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. 2015 Feb 20;107(3):dju429.
doi: 10.1093/jnci/dju429. Print 2015 Mar.

A statistical evaluation of dose expansion cohorts in phase I clinical trials

Philip S Boonstra  1 , Jincheng Shen  2 , Jeremy M G Taylor  2 , Thomas M Braun  2 , Kent A Griffith  2 , Stephanie Daignault  2 , Gregory P Kalemkerian  2 , Theodore S Lawrence  2 , Matthew J Schipper  2
Affiliations

A statistical evaluation of dose expansion cohorts in phase I clinical trials

Philip S Boonstra et al. J Natl Cancer Inst. .

Abstract

Background: Phase I trials often include a dose expansion cohort (DEC), in which additional patients are treated at the estimated maximum tolerated dose (MTD) after dose escalation, with the goal of ensuring that data are available from more than six patients at a single dose level. However, protocols do not always detail how, or even if, the additional toxicity data will be used to reanalyze the MTD or whether observed toxicity in the DEC will warrant changing the assigned dose. A DEC strategy has not been statistically justified.

Methods: We conducted a simulation study of two phase I designs: the "3+3" and the Continual Reassessment Method (CRM). We quantified how many patients are assigned the true MTD using a 10 to 20 patient DEC and how a sensible reanalysis using the DEC changes the probability of selecting the true MTD. We compared these results with those from an equivalently sized larger CRM that does not include a DEC.

Results: With either the 3+3 or CRM, reanalysis with the DEC increased the probability of identifying the true MTD. However, a large CRM without a DEC was more likely to identify the true MTD while still treating 10 or 15 patients at this dose level.

Conclusions: Where feasible, a CRM design with no explicit DEC is preferred to designs that fix a dose for all patients in a DEC.

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Figures

Figure 1.
Figure 1.
Probabilities of selecting each dose level for six DTCs. The columns correspond to designs, and the rows correspond to the true probabilities of toxicity (the bottom row denotes the probability of declaring all doses too toxic). Within a column, the area of the circle is proportional to the proportion of simulations that selected that dose as the MTD. The rows corresponding to the true MTD (closest to 0.30) are shaded gray and annotated with the probabilities of selecting that dose. 3+3 = `3+3’ trial; 3+3+DEC = `3+3’ trial followed by dose-expansion cohort; CRMS = small continual reassessment method trial; CRMS+DEC = small continual reassessment method trial followed by dose-expansion cohort; CRML = large continual reassessment method trial; DTC = dose-toxicity curve; MTD = maximum tolerated dose
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