Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials

Abstract

Despite more than two decades of publications that offer more innovative model-based designs, the classical 3 + 3 design remains the most dominant phase I trial design in practice. In this article, we introduce a new trial design, the Bayesian optimal interval (BOIN) design. The BOIN design is easy to implement in a way similar to the 3 + 3 design, but is more flexible for choosing the target toxicity rate and cohort size and yields a substantially better performance that is comparable with that of more complex model-based designs. The BOIN design contains the 3 + 3 design and the accelerated titration design as special cases, thus linking it to established phase I approaches. A numerical study shows that the BOIN design generally outperforms the 3 + 3 design and the modified toxicity probability interval (mTPI) design. The BOIN design is more likely than the 3 + 3 design to correctly select the MTD and allocate more patients to the MTD. Compared with the mTPI design, the BOIN design has a substantially lower risk of overdosing patients and generally a higher probability of correctly selecting the MTD. User-friendly software is freely available to facilitate the application of the BOIN design. Clin Cancer Res; 22(17); 4291-301. ©2016 AACR.

Conflict of interest statement

of Potential Conflicts of Interest: Y. Yuan is a consultant/advisory board member for Agenus. K.R. Hess is an uncompensated consultant/advisory board member for Angiochem. No potential conflicts of interest were disclosed by the other authors.

©2016 American Association for Cancer Research.

Figures

Figure 1

Flowchart of the BOIN design.

Figure 2

A hypothetical phase I clinical trial using the BOIN design. The numbers indicate the patient’s identification. Three patients in each box form a cohort.

Figure 3

Percentage of correct selection of the MTD under the 3+3, mTPI and BOIN designs when the target toxicity rate is 15%, 20%, 25% and 30%. A higher value is better.

Figure 4

Average number of patients allocated to the MTD under the 3+3, mTPI and BOIN designs when the target toxicity rate is 15%, 20%, 25% and 30%. A higher value is better.

Figure 5

Risk of overdosing 60% or more of patients under the 3+3, mTPI and BOIN designs when the target toxicity rate is 15%, 20%, 25% and 30%. A lower value is better.

Figure 6

Risk of overdosing 80% or more of patients under the 3+3, mTPI and BOIN designs when the target toxicity rate is 15%, 20%, 25% and 30%. A lower value is better.

Figure 7

Risk of underdosing (i.e., assigning more than 80% of patients to doses below the MTD) under the 3+3, mTPI and BOIN designs when the target toxicity rate is 15%, 20%, 25% and 30%. A lower value is better.