ARTICLES Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice

such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs. Methods: We retrieved 60 publications of phase I studies involving 31 single agents representative of the most com-mon targets of interest in the oncology literature. For each publication, we abstracted data regarding patient popula-tion, starting dose, methods of dose escalation and determi-nation of recommended phase II dose, and inclusion of cor