Using the tolerable-dose diagram in the design of phase I combination chemotherapy trials.

Abstract

PURPOSE Choosing maximum-tolerated doses (MTDs) of agents to be administered in combination is more complicated than choosing the MTD for a single agent. This is because there are many combinations of doses that will be tolerated. We offer guidance in targeting specific MTD combinations, and suggest trial designs to achieve these targets. METHODS A graphical method based on a simple, previously described mathematical model is used to guide the phase I trial design. The method involves constructing a tolerable-dose diagram, which displays the toxicities that are expected to occur at various dose combinations. The data required for the method are the single-agent toxicity profiles of the agents. Designs for combinations of taxol with fluorouracil, carboplatin, doxorubicin, cyclophosphamide, and cisplatin are used to demonstrate the methods. RESULTS For all of the drugs considered here, leukopenia is dose-limiting or nearly dose-limiting. Consequently, no major improvement in total dose-intensity is achievable by combining these drugs. If leukopenia can be eliminated or substantially reduced by use of chemoprotective agents, then a cyclophosphamide/taxol combination appears promising from a dose-intensity point of view. For other combinations, the doses must be reduced from single-agent MTD levels. In the absence of biologic information such as concentrations needed for optimal modulation, it is suggested that single-agent MTDs be reduced approximately proportionately for each drug in the combination. CONCLUSION Tolerable-dose diagrams are useful for planning phase I trials of combinations of agents. They can suggest which combinations are promising from a dose-intensity perspective, as well as dose-escalation schemes for combinations to be pursued for dose-intensity or other considerations.