522 – Contributed Oral Poster Presentations: Biopharmaceutical Section
Escalation with Overdose Control Using Ordinal Toxicity Grades for Cancer Phase I Clinical Trials
Galen Cook-Wiens
Cedars Sinai Medical Center
Andre Rogatko
Cedars Sinai Medical Center
Mourad Tighiouart
Cedars Sinai Medical Center
Dose finding studies in early phase cancer clinical trials are sequential designs aimed at estimating a maximum tolerated dose (MTD) for further phase II studies of efficacy. The majority of the statistical designs that were proposed in the last two decades allocate future doses based on a binary outcome of dose limiting toxicity (DLT) of previously treated patients. Such designs may not be efficient in the sense that the dose recommended for the next patient is the same regardless whether the previously treated patient had no toxicity or had intermediate grade 2 toxicity. In this article, 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 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 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.
