Continual Reassessment Method for Partially Ordered Groups

• Activity Number: 620 - Dose-Finding for Monotherapy and Combination Therapy in Oncology and Other Complex Studies
• Type: Contributed
• Date/Time: Thursday, August 3, 2017 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Bethany Horton* and Nolan Wages and Mark Conaway
• Companies: The University of Virginia and The University of Virginia and The University of Virginia
• Keywords: Continual Reassessment Method ; Dose-finding studies ; Clinical trials ; Phase I designs ; Partially ordered groups

Abstract

The two-stage continual reassessment method (CRM) is used for dose-finding in studies involving three or more groups where group frailty order is partially known. With partial ordering, group frailty order is known between some but not all groups. This is an extension of the existing CRM shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose (MTD) selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the MTD for this group should not exceed the MTD recommended for any other group. With limited alternatives for dose finding with partially ordered groups, this method is compared to independent two-stage CRM trials for each group. Simulations show that when ignoring information on order, using independent CRM trials, in 30% of simulations the MTD selection is out of order between groups. In addition, the two-stage CRM for partially ordered groups selects the MTD more often and assigns more patients to the MTD compared to using independent CRM trials within each group. CRM for partially ordered groups ensures appropriate MTD order and improves accuracy of MTD selection.