Dose-escalation strategies which use subgroup information.

Abstract

Dose‐escalation trials commonly assume a homogeneous trial population to identify a single recommended dose of the experimental treatment for use in future trials. Wrongly assuming a homogeneous population can lead to a diluted treatment effect. Equally, exclusion of a subgroup that could in fact benefit from the treatment can cause a beneficial treatment effect to be missed. Accounting for a potential subgroup effect (ie, difference in reaction to the treatment between subgroups) in dose‐escalation can increase the chance of finding the treatment to be efficacious in a larger patient population.A standard Bayesian model‐based method of dose‐escalation is extended to account for a subgroup effect by including covariates for subgroup membership in the dose‐toxicity model. A stratified design performs well but uses available data inefficiently and makes no inferences concerning presence of a subgroup effect. A hypothesis test could potentially rectify this problem but the small sample sizes result in a low‐powered test. As an alternative, the use of spike and slab priors for variable selection is proposed. This method continually assesses the presence of a subgroup effect, enabling efficient use of the available trial data throughout escalation and in identifying the recommended dose(s). A simulation study, based on real trial data, was conducted and this design was found to be both promising and feasible.