Use of expansion cohorts in phase 1 trials and probability of success in phase 2 for 381 anticancer drugs

Purpose <p>Evaluate the association between the use of phase 1 (P1) expansion cohorts (ECs) and drug performance in phase 2 (P2) as well as time to approval by the U.S. Food and Drug Administration (FDA).</p> <p>Methods </p> <p>We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology P1 trials published 2006-2011 and subsequent P2 trials. Successful P2 trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website April 2014. A logistic regression model was used to determine the associations between variables and success in P2.</p> <p>Results </p> <p>We identified 533 P1 trials evaluating 381 drugs; 112 drugs had at least one P1 trial with an EC. P1 trials with ECs of 2-20 patients were associated with a higher rate of successful P2 trials than those with no EC (48% vs 27%, OR 2.1, 95%CI 1.1-4.0, p = 0.037). P2 success rates were the same for EC with 2-20 and more than 20 patients (48% vs 52%). Other positive associations were: disease-specific trials (OR 1.7, 95%CI 1.0-2.9, p=0.037), industry sponsorship (OR 2.9, 95%CI 1.5-5.7, p = 0.0024) and response rate of 6%-20% (OR 2.89, 95%CI 1.6-5.2, p = 0.0007). Drugs tested in P1 trials with ECs had a higher rate of 5-year-approval (19% vs 5%, HR 4.4, 95% CI 2.2-8.8, p < 0.001).</p> <p>Conclusion </p> <p>The use of ECs in P1 trials was associated with success of subsequent P2 trials. However, confounders may play a role in this association.

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