One purpose of a phase I clinical trial of a new cytotoxic drug is to determine the side effects associated with increasing drug dose, i.e., determine the dose that produces the maximum effect at which the toxicity can still be tolerated. New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to this paradigm because they can achieve their maximum effect at levels lower than the maximum tolerated dose.
In a new study, Wendy R. Parulekar, M.D., and Elizabeth A. Eisenhauer, M.D., of Queen's University in Kingston, Ontario, reviewed endpoints used in 60 published phase I studies of targeted, non-cytotoxic anticancer agents. They found that the majority of studies used the traditional endpoint of toxicity to determine the recommended dose for the phase II trials. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection.
The authors conclude that although phase I studies of targeted anticancer agents in general continue to use traditional endpoints for selection of the recommended phase II dose, suitable molecular measures of drug effect and the means to incorporate them in the early drug development process are needed to optimize dose selection and drug development strategies.
In an editorial, Edward L. Korn, Ph.D., of the National Cancer Institute, discusses the assumptions and considerations required for choosing an endpoint in a phase I trial of a cytotoxic agent, and the challenges in using nontraditional endpoints for the dose selection of targeted, non-cytotoxic agents.
Contact: Wendy Parulekar, Queen's University, email@example.com