Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III.

Purpose: Because the appropriate design and end points for phase II evaluation of targeted anticancer agents are unclear, we undertook a review of recent reports of phase II trials of targeted agents to determine the types of designs used, the planned end points, the outcomes, and the relationship between trial outcomes and regulatory approval.

Methods: We retrieved reports of single-agent phase II trials in six solid tumors for 19 targeted drugs. For each, we abstracted data regarding planned design and actual results. Response rates were examined for any relationship to eventual success of the agents, as determined by US Food and Drug Administration approval for at least one indication.

Results: Eighty-nine trials were identified. Objective response was the primary or coprimary end point in the majority of trials (61 of 89 trials). Fourteen reports were of randomized studies generally evaluating different doses of agents, not as controlled experiments. Enrichment for target expression was uncommon. Objective responses were seen in 38 trials; in 19 trials, response rates were more than 10%, and in eight, they were more than 20%. Agents with high response rates tended to have high nonprogression rates; renal cell carcinoma was the exception to this. Higher overall response rates were predictive of regulatory approval in the tumor types reviewed (P = .005).

Conclusion: In practice, phase II design for targeted agents is similar to that for cytotoxics. Objective response seems to be a useful end point for screening new targeted agents because, in our review, its observation predicted for eventual success. Improvements in design are recommended, as is more frequent inclusion of biological questions as part of phase II trials.