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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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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 -