Confirmatory adaptive group sequential designs for single‐arm phase II studies with multiple time‐to‐event endpoints

Existing methods concerning the assessment of long‐term survival outcomes in one‐armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adapt...

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Bibliographic Details
Published in:Biometrical journal 2022-02, Vol.64 (2), p.312-342
Main Authors: Danzer, Moritz Fabian, Terzer, Tobias, Berthold, Frank, Faldum, Andreas, Schmidt, Rene
Format: Article
Language:English
Subjects:
Adaptive sampling
Carcinoma, Non-Small-Cell Lung
Clinical Trials, Phase II as Topic
Computer Simulation
Design modifications
Endpoint Determination - methods
Humans
Lung cancer
Lung Neoplasms
martingale theory
multi‐state models
Non-small cell lung carcinoma
Research Design
Sample Size
sample size recalculation
Survival
survival analysis
Toxicity
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Summary:Existing methods concerning the assessment of long‐term survival outcomes in one‐armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one‐sample tests for testing hypotheses on the multivariate survival distribution derived from multi‐state models, while making provision for data‐dependent design modifications based on all involved time‐to‐event endpoints. We explicitly elaborate application of the methodology to one‐sample tests for the joint distribution of (i) progression‐free survival (PFS) and overall survival (OS) in the context of an illness‐death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi‐state model for non‐small cell lung cancer is used to illustrate the adaptive procedure.
ISSN:0323-3847
1521-4036
DOI:10.1002/bimj.202000205