Dose Escalation with Overdose Control using a Quasi-Continuous Toxicity Score in Cancer Phase I Clinical Trials

• Type of Material: Article
• Authors: Zhengjia Chen, Emory University; Mourad Tighiouart, Cedars-Sinai Medical Center; Jeanne Kowalski, Emory University
• Language: English
• Date: 2012-09
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012, Elsevier
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://www.journals.elsevier.com/contemporary-clinical-trials/
• Title of Journal or Parent Work: Contemporary Clinical Trials
• ISSN: 1551-7144
• Volume: 33
• Issue: 5
• Start Page: 949
• End Page: 958
• Grant/Funding Information: Supported in part by NIH/NCI Grants No. 1 P01 CA116676 (Z.C. and M.T.), P30 CA138292-01 (Z.C. and M.T. and J.K.), 5 P50 CA128613 (Z.C. and M.T.), and CTSI Grant UL1RR033176 (M.T) and the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124.
• Keywords: Quasi-continuous; Toxicity Score System; Normalized Equivalent Toxicity Score; Escalation with Overdose Control; Maximum Tolerated Dose; Multiple Toxicities
• Research Categories: Biology, Bioinformatics; Health Sciences, Oncology; Biology, Biostatistics

Abstract

SUMMARY Escalation with overdose control (EWOC) is a Bayesian adaptive design for selecting dose levels in cancer Phase I clinical trials while controlling the posterior probability of exceeding the maximum tolerated dose (MTD). EWOC has been used by clinicians to design many cancer Phase I clinical trials, see e.g [1-4]. However, this design treats the toxicity response as a binary indicator of dose limiting toxicity (DLT) and does not account for the number and specific grades of toxicities experienced by patients during the trial. Chen et al. (2010) proposed a novel toxicity score system to fully utilize all toxicity information using a normalized equivalent toxicity score (NETS). In this paper, we propose to incorporate NETS into EWOC using a quasi-Bernoulli likelihood approach to design cancer Phase I clinical trials. We call the design escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS). Simulation results show that this design has good operating characteristics and improves the accuracy of MTD, trial efficiency, therapeutic effect, and overdose control relative to EWOC which is used as a representative of designs treating toxicity response as a binary indicator of DLT. We illustrate the performance of this design using real trial data in identifying the Phase II dose.