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Phase I design for completely or partially ordered treatment schedules.

ABSTRACT: The majority of methods for the design of phase I trials in oncology are based upon a single course of therapy, yet in actual practice, it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose-limiting toxicity may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. Past literature on designing these trials has entailed the assumption that toxicity increases monotonically with both dose and schedule. In this article, we relax this assumption for schedules and present a dose-schedule finding design that can be generalized to situations in which we know the ordering between all schedules and those in which we do not. We present simulation results that compare our method with other suggested dose-schedule finding methodology.

SUBMITTER: Wages NA

PROVIDER: S-EPMC3947103 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Phase I design for completely or partially ordered treatment schedules.

Wages Nolan A NA O'Quigley John J Conaway Mark R MR

Statistics in medicine 20130930 4

The majority of methods for the design of phase I trials in oncology are based upon a single course of therapy, yet in actual practice, it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose-limiting toxicity may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. ...[more]

PMID: 24114957

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Project description:BackgroundLimited options are available for dose-finding clinical trials requiring group-specific dose selection. While conducting parallel trials for groups is an accessible approach to group-specific dose selection, this approach allows for maximum tolerated dose selection that does not align with clinically meaningful group order information.MethodsThe two-stage continual reassessment method is developed for dose-finding in studies involving three or more groups where group frailty order is known between some but not all groups, creating a partial order. This is an extension of the existing continual reassessment method shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the recommended maximum tolerated dose for this group should not exceed the maximum tolerated dose recommended for any other group.ResultsWith limited alternatives for dose-finding in partially ordered groups, this method is compared to two alternatives: (1) an existing method for dose-finding in partially ordered groups which is less computationally accessible and (2) independent trials for each group using the two-stage continual reassessment method. Simulation studies show that when ignoring information on group frailty, using independent continual reassessment method trials by group, 30% of simulations would result in maximum tolerated dose selection that is out of order between groups. In addition, the two-stage continual reassessment method for partially ordered groups selects the maximum tolerated dose more often and assigns more patients to the maximum tolerated dose compared to using independent continual reassessment method trials within each group. Simulation results for the proposed method and the less computationally accessible approach are similar.ConclusionThe proposed continual reassessment method for partially ordered groups ensures appropriate maximum tolerated dose order and improves accuracy of maximum tolerated dose selection, while allowing for trial implementation that is computationally accessible.

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Phase I design for completely or partially ordered treatment schedules.

Publications

Phase I design for completely or partially ordered treatment schedules.

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