Early-Phase Cancer Clinical Trials

Abstract

The primary objective of early-phase (phase I, or phase I/II) clinical trials of a given anticancer agent is to determine its optimal dose (OD) to be administered to a cancer patient, so as to obtain the highest efficacy while maintaining admissible toxicity. Thus, in oncology, early-phase trials for anticancer agents are also called “dose-finding” trials. For a chemotherapeutic or cytotoxic agent, classically, the OD is determined in the phase I trial, in which toxicity alone is primarily evaluated. Here, the highest tested safe dose with tolerable toxicity, called the “maximum tolerated dose (MTD),” is determined. This approach is adopted because monotonic increases in both toxicity and efficacy with increasing dose are assumed; thus, the MTD corresponds to the recommended phase II dose, and is also expected to yield the highest efficacy among the tested doses. However, this reasoning may not hold for molecularly targeted or cytostatic agents, or for immunotherapeutic agents (IAs). The ODs of such agents are found in phase I/II trials, in which both toxicity and efficacy are evaluated to determine the dose that yields the highest efficacy and admissible toxicity, or the dose that also yields the required immune response (particularly for IAs). This distinction exists because the efficacy does not always monotonically increase with a higher dose, even if the toxicity increases in this manner. In this chapter, we overview the clinical research and development process of anticancer drugs, describe the basic concepts of early-phase trials, and outline various dose-finding designs for early-phase trials.