ArticleClinical trials (London, England)2023
Comparison of design methods for a safety run-in phase of a phase II clinical trial.
Article in Clinical trials (London, England), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Risk-stratified treatment of sonrotoclax with chemotherapy in newly diagnosed acute myeloid leukemia: a study protocol.Future oncology (London, England) · 2025Article
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Abstract
BACKGROUND/
aimsIn 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.
methodsExtensive 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.
resultsThe 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.
conclusionsDespite 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.
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