Optimal Biological Dose for Molecularly‐Targeted Therapies

Abstract Phase I cancer clinical trials are small dose‐finding studies designed to rapidly identify the optimal dose of a new anticancer agent. The optimal dose has been defined as the maximum tolerated dose (MTD) for conventional cytotoxic anticancer drugs, and this dose is typically recommended as the phase II dose. In the past decade, a new approach for cancer treatment has emerged. This new approach, now widely referred to as “molecularly targeted therapy” is designed a priori, based on the knowledge of various physiological molecules that have been obtained by the development of molecular biology. Most molecularly targeted agents slow or stop the growth of tumors. Such agents are, in general, less toxic than conventional cytotoxic agents; as a result, the maximum therapeutic effect may occur at doses well below the MTD. With the emergence of a growing number of molecularly targeted agents, approaches to early drug development are changing. We present dose‐finding designs for phase I clinical trials of molecularly targeted drugs. There is an increasing need to develop designs to find the optimal biological dose for molecularly targeted agents, and the utility of designs needs to be prospectively evaluated in future clinical dose‐finding trials for a variety of molecularly targeted agents.