Application of a Class of Copula-Type Models in Early-Phase Dose Drug Combination Trials Using Conditional Escalation with Overdose Control

• Activity Number: 372
• Type: Contributed
• Date/Time: Tuesday, August 11, 2015 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Galen Cook-Wiens* and Mourad Tighiouart and Andre Rogatko
• Companies: Cedars Sinai Medical Center and Cedars Sinai Medical Center and Cedars Sinai Medical Center
• Keywords: Cancer Phase I trials ; Maximum tolerated dose ; Escalation With Overdose Control ; Dose limiting toxicity ; Drug Combination ; Copula type models

Abstract

We propose a dose finding design of a combination of two drugs with continuous dose levels in cancer phase I clinical trials with the goal of estimating the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. Copula type models are used to describe the relationship between the doses and the probability of dose limiting toxicity (DLT). Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. The method is further adapted to the case of a pre-specified discrete set of dose combinations and we show how more than one dose combination can be recommended as the MTD. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship.