Nontoxicity endpoints in phase I trial designs for targeted, non-cytotoxic agents.

Phase I trial designs for cytotoxic agents are based on the assumptions that (a) the clinical benefit of the agent increases with increasing dose, (b) the toxicity of the agent increases with increasing dose, and (c) there is a dose with acceptable toxicity that offers clinical benefit. For a targeted, non-cytotoxic agent, researchers and clinicians still obviously use the third assumption, but the first and second assumptions require additional consideration. When the first or second assumptions are not reasonable for an agent, one might want to consider using a dose escalation design that is not based on occurrences of toxicity, as in a standard phase I trial, but is based on some other endpoint. In this issue of the Journal, Parulekar and Eisenhauer (1) explore this possibility for targeted, non-cytotoxic agents and report the results of a survey of trial designs of completed phase I trials using such agents. They find that, in determining the recommended phase II dose from a phase I trial, the primary basis for the recommendation is still toxicity in the majority of trials, with pharmacokinetic data being used as the primary basis for the recommendation approximately 20% of the time. In only two trials (out of 60) was a targeted endpoint or surrogate tissue finding used as the primary basis for determining the recommended phase II dose. Why are so few phase I trials using nontoxicity endpoints? As