Home > Research > Publications & Outputs > A flexible design for advanced Phase I/II clini...

Links

Text available via DOI:

View graph of relations

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Published

Standard

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints. / Mozgunov, Pavel; Jaki, Thomas.
In: Biometrical Journal, Vol. 61, No. 6, 01.11.2019, p. 1477-1492.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

APA

Vancouver

Mozgunov P, Jaki T. A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints. Biometrical Journal. 2019 Nov 1;61(6):1477-1492. Epub 2019 Jul 12. doi: 10.1002/bimj.201800313

Author

Bibtex

@article{4960b8a4529649e1b3c5472b9e168b83,
title = "A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints",
abstract = "There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.",
keywords = "combination trial, continuous endpoint, nonmonotonic efficacy, Phase I/II clinical trial",
author = "Pavel Mozgunov and Thomas Jaki",
year = "2019",
month = nov,
day = "1",
doi = "10.1002/bimj.201800313",
language = "English",
volume = "61",
pages = "1477--1492",
journal = "Biometrical Journal",
issn = "0323-3847",
publisher = "Wiley-VCH Verlag",
number = "6",

}

RIS

TY - JOUR

T1 - A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints

AU - Mozgunov, Pavel

AU - Jaki, Thomas

PY - 2019/11/1

Y1 - 2019/11/1

N2 - There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

AB - There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

KW - combination trial

KW - continuous endpoint

KW - nonmonotonic efficacy

KW - Phase I/II clinical trial

U2 - 10.1002/bimj.201800313

DO - 10.1002/bimj.201800313

M3 - Journal article

VL - 61

SP - 1477

EP - 1492

JO - Biometrical Journal

JF - Biometrical Journal

SN - 0323-3847

IS - 6

ER -