Optimal biological dose selection in dose-finding trials with model-assisted designs based on efficacy and toxicity: a simulation study

ABSTRACT

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection.

KEYWORDS:

• Bayesian optimal interval design
• model-assisted design
• Phase I/II dose-finding trial
• optimal biological dose
• utility

Acknowledgements

We are grateful to two reviewers for their valuable comments, which improved the presentation of this article.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10543406.2023.2202259.

Additional information

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.