Date of Award

1-1-2009

Embargo Period

1-1-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biostatistics and Epidemiology

College

College of Graduate Studies

First Advisor

Elizabeth Garrett-Mayer

Second Advisor

Dipankar Bandyopadhyay

Third Advisor

Pierre Giglio

Fourth Advisor

Renee H. Martin

Fifth Advisor

Yuko Y. Palesch

Sixth Advisor

Abhay Varma

Abstract

Currently many dose finding clinical trial designs, including the continual reassessment method (CRM) and the standard 3 + 3 design, dichotomize toxicity outcomes based on pre-specified dose-limiting toxicity criteria. This loss of information is particularly inefficient due to the small sample sizes in phase I trials. Common Toxicity Criteria (CTCAE v3 .0) classify adverse events into grades 1 through 5, which range from 1 as a mild adverse event to 5 as death related to an adverse event. In this paper, we extend the CRM to include ordinal toxicity outcomes as specified by CTCAEv3.0 using the proportional odds model and compare results with the dichotomous CRM. A sensitivity analysis of the new design compares various prior distributions, target dose-limiting toxicity rates, sample sizes, and cohort sizes. This design is also assessed under various dose-toxicity relationship models including proportional odds models as well as those that violate the proportional odds assumption. A simulation study shows that the proportional odds CRM performs as well as the dichotomous CRM on all criteria compared, and notably with more precision to estimate the maximum tolerated dose (MTD). These findings suggest that it is beneficial to incorporate ordinal toxicity endpoints into phase I trial designs.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

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