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Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design

Jeffrey M. Skolnik, Jeffrey S. Barrett, Bhuvana Jayaraman, Dimple Patel, Peter C. Adamson

From the Division of Clinical Pharmacology and Therapeutics; and Division of Oncology, the Children's Hospital of Philadelphia, Philadelphia, PA

Corresponding author: Jeffrey M. Skolnik, MD, the Children's Hospital of Philadelphia, Abramson Research Center 916, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318; e-mail: skolnik{at}email.chop.edu

Purpose: 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).

Conclusion: 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' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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