Continual Reassessment Method vs. Traditional Empirically Based Design: Modifications Motivated by Phase I Trials in Pediatric Oncology by the Pediatric Brain Tumor Consortium

Abstract

In this article we provide additional support for the use of a model-based design in pediatric Phase I trials and present our modifications to the continual reassessment method (CRM), which were largely motivated by specific challenges we encountered in the context of the Pediatric Brain Tumor Consortium trials. We also summarize the results of our extensive simulations studying the operating characteristics of our modified approach and contrasting it to the empirically based traditional method (TM). Compared to the TM, our simulations indicate that the modified version of CRM is more accurate, exposes fewer patients to potentially toxic doses, and tends to require fewer patients. Further, the CRM-based MTD has a consistent definition across trials, which is important, especially in a consortium setting where multiple agents are being tested in studies that are often running simultaneously and accruing from the same patient population.

Key Words:

• Continual reassessment method
• Dose finding
• Dose-toxicity model
• Simulation
• Up-and- down studies

ACKNOWLEDGMENT

This work was supported in part by NIH grant U01 CA81457 for the Pediatric Brain Tumor Consortium (PBTC) and American Lebanese Syrian Associated Charities. The authors acknowledge helpful discussions with Dana Wallace, Coordinating Biostatistician of the Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium and the support of the PBTC investigators and, in particular, the helpful comments of Dr. Larry Kun, Chair of the PBTC.

Notes

∗Values in parentheses represent percentage of cases where the MTD was deemed to be below dose level 1.

∗Values in parentheses represent percentage of cases where the MTD was deemed to be below dose level 1.

∗Values in parentheses represent percentage of cases where the MTD was deemed to be below dose level 1.

∗Values in parentheses represent percentage of cases where the MTD was deemed to be below dose level 1.

^#Values in parentheses represent percentage of cases where the MTD was deemed to be above dose level 6.

The values in columns titled D1–D6 represent DLT probabilities for each dose level for the 6 distributions.