Comparison of design methods for a safety run-in phase of a phase II clinical trial

Abstract

Background/Aims: In pediatric oncology, a Phase II trial often utilizes a safety run-in phase followed by an efficacy phase that enrolls at the dose level selected based on the safety run-in. Different from a Phase I trial, a Phase II safety run-in often assesses a very small number of dose levels. In the context of a safety run-in that assesses two or three dose levels, this article aims to compare three design methods, including the algorithm-based designs 3 + 3 and Rolling 6, and the model-assisted designs such as the Bayesian optimal interval design. Methods: Extensive simulations were conducted to evaluate and compare operating characteristics of the three design methods for a safety run-in with two or three dose levels, varying the starting dose level. Results: The performance of algorithm-based and model-assisted designs can be influenced by selection of the starting dose level, with trials starting at a lower dose level having a higher probability of selecting a low dose or considering all doses as toxic. The impact is larger for 3 + 3 and Rolling 6 but to a lesser extent for Bayesian optimal interval design. For a safety run-in with two dose levels, using 3 + 3 or Rolling 6 and starting at the higher dose often lead to similar performance to Bayesian optimal interval design. For safety run-in with three dose levels, starting at the middle dose with 3 + 3, Rolling 6 or Bayesian optimal interval design is a good compromise between improving correct dose selection and imposing a toxic dose to less patients. Conclusions: Despite being sensitive to the starting dose level, the 3 + 3, Rolling 6 and Bayesian optimal interval designs overall demonstrate reasonable performance, which can be further improved with wise selection of the starting dose level. The Rolling 6 design remains the recommended design method especially if pharmacokinetics is important or required with this design having the feature of treating six patients per dose level. When designing a safety run-in, selection of a design method or selection of a starting dose should consider both the performance of the design approaches with different choices of a starting dose level and the magnitude of safety concerns with the dose levels under investigation.