A Bayesian dose finding design for oncology clinical trials of combinational biological agents

作者：Cai Chunyan; Yuan Ying^*; Ji Yuan

来源：Journal of the Royal Statistical Society - Series C: Applied Statistics , 2014, 63(1): 159-173.

DOI：10.1111/rssc.12039

• Adaptive design
• Biologically optimal dose combination
• Change point model
• Dose finding
• Drug combination
• Non-monotonic pattern

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose finding design to identify the biologically optimal dose combination, which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the design proposed has desirable operating characteristics in identifying the biologically optimal dose combination under various patterns of dose-toxicity and dose-efficacy relationships.

• 出版日期2014-1