Proposal for size justification of expanded cohort at phase-2-recommended dose.
OBJECTIVE
Most current dose-seeking phase 1 trials include an expanded cohort at phase-2-recommended dose (P2RD) to better characterize the drug safety or to obtain a better estimate of secondary endpoints. Nevertheless, the sample size of this expanded cohort has generally not been justified.


METHODS
We reviewed 330 phase 1 trials (1998-2008). We estimated the rate of patients experiencing dose-limiting toxicity (DLT) at P2RD. Next, we estimated the probability of observing 1, 2 or 3 DLT in different fictive cohorts (from 8 to 22 patients).


RESULTS
In the literature, the rate of patients experiencing DLT at P2RD was 367/2433, or 15.0%. We drew a table estimating the probability of observing 1, 2 or 3 DLTs in the different fictive cohorts. For example, in a cohort of 16 patients, the probabilities of observing 1, 2 or 3 DLTs are about 92.6%, 91.3 and 91.1% respectively.


CONCLUSIONS
This simple tool could provide a justification for the sample size of an expanded cohort when DLT remains the metric for dose-seeking.
Penel
Nicolas
N
Département de Cancérologie Générale, Centre Oscar Lambret, Lille, France. n-penel@o-lambret.fr
Fournier
Charles
C
Bérille
Jocelyne
J
D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D011336:Probability; D018401:Sample Size