Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice

Journal of the National Cancer Institute
Wendy R Parulekar, E A Eisenhauer

Abstract

New targeted, non-cytotoxic anticancer agents, 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. We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct. Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetic data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not ro...Continue Reading

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