Evaluation of Statistical Designs in Phase I Expansion Cohorts: The Dana-Farber/Harvard Cancer Center Experience

Background Phase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess end-points in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined. Methods Adult therapeutic phase I trials opened within Dana-Farber/Harvard Cancer Center (DF/HCC) from 1988 to 2012 were identified for sample size details. Statistical designs and study objectives of those submitted in 2011 were reviewed for expansion cohort details. Results Five hundred twenty-two adult therapeutic phase I trials were identified during the 25 years. The average sample size of a phase I study has increased from 33.8 patients to 73.1 patients over that time. The proportion of trials with planned enrollment of 50 or fewer patients dropped from 93.0% during the time period 1988 to 1992 to 46.0% between 2008 and 2012; at the same time, the proportion of trials enrolling 51 to 100 patients and more than 100 patients increased from 5.3% and 1.8%, respectively, to 40.5% and 13.5% (chi(2) test, two-sided P < .001). Sixteen of the 60 trials (26.7%) in 2011 enrolled patients to three or more sub-cohorts in the expansion phase. Sixty percent of studies provided no statistical justification of the sample size, although 91.7% of trials stated response as an objective. Conclusions Our data suggest that phase I studies have dramatically changed in size and scientific scope within the last decade. Additional studies addressing the implications of this trend on research processes, ethical concerns, and resource burden are needed.