The Reversed Multi-Arm Two-Stage (RevMATS) Design in Oncology Dose Optimization.

The multi-arm two-stage (MATS) design combines proof-of-concept and dose optimization in a single study, which starts from parallel enrollments of participants across multiple cohorts (indications) at a dose selected from the dose-escalation study, which is usually the maximum tolerable dose (MTD) in traditional oncology dose-escalation studies, followed by randomizing subjects into two dose levels only for those "efficaciously promising" cohorts at the second stage. Here, we communicate a variant of the MATS design by "reversing" the two stages so that randomization to two dose levels for each indication-specific cohort precedes potential further enrollment at the dose selected for optimal efficacy/safety profile based on the randomization stage. This "Reversed MATS" (RevMATS) design fits into certain situations when prior data evidence indicates two doses may result in similar activities or there is not enough evidence to favor one dose over the other in terms of preliminary activities, thus justifying earlier randomization of two doses instead of delaying to the second stage. It also fits when one dose has revealed promising early efficacy signals in a heterogenous population and there is reasonable belief of effectiveness across indications (so that a larger upfront investment is justified so that the second stage of MATS may be skipped). The RevMATS design further improves the underlying Bayesian hierarchical model in the MATS design by accounting for broader (potential) efficacy profiles of candidate doses and explicitly incorporating collective data evidence, such as estimated dose-response curves (from dose escalation), to boost efficiency in decision-making.