A Phase I Bayesian Adaptive Design to Simultaneously Optimize Dose and Schedule Assignments Both Between and Within Patients

Abstract

In traditional schedule or dose–schedule finding designs, patients are assumed to receive their assigned dose–schedule combination throughout the trial even though the combination may be found to have an undesirable toxicity profile, which contradicts actual clinical practice. Since no systematic approach exists to optimize intrapatient dose–schedule assignment, we propose a Phase I clinical trial design that extends existing approaches to optimize dose and schedule solely between patients by incorporating adaptive variations to dose–schedule assignments within patients as the study proceeds. Our design is based on a Bayesian nonmixture cure rate model that incorporates multiple administrations each patient receives with the per-administration dose included as a covariate. Simulations demonstrate that our design identifies safe dose and schedule combinations as well as the traditional method that does not allow for intrapatient dose–schedule reassignments, but with a larger number of patients assigned to safe combinations. Supplementary materials for this article are available online.

KEY WORDS:

• Bayesian statistics
• Clinical trial
• Dose-escalation study
• Dynamic treatment regime
• Nonmixture cure model

Acknowledgments

The research is supported by National Institute of Health grant 5R01CA148713. The authors thank the editor, associate editor, and a referee for their constructive and helpful comments that substantially improved the article.

Notes

NOTE: Vectors of remaining administration times are , and

NOTE: For each design, there are four columns. Under “Selection” list, the percentage of simulations in which the MTC was not identified was identified at combinations with DLT rates below that desired, within that desired, and above that desired, respectively. Corresponding columns are listed under “Assignment” to describe the average percentage of patients assigned to each combination. DLT = mean proportion of patients who experienced DLT. The columns under “Reassignment” gives summary statistics on reassignment. Rp = average proportion of patients receiving at least one reassignment during the study; Rm (Rsd) = mean (standard deviation) of number of reassignments a patient received; R1 (Rn) = the average minimum (maximum) number of reassignments a patient received. Boldfaced values indicate dose and schedule combinations with DLT rates within 10 points of the desired DLT rate.

NOTE: The boldfaced values correspond to acceptable combinations.

NOTE: Boldfaced values indicate dose and schedule combinations with DLT rates within 10 points of the desired DLT rate η = 0.30.

NOTE: For each design, columns “Selection” give the percentage of identifying three categories of combinations as the MTC: unacceptable inefficacious combinations (“L”), acceptable combinations (“In”), and too toxic combinations (“H”). For each design, columns “Assignment” give the mean proportion of patients assigned to the three categories and columns “DLT” give the mean proportion of patients who experienced DLTs. Boldfaced values indicate dose and schedule combinations with DLT rates within 10 points of the desired DLT rate.