title: Evolution of clinical trial design in early drug development: systematic review of expansion cohort use in single-agent phase I cancer trials.
abstract: OBJECTIVE
  To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use.
  
  
  METHODS
  We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression.
  
  
  RESULTS
  We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation.
  
  
  CONCLUSIONS
  The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.
authors.affiliation: Arif Manji, Irene Brana, Eitan Amir, Ian F. Tannock, Philippe L. Bedard, Amit Oza, Lillian L. Siu, and Albiruni R. Abdul Razak, Princess Margaret Cancer Centre, University Health Network; George Tomlinson, University of Toronto; and Arif Manji, Hospital for Sick Children, Toronto, and Southlake Regional Health Centre, Newmarket, Ontario, Canada.
authors.forename: Arif
authors.initials: A
authors.lastname: Manji
authors.forename: Irene
authors.initials: I
authors.lastname: Brana
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
authors.forename: George
authors.initials: G
authors.lastname: Tomlinson
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Albiruni R Abdul
authors.initials: AR
authors.lastname: Razak
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods / Q000706:statistics & numerical data*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016015:Logistic Models; D015999:Multivariate Analysis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D012107:Research Design / Q000592:standards / Q000706:statistics & numerical data* / Q000639:trends
chemical_list: D000970:Antineoplastic Agents