Optimal adaptive two-stage designs for phase II cancer clinical trials

Biom J. 2013 Nov;55(6):955-68. doi: 10.1002/bimj.201200220. Epub 2013 Jul 19.


In oncology, single-arm two-stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simon's optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.

Keywords: Adaptive design; Branch-and-bound algorithm; Phase II clinical trial; Sample size; Two-stage design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Biometry
  • Clinical Trials, Phase II as Topic / methods*
  • Humans
  • Neoplasms / drug therapy*
  • Sample Size
  • Treatment Outcome