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A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up.

ABSTRACT: In phase II oncology trials, the use of new cytostatic drugs raises some questions regarding the endpoint. Time-to-event endpoints such as Progression-Free Survival have been recommended and led to new designs. In 2003, Case and Morgan proposed a design based on the comparison of the cumulative hazards at a clinically relevant timepoint. In 2013, Kwak proposed a design based on the one-sample log-rank test. If all the patients are followed from their entry time to the analysis date, the Kwak and Jung's design leads to a smaller sample size as compared to the Case-Morgan's design. However, the Case and Morgan's design requires less information since it only needs to follow every patient during a fixed interval of time. We propose a trade-off between these two approaches that corresponds to an adaptation of Kwak and Jung's design when the follow-up is expected to be restricted. Our proposal is based on the one-sample log-rank test as the Kwak and Jung's design but it uses the same follow-up information as the Case-Morgan's design. Simulation study shows that our proposal allows reducing the sample size as compared to the Case-Morgan's design (median difference of 23% [15%-33%]). Type I and type II error rates are close to their nominal rates planned in the protocol. A real phase II clinical trial in cervical cancer illustrated the interest of this new design. Thus, our proposal can be recommended as an alternative to the Kwak's design when patients' follow-up is restricted.

SUBMITTER: Belin L

PROVIDER: S-EPMC5898579 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up.

Belin Lisa L De Rycke Yann Y Broët Philippe P

Contemporary clinical trials communications 20171001

In phase II oncology trials, the use of new cytostatic drugs raises some questions regarding the endpoint. Time-to-event endpoints such as Progression-Free Survival have been recommended and led to new designs. In 2003, Case and Morgan proposed a design based on the comparison of the cumulative hazards at a clinically relevant timepoint. In 2013, Kwak proposed a design based on the one-sample log-rank test. If all the patients are followed from their entry time to the analysis date, the Kwak and ...[more]

PMID: 29696201

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Project description:BackgroundGiven the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion.ResultsSimulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity.ConclusionsIn a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

Dataset Information

A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up.

Publications

A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up.

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