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arXiv · 2607.17692

A Globally Calibrated Bayesian Optimal Phase II Design for Adaptive Enrichment Trials

Masahiro Kojima·Hisato Sunami·Masaaki Kuriki
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Abstract

Adaptive enrichment allows development of an experimental treatment to continue when its activity is insufficient in an all-comer population but remains promising in a prespecified biomarker-positive subgroup. However, sequential application of separately calibrated phase II designs can inflate the probability of a false-positive efficacy conclusion. We develop a globally calibrated Bayesian optimal phase II (BOP2) design for branching adaptive enrichment trials. At prespecified all-comer interim analyses, the trial either continues all-comer enrollment or, after crossing the all-comer futility boundary, evaluates the accumulated biomarker-positive data. Enrichment is initiated only when a prespecified minimum number of biomarker-positive patients is available and the biomarker-positive futility boundary is not crossed; otherwise, the trial stops. The all-comer and biomarker-positive thresholds are jointly calibrated for the union of the two possible efficacy claims while accounting for the random subgroup sample size available when enrichment is considered. All decision rules are prespecified before trial initiation. For a binary endpoint, an exact finite-state recursive enumeration enables calibration and operating-characteristic evaluation without Monte Carlo error. Under the prespecified point global null, the proposed design controlled the global type I error rate over the prespecified set of biomarker-positive prevalence values while achieving higher power than the independently calibrated BOP2 comparator across the evaluated alternative scenarios. In the numerical study, the independently calibrated comparator exceeded the nominal global type I error level after its components were embedded in the branching procedure. The framework is also extended to complex categorical endpoints using a Dirichlet--multinomial formulation, with calibration and evaluation performed by simulation.

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Masahiro Kojima, Hisato Sunami, Masaaki Kuriki. 2026-07-20. A Globally Calibrated Bayesian Optimal Phase II Design for Adaptive Enrichment Trials. https://arxiv.org/abs/2607.17692

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