Escalation with Overdose Control Using Ordinal Toxicity Grades for Cancer Phase I Clinical Trials

Abstract

We extend a Bayesian adaptive phase I clinical trial design known as escalation with overdose control (EWOC) by introducing an intermediate grade 2 toxicity when assessing dose-limiting toxicity (DLT). Under the proportional odds model assumption of dose-toxicity relationship, we prove that in the absence of DLT, the dose allocated to the next patient given that the previously treated patient had a maximum of grade 2 toxicity is lower than the dose given to the next patient had the previously treated patient exhibited a grade 0 or 1 toxicity at the most. Further, we prove that the coherence properties of EWOC are preserved. Simulation results show that the safety of the trial is not compromised and the efficiency of the estimate of the maximum tolerated dose (MTD) is maintained relative to EWOC treating DLT as a binary outcome and that fewer patients are overdosed using this design when the true MTD is close to the minimum dose.