Optimization of EWOC principle in BLRM design for phase 1 oncology trials.

ABSTRACT

Bayesian logistic regression model (BLRM) is widely used to guide dose escalation decisions in phase 1 oncology trials. An important feature of BLRM design is the appealing safety performance due to its escalation with overdose control (EWOC). However, some recent literature indicates that BLRM with EWOC may have a relatively low probability to find the maximum tolerated dose (MTD) compared to some other dose escalation designs. This work discusses this design problem and proposes a practical solution to improve the performance of BLRM design. Specifically, we suggest increasing the EWOC cutoff from routine value 0.25 to a value between 0.3 and 0.4, which will increase the chance of finding the correct MTD with minimal compromise to overdosing risk. Our comparative simulation studies indicate that BLRM with an increased EWOC cutoff has comparable operating characteristics on the correct MTD selection and over-toxicity control as other dose escalation designs (BOIN, mTPI, keyboard, etc.). Moreover, we compare the methodology and operating characteristics of BLRM designs with various decision rules that allow more flexible overdosing control. A case study of dose escalation in a recent phase 1 oncology trial is provided to show how BLRM with optimal EWOC cutoff operates well in practice.