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Pharmacodynamic end points in early phase oncology trials

Giovanna Speranza, James H Doroshow, Shivaani Kummar

Recent insights into cancer biology and the advent of molecularly targeted agents have presented exciting opportunities for the development of cancer therapeutics. However, excessive timelines for drug development, high costs that cannot be sustained and lack of translation of efficacy from preclinical models to humans, underscore the difficulties inherent in this effort. Optimal development of molecularly targeted agents requires an understanding of a specific drug–target interaction, which depends on many factors, such as the structural features of the target, its relationship to a broad array of signaling networks, as well as what the drug does to the target itself. Proof-of-mechanism clinical trials, with incorporation of validated biomarker assays early in the development process, can provide essential human tumor data to make go or no-go decisions early in the drug-development process. Pharmacodynamic data generated in early clinical trials process could potentially expedite development of promising candidates.