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.

Keywords: Bayesian model-based method; dose-escalation; spike and slab; subgroup effect.

Figure 1

Example of a mixture prior on β composed of a normal slab and Dirac delta function spike

Figure A1

The dose‐toxicity curves used to generate data in additional Scenarios 7 to 11. Horizontal lines are references at $\mathbb{P}(\text{DLT}|d)=0.16$ and 0.35. The solid black curve on each plot represents that of the biomarker negative subgroup in all scenarios. The dose‐toxicity curves for the biomarker positive group in these scenarios are shown for Scenarios 7 to 11 by the dashed red, green, dark blue, light blue and purple curves, respectively