Design considerations for dose-expansion cohorts in phase I trials

Abstract

Phase I trials are increasingly including dose-expansion cohorts after the maximum-tolerated dose (MTD) has been reached to better characterize the toxicity profile or identify early signs of efficacy within a specific disease population. This article provides guidelines on how to monitor safety and re-evaluate the MTD using data obtained from expansion cohorts of phase I protocols. We illustrate how to implement a sequential monitoring rule for safety using a completed phase I trial that included an expansion cohort. We compare the accuracy of the revised MTD with the MTD obtained before expansion and with the true MTD based on simulated trials. The percent of trials that led to a change in the MTD, how far the revised MTD was from the true MTD, and the toxicity rates associated with each level are reported. When toxicity outcomes from the expansion cohort are taken into account, there is a 50% chance that a new, higher MTD will be recommended. Significant improvement in the accuracy of the MTD is obtained 30% of the time (ie, revised MTD is exactly the true MTD), and moderate improvement is obtained 80% of the time when the revised MTD is within a level from true MTD. Failure to include toxicity outcomes from additional patients treated during the expansion phase may result in a less accurate estimate of the MTD. This article provides investigators of phase I protocols with methodological tools to monitor safety and/or efficacy for patients accrued during the expansion phase and to update or confirm the established MTD.

Fig 1.

Percentage of 1,000 simulated trials that recommended each level based on dose-escalation phase alone (x-axis) versus revised maximum-tolerated dose (MTD) based on dose-escalation and -expansion cohorts (y-axis). Diagonal cells falling along solid black line indicate agreement between the two procedures. True MTDs are levels 4, 5, 4, and 6 (indicated in brackets) for scenarios (A) 1, (B) 2, (C) 3, and (D) 4, respectively.

Fig 2.

Percent of 1,000 simulated trials in which dose recommended by combined analysis using dose-escalation and -expansion cohorts was same as level recommended by dose-escalation alone, regardless if that is true maximum-tolerated dose (MTD). Within a level is defined as dose ± one level from true MTD; exact is defined as true MTD; other includes dose recommendations that are within two levels from true MTD.

Fig A1.

Hypothetical true dose-limiting toxicity (DLT) risk per patient for each scenario (ie, true dose-toxicity curves). Acceptable rate of 25% or 30% was used to vary location of true MTD. Scenarios S₁ to S₄ target 30% DLT rate. Scenarios S₅ to S₁₀ target 25% DLT rate and were studied previously.