title: Shortening the timeline of pediatric phase I trials: the rolling six design.
abstract: OBJECTIVE
  To shorten the study conduct timeline of pediatric phase I oncology trials by employing a novel trial design.
  
  
  METHODS
  A comparison of the traditional 3 + 3 patients per cohort, phase I trial design with a novel, rolling six design was performed by using discrete event simulation. The rolling six design allows for accrual of two to six patients concurrently onto a dose level based on the number of patients currently enrolled and evaluable, the number experiencing dose-limiting toxicity (DLT), and the number still at risk of developing a DLT. Clinical trial simulations (n = 1,000) were based on historical data and were performed using SAS 9.1.3 (SAS Institute, Cary, NC). Study timelines and patient numbers were determined for each design, and safety was assessed as a function of the number of DLTs observed.
  
  
  RESULTS
  In twelve completed historical studies, the median time to study completion was 452 days (range, 220 to 606 days); number of evaluable participants enrolled was 22 (range, 11 to 33), and DLTs occurring per study was three (range, 0 to 5). In 1,000 study simulations, in which the average time to new patient accrual was 10 days, the average +/- standard deviation (SD) time to study completion was 294 +/- 75 days for the rolling six design versus 350 +/- 84 days for the 3 + 3 design, whereas the number of DLTs per study was the same (average +/- SD, 3.3 +/- 1.1 v 3.2 +/- 1.1 for the rolling six and 3 + 3 designs, respectively).
  
  
  CONCLUSIONS
  The rolling six design may significantly decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The design will be tested prospectively in upcoming Children's Oncology Group phase I trials.
authors.affiliation: Children's Hospital of Philadelphia, Abramson Research Center 916, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318, USA. skolnik@email.chop.edu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Jayaraman
authors.forename: Dimple
authors.initials: D
authors.lastname: Patel
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D017321:Clinical Trials, Phase I as Topic / Q000592:standards*; D004334:Drug Administration Schedule; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents