii trials also i dentify new potential SEBs. Late-phase I and II trials usually are per formed in high-risk cohorts. Drugs showing minimal toxicity and good m odulation of SEBs are advanced to randomized phase III trials in high- risk cohorts. Endpoints for phase III trials are decreased cancer inci dence, validation of potential SEBs identified in phase II trials, and a decrease in cancer-specific and overall mortality. This article rev iews the authors' experience with phase I and II breast cancer chemopr evention trials, and makes recommendations for future studies based on the authors' recent experience.