TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

Abstract

One of the primary purposes of an oncology dose-finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de-escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late-onset outcomes. To solve these issues, we propose the time-to-event Bayesian optimal interval design to accelerate dose-finding based on cumulative and pending data of both efficacy and toxicity. The new design, named "TITE-BOIN-ET" design, is nonparametric and a model-assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dosefinding trials compared with the model-based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE-BOIN-ET design has advantages compared with the modelbased approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE-BOIN-ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose-finding trials.

An overview of the BOIN design and its current extensions for novel early-phase oncology trials

“…TITE-BOIN-ET selects the OBD more accurately and puts a higher average number of patients at the OBD than model-based approaches such as the design by Thall and Cook and that by Jin et al [ 37 ]. The trial duration is significantly shortened when using TITE-BOIN-ET compared to using designs without sequential enrollment [ 37 ]. When the efficacy response rate is sufficient at lower doses, the TITE-BOIN-ET design tends to allocate more patients to doses higher than the OBD.…”

“…In such a case, suspension rules as in Refs. [ 22 , 25 ] may need to be considered to delay the dosing decisions until adequate information is available [ 37 ]. Takeda et al provide SAS code upon request to implement the TITE-BOIN-ET design.…”

“…The TITE-BOIN-ET is a model-assisted design that considers cumulative and pending toxicity and efficacy data. The TITE-BOIN-ET (Time-to-Event-BOIN Efficacy Toxicity) design is an extension of the BOIN-ET design that has been proposed to consider the following factors in dose finding: 1) fast accrual rates, 2) the difference in evaluation periods for toxicity and efficacy, and 3) the late onset outcomes [ 37 ].…”

“…Takeda et al provide SAS code upon request to implement the TITE-BOIN-ET design. The following reference provides an example dosing decision table for cohort size 3 to implement the TITE-BOIN-ET design [ 37 ].…”

“…The TITE-BOIN-ET design is robust, much simpler, and easier to implement than model-based approaches. A simulation study across a range of realistic settings shows that the TITE-BOIN-ET design selects the OBD more accurately and puts a higher average number of patients at the OBD than model-based approaches such as the design by Thall and Cook and the design by Jin et al [ 37 , 43 ]. The trial duration is also significantly shortened when using the TITE-BOIN-ET design compared to using designs without sequential enrollment [ 37 ].…”