[Combination phase I trials]

Most successes in the treatment of advanced cancers have required the use of combinations of cytotoxic agents. Therefore, the development of combinations of new active compounds is one of the key challenges of clinical oncology. Reasons for the use of combinations include: 1) biochemical synergism, 2) lack of cross-resistance, and 3) higher achievable dose-intensity by exploiting nonoverlapping dose-limiting toxicities. The first step in clinical development of combinations is to find doses of the drugs that are tolerated when administered together. This is a purpose of a phase I study. However, there are some differences in phase I trials between single agents and combinations. For combinations of drugs, the maximum-tolerated does (MTD) of both active agents is already known. There are almost countless possibilities as to which drugs to combine and in what proportions. A method for selecting drugs and doses for a combination regimen from among many possibilities was discussed in this symposium.