Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design

Abstract

In phase 1 dose escalation studies, dose limiting toxicities (DLTs) are defined as adverse events of concern occurring during a predefined time window after first dosing of patients. Standard dose escalation designs, such as the continual reassessment method (CRM), only utilize this binary DLT information. Thus, late-onset DLTs are usually not accounted for when CRM guiding the dose escalation and finally defining the maximum tolerated dose (MTD) of the drug, which brings safety concerns for patients. Previously, several extensions of CRMs, such as the time-to-event CRM (TITE-CRM), fractional CRM (fCRM) and the data augmented CRM (DA-CRM), have been proposed to handle this issue without prolonging trial duration. However, among the model-based designs, none of the designs have explicitly controlled the risk of overdosing as in the escalation with overdose control (EWOC) design. Here we propose a novel dose escalation with overdose control design using a two-parameter logistic regression model for the probability of DLT depending on the dose and a piecewise exponential model for the time to DLT distribution, which we call rolling-CRM design. A comprehensive simulation study has been conducted to compare the performance of the rolling-CRM design with other dose escalation designs. Of note, the trial duration is significantly shorter compared to traditional CRM designs. The proposed design also retains overdose control characteristics, but might require a larger sample size compared to traditional CRM designs.

Keywords: Continual reassessment method; Data augmentation; Dose escalation; Overdose control; Phase 1 study; Rolling enrollment.