A Randomized Basket Trial Design for Dose Optimization Based on Bayesian Model Averaging Using Spike-and-Slab Priors.

The FDA initiated Project Optimus and issued guidance for dose optimization, recommending randomized parallel dose-response cohorts to generate additional data at promising dose levels and implying that different dosages may be needed for different indications. In addition to dose optimization, with recent advancements in precision medicine and cancer biology, the development of cancer treatments has shifted toward the search for agents targeted to specific molecular profiles that may appear in more than one type of cancer. The basket trials are clinical trial designs that enable the simultaneous assessment of a new treatment in multiple indications. Concerning the FDA's dose optimization perspective and the recent trend of basket trials in early-phase clinical trials, this paper proposes a dose-ranging basket trial design based on a Bayesian model-averaging approach considering efficacy and toxicity outcomes, where indications and dose levels define baskets. A key benefit of the proposed approach is that it explicitly accounts for the possible heterogeneity of response rates among baskets. Our simulation study shows that the proposed approach outperforms other methods, offering higher statistical power, better control of Type I error rates, precise optimal dose selection, and sample size savings in various scenarios with heterogeneous treatment effects between baskets.