Interactive Software for Dose Calculation and Simulation of Phase I Cancer Clinical Trial Using EWOC-NETS Design Open Access

Abstract

Phase I clinical trials signify the first stage experimentation of a new drug in human use. Because cancer patients who respond poorly to conventional treatment usually resort to experimental treatment options such as phase I cancer clinical trials, additional concerns arise in the design of such trials. A combination of accuracy of Maximum Tolerated Dose (MTD) prediction and rapidity of dose escalation is required to maximize the therapeutic effect and minimize the toxic effect for enrolled patients. It is with such considerations that Escalation With Overdose Control – Normalized Equivalent Toxicity Score (EWOC-NETS) was created. Incorporating Bayesian statistics and a novel quasi-continuous toxicity grading system, EWOC-NETS has been shown to outperform various rule-based and adaptive models. However, due to its statistical complexity, it is exceedingly difficult to implement. Because of that, its usage in clinical settings has been significantly hindered. Here, we introduce a user-friendly, standalone software that enables both MTD calculation during trial progress and trial simulations. Our software enables clinicians to both implement and simulate EWOC-NETS clinical trials. It is our hope that the prevalent usage of EWOC-NETS resulting from the development of our software can facilitate and catalyze the efforts in cancer drug development worldwide.

Table of Contents

Abstract 1

Acknowledgement 1

Introduction 2

Project Objectives and Goals . . . . . . . . . . . . . . . . 2

Toxicity Information Categorization Methods . . . . . . . . . . . 3

Common Terminology Criteria for Adverse Events (CTCAE) . . . . . 3

Traditional Toxicity Information Categorization Methods . . . . . 4

Normalized Equivalent Toxicity Score (NETS) Quasi-continuous Categorization Methods . . . . . .5

Target Toxicity Level (TTL) vs. Target NETS . . . . . . . . . . 7

Phase I Cancer Clinical Trial Designs . . . . . . . . . . . . . . 8

Rule-Based Clinical Trial Designs . . . . . . . . . . . . . 8

Continual Reassessment Method (CRM) . . . . . . . . . . . 9

Bayesian Optimal INterval (BOIN) Design . . . . . . . . . . 10

Toxicity EQuivalance Range (TERQ) Design . . . . . . . . . . 11

Escalation With Overdose Control (EWOC) . . . . . . . . . . 12

EWOC-NETS Design . . . . . . . . . . . . . . . . . 12

Comparison between Dose Escalation Models . . . . . . . . . 13

Methods 13

Model Computation . . . . . . . . . . . . . . . . . . . 13

EWOC Model Computation . . . . . . . . . . . . . . 13

NETS Model Computation . . . . . . . . . . . . . . . 15

EWOC-NETS Model Computation . . . . . . . . . . . . . 15

EWOC-NETS Simulation . . . . . . . . . . . . . . . . 17

Programming . . . . . . . . . . . . . . . . . . . . . 18

Programming language . . . . . . . . . . . . . . . . 18

R packages . . . . . . . . . . . . . . . . . . . 18

Deploying procedures . . . . . . . . . . . . . . . . 19

Results 19

EWOC-NETS Calculator . . . . . . . . . . . . . . . . . . 19

Input Parameters . . . . . . . . . . . . . . . . . 19

Obtaining and Interpreting Results . . . . . . . . . . . . 21

EWOC-NETS Simulator . . . . . . . . . . . . . . . . . . 22

Input Parameters . . . . . . . . . . . . . . . . . 22

Obtaining and Interpreting Results . . . . . . . . . . . . 23

Downloading Software . . . . . . . . . . . . . . . . . . 23

Discussion 24

List of Tables 26

List of Figures 29

References 38

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Statistics Health Sciences, Toxicology Health Sciences, Oncology
Keyword	Clinical Trial Design EWOC Software NETS Phase I clinical trial EWOC-NETS
Committee Chair / Thesis Advisor	Chen Zhengjia, Emory University
Committee Members	Weissman Daniel, Emory University Kutner Michael, Emory University

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