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PHASE I CLINICAL TRIAL DESIGNS: RANGE AND TREND OF EXPECTED TOXICITY LEVEL IN STANDARD A+B DESIGNS AND AN EXTENDED ISOTONIC DESIGN TREATING TOXICITY AS A QUASI-CONTINUOUS VARIABLE by Zhengjia Chen A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOSTATISTICS) May 2009 Copyright 2009 Zhengjia Chen
|Title||Phase I clinical trial designs: range and trend of expected toxicity level in standard A+B designs and an extended isotonic design treating toxicity as a quasi-continuous variable|
|Author firstname.lastname@example.org; email@example.com|
|Degree||Doctor of Philosophy|
|School||Keck School of Medicine|
|Advisor (committee chair)||
Azen, Stanley P.
Krailo, Mark D.
|Advisor (committee member)||
Stram, Daniel O.
Wilcox, Rand R.
|Abstract||The current designs of Phase I trials are comprehensively reviewed and classified by algorithm (assumption and dose-toxicity relationship) as rule based designs vs model based designs or by number of stages as one stage designs vs two stage designs. Standard 3+3 designs are most widely used for their practical simplicity. Through simulation study, the expected toxicity levels (ETL) at maximum tolerated dosage (MTD) are originally found to decrease monotonically from about 30% to 0% as the number of dose levels increase from 3 to infinity, which solves the previously unexamined issue of the number of dose levels that are planned in a study. We conclude that the number of specified dose levels is an important factor affecting substantially the ETL at MTD and recommend that fewer than 20 dose levels be designated. In Standard 3+3 designs, target toxicity level (TTL) can not be pre-specified and toxicity response is treated as a binary indicator of dose limiting toxicity (DLT), discarding lots of valuable toxicity information. Therefore, a novel toxicity score system is proposed to measure quantitatively the overall severity of multiple toxicities of each patient, and then coupled with Isotonic Regression (IR) to create an extended isotonic design (EID) which allow pre-specification of TTL, treat toxicity response as a quasi-continuous variable, and fully utilize all toxicity information. Simulation studies and applications of EID to two real Phase I trials demonstrate that EID can always estimate an more accurate MTD with less sample size according to the exact toxicity profile while designs treating toxicity response as a binary variable can’t accomplish that. Our EID is practical, objective, model free, simple to use, and more accurate in MTD estimation so that it is of great practical value and will help to begin a new era in which toxicity response is really treated as a quasi-continuous variable.|
|Keyword||phase I clinical trial designs; isotonic regression; maximum tolerated dosage; extended isotonic design; quasi-continuous variable; dose limiting toxicity; binary indicator; toxicity response|
|Part of collection||University of Southern California dissertations and theses|
|Publisher (of the original version)||University of Southern California|
|Place of publication (of the original version)||Los Angeles, California|
|Publisher (of the digital version)||University of Southern California. Libraries|
|Provenance||Electronically uploaded by the author|
|Legacy record ID||usctheses-m1987|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Full text||PHASE I CLINICAL TRIAL DESIGNS: RANGE AND TREND OF EXPECTED TOXICITY LEVEL IN STANDARD A+B DESIGNS AND AN EXTENDED ISOTONIC DESIGN TREATING TOXICITY AS A QUASI-CONTINUOUS VARIABLE by Zhengjia Chen A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOSTATISTICS) May 2009 Copyright 2009 Zhengjia Chen|