Dose escalation with overdose control using a quasi-continuous toxicity score in cancer Phase I clinical trials

Zhengjia Chen, Mourad Tighiouart, Jeanne Kowalski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)949-958
Number of pages10
JournalContemporary Clinical Trials
Volume33
Issue number5
DOIs
StatePublished - Sep 2012
Externally publishedYes

Fingerprint

Clinical Trials, Phase I
Maximum Tolerated Dose
Neoplasms
Therapeutic Uses

Keywords

  • Escalation with overdose control
  • Maximum tolerated dose
  • Multiple toxicities
  • Normalized equivalent toxicity score
  • Quasi-continuous
  • Toxicity score system

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Medicine(all)

Cite this

Dose escalation with overdose control using a quasi-continuous toxicity score in cancer Phase I clinical trials. / Chen, Zhengjia; Tighiouart, Mourad; Kowalski, Jeanne.

In: Contemporary Clinical Trials, Vol. 33, No. 5, 09.2012, p. 949-958.

Research output: Contribution to journalArticle

Chen, Zhengjia ; Tighiouart, Mourad ; Kowalski, Jeanne. / Dose escalation with overdose control using a quasi-continuous toxicity score in cancer Phase I clinical trials. In: Contemporary Clinical Trials. 2012 ; Vol. 33, No. 5. pp. 949-958.
@article{c7b9b8f571564894ac43b67cc61530d5,
title = "Dose escalation with overdose control using a quasi-continuous toxicity score in cancer Phase I clinical trials",
abstract = "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.",
keywords = "Escalation with overdose control, Maximum tolerated dose, Multiple toxicities, Normalized equivalent toxicity score, Quasi-continuous, Toxicity score system",
author = "Zhengjia Chen and Mourad Tighiouart and Jeanne Kowalski",
year = "2012",
month = "9",
doi = "10.1016/j.cct.2012.04.007",
language = "English (US)",
volume = "33",
pages = "949--958",
journal = "Contemporary Clinical Trials",
issn = "1551-7144",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Dose escalation with overdose control using a quasi-continuous toxicity score in cancer Phase I clinical trials

AU - Chen, Zhengjia

AU - Tighiouart, Mourad

AU - Kowalski, Jeanne

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

KW - Escalation with overdose control

KW - Maximum tolerated dose

KW - Multiple toxicities

KW - Normalized equivalent toxicity score

KW - Quasi-continuous

KW - Toxicity score system

UR - http://www.scopus.com/inward/record.url?scp=84864313283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864313283&partnerID=8YFLogxK

U2 - 10.1016/j.cct.2012.04.007

DO - 10.1016/j.cct.2012.04.007

M3 - Article

C2 - 22561391

AN - SCOPUS:84864313283

VL - 33

SP - 949

EP - 958

JO - Contemporary Clinical Trials

JF - Contemporary Clinical Trials

SN - 1551-7144

IS - 5

ER -