期刊
STATISTICS IN MEDICINE
卷 40, 期 9, 页码 2113-2138出版社
WILEY
DOI: 10.1002/sim.8889
关键词
change‐ point model; cumulative toxicities; joint modeling; plateau identification
类别
资金
- French NCI (INCA-Optidose)
- H2020 Marie Sklodowska-Curie Actions [633567]
- Marie Curie Actions (MSCA) [633567] Funding Source: Marie Curie Actions (MSCA)
This article introduces a joint modeling approach for designing phase I/II trials for targeted therapies and immunotherapies to identify the optimal dose and monitor activity through analyzing toxicity data and biomarker measurements.
This article presents a phase I/II trial design for targeted therapies and immunotherapies, with the objective of identifying the optimal dose (OD). We employ a joint modeling technique for discrete time-to-event toxicity data and repeated and continuous biomarker measurements. For the biomarker measurements, we implement a change point linear mixed effects skeleton model. This model can accommodate both plateauing and nonplateauing dose-activity relationships. For each new cohort of patients, we estimate the maximum tolerated dose (MTD) taking toxicity as a cumulative endpoint, over six treatment cycles. Then, we select the OD using two different criteria. The OD is a dose that is equally active to the MTD or a dose located on the beginning of the plateau of the dose-activity relationship. Joint modeling allows us to take into account informative censoring due to toxicities or lack of activity and we also consider consent withdrawal and intermittent missing responses. Model estimation relies on likelihood inference.
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