Pharmacokinetic Measurements in Dose Finding Model Guided by Escalation with Overdose Control

Abstract

Oncology drug development starts with a dose escalation phase to find the maximal tolerable dose (MTD). Dose limiting toxicity (DLT) is the primary endpoint for dose escalation phase. Traditionally, model-based dose escalation trial designs recommend a dose for escalation based on an assumed dose-DLT relationship. Pharmacokinetic (PK) data are often available but are currently only used by clinical teams in a subjective manner to aid decision making. Formal incorporation of PK data in dose-escalation models can make the decision process more efficient and lead to an increase in precision. In this talk we present a Bayesian joint modeling framework for incorporating PK data in Oncology dose escalation trials. This framework explores the dose-PK and PK-DLT relationships jointly for better model informed dose escalation decisions. Utility of the proposed model is demonstrated through a real-life case study along with simulation.