A Statistical Evaluation of Dose Expansion Cohorts in Phase I Clinical Trials

In phase I clinical trial design, it has become common to extend the protocol beyond the standard dose escalation phase (eg, the cohorts-of-three “3+3” algorithm, accelerated titration, or continual reassessment method [CRM] [1,2]), which estimates a maximum tolerated dose (MTD). This protocol extension, called a dose expansion cohort (DEC), treats additional patients at the estimated MTD, sometimes stratifying enrollment of the DEC by multiple disease sites. The typical aim is to ensure that a sufficient number of patients has been treated at the estimated MTD by the trial’s completion to begin to characterize efficacy, tolerability, and pharmacokinetic or pharmacodynamic (PK/PD) endpoints (3–11). Recent discussions have highlighted the increasing size and complexity of DECs as well as the need to prospectively justify corresponding aims and analyses, which may be lacking (9–11). This paper provides a statistically based assessment of DECs and offers recommendations based on these results. A systematic review of 611 single-agent phase I trials published from 2006 to 2011 found that 149 (24%) included a DEC, with the use of DECs increasing over time (9). Thirty-eight of these trials did not include any specific objectives for the DEC; among those that did, safety was most common (89 trials, 60%), followed by efficacy (50 trials, 34%). There is also heterogeneity in the size of DECs. Among the 149 trials identified by Manji, et al., the median DEC size was 17, and the range was two to 271 (9). In 10 case studies from Iasonos and O’Quigley, seven had a DEC of size less than 25, and the remaining three were 43, 97, and 100 (10). Dahlberg, et al. report a median DEC size of 27 from 60 phase I trials submitted at Harvard in 2011 (11). Reviewing all phase I trials at our institution (University of Michigan Comprehensive Cancer Center) currently enrolling patients (as of June, 2014), we found that 54 have a planned DEC in the trial protocol, with a median size of 19 and range of four to 105. Trials with a small DEC, eg, fewer than 25 patients, are of greatest relevance in a phase I context, where safety remains of primary importance and preliminary evidence of efficacy is secondary. Because these studies are not statistically powered to evaluate efficacy, they fall short of being true phase I/II trials. Recent papers have proposed dose-finding designs based on efficacy and toxicity (12–14). Although DECs may have additional endpoints beyond toxicity, a DEC strategy should first be rigorously evaluated with regard to patient safety, both to future patients, that is, finding the true MTD, as well as patients in the current trial, that is, treating many current patients at the true MTD (15–17). Thus, our focus here is on the role of DECs in traditional phase I designs based on toxicity considerations. A principled dose escalation mechanism should operate for the duration of the trial to satisfy the safety metrics just described. We support this assertion with a simulation study of trial designs with a 10 to 20 patient DEC. The benefit conferred by a DEC may depend on the trial design, and we evaluate two common dose escalation designs: the 3+3 algorithm and the CRM (18). Because the final sample size of a 3+3 is not predetermined, adding a DEC increases the size of a trial that might otherwise be small. In contrast, the sample size of the CRM design may be predetermined, leading to a decision between inclusion of a DEC following completion of the CRM or a larger CRM in which the dose assignment mechanism operates throughout the entire trial. In investigator-initiated trials at our institution, the CRM design is used exclusively, making this decision crucial and recurrent. To the best of our knowledge, however, the strategy of appending a DEC to a CRM trial has not been statistically justified. Thus, we consider a small CRM trial paired with a DEC and an equivalently sized “large” CRM trial with no DEC. Iasonos and O’Quigley provide guidance for safety monitoring during the DEC and present four strategies for reevaluating estimated dose-toxicity rates during and after the DEC based on safety or efficacy data (10). Also included was a simulation study of the 3+3 design to assess how frequently the final MTD estimate, after analyzing the DEC data, differs from the initial MTD estimate. Extending rule-based designs like the 3+3 with DECs is natural because such trials may otherwise terminate before enrolling enough patients to precisely evaluate secondary objectives such as efficacy or PK/PD (eg, 3–6). The authors found that the post-DEC MTD estimate from a complete analysis was more accurate than the pre-DEC estimate but did not report the frequency in which patients in the trial were assigned the true MTD. A final important and distinguishing feature of this paper is that we differentiate between the final estimated, or selected, MTD and the true, unknown MTD, the latter being the dose level that induces dose-limiting toxicity (DLT) in x% of patients, where x may be selected based on characteristics of a particular therapy. Treating more than six patients at the estimated MTD is the motivation for using DECs and drives how precisely efficacy endpoints such as response rates may be estimated. However, although it is often implicitly assumed that the MTD determined from the dose-escalation phase is the true MTD, eg, “[t]he MTD was defined as the highest dose level with DLTs in <33% of the patients enrolled in the cohort” (p.700 [4]), this assumption is not true (19). Rather, this selected dose level is an estimate of the true MTD based on the limited available data. Given the small size of phase I studies, it frequently differs from the true MTD in a much larger population of patients. A DEC comprised of patients that are not enrolled at the true MTD will be less useful for characterizing later endpoints such as efficacy or PK/PD.