Development of investigational radiation modifiers

Abstract

Positive, appropriate, preclinical data that are adequately reviewed are a prerequisite for clinical trials of radiation modifiers. The appropriate tumor models, dosing schedules, and assays should be based on the mechanism of action of the proposed radiation modifier. The activity of a radiation modifier should be correlated with its activity against a target. Priority for clinical development should be given to agents that have known, assay-able targets or that produce extraordinary preclinical efficacy data. Phase I trials of radiation modifiers with radiation should efficiently and safely determine a recommended phase II dose. The recommended phase II dose for radiation modifier plus radiation trials is not necessarily the maximum tolerated dose of the combination, nor is it necessarily related to the recommended phase II dose of the agent alone or in combination with other drugs. The schedule of the combination of radiation modifier and radiation should be based on preclinical optimization experiments. Clinically useful endpoints in radiation modifier plus radiation trials usually include time to progression, locoregional control, and survival rather than overall response rates. Clinical development of radiation modifiers plus radiation should consist of building the radiation modifier into acceptable standard of care regimens utilizing full-dose radiation.