Phase I dose-escalation oncology trials with sequential multiple schedules

Abstract

Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing schedules to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results In a simulation study, the developed approach is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-predictive prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The and code for the implementation of an illustrative sequential phase I trial example in oncology is publicly available (https://github.com/gunhanb/TITEPK_sequential). Conclusion In phase I oncology trials with sequential multiple schedules, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

A straightforward meta‐analysis approach for oncology phase I dose‐finding studies

“…The aim of this article is to propose a simple meta‐analysis approach for the estimation of the MTD from multiple phase I dose‐finding studies. The proposed two‐stage approach is easier to implement than a one‐stage approach that would require additional assumptions on the model, such as the control group response or the implementation of pooling and stratification schemes 84 …”

“…The proposed two-stage approach is easier to implement than a one-stage approach that would require additional assumptions on the model, such as the control group response or the implementation of pooling and stratification schemes. 84 F I G U R E 6 A forest plot illustrating the meta-analysis for the Irinotecan/S-1 example data. MTD estimates are given on the logarithmic as well as on the dose scale…”

A semi‐mechanistic dose‐finding design in oncology using pharmacokinetic/pharmacodynamic modeling

“…Their model construction is similar to the model components used in our proposed approach, yet based on multi‐step estimation, as opposed to joint modeling. Other authors have incorporated external PK information into dose‐finding designs in the presence of multiple schedules using a time‐to‐event PK model 18,19 …”

“…Other authors have incorporated external PK information into dose-finding designs in the presence of multiple schedules using a time-to-event PK model. 18,19 The existing approaches in the area of dose-finding trial designs using PK and/or PD information have some limitations. First, the use of a pre-specified summary measure of PK may limit the information that can be gained, as opposed to dynamic modeling of the full PK profile.…”

Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial

“…In parallel to our work, two new approaches were proposed recently. Günhan et al [ 27 , 28 ] offer an elegant solution to support dose-escalation relying on a drug exposure-time to event model. This approach requires prior knowledge (or assumptions) on the PK profiles of the IMP, and uses time to DLT as an endpoint to drive the dose escalation.…”