Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding
Year: 2015
Type: article
Abstract: The standard 3 + 3 or "modified Fibonacci" up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. In June 2012, the U S Food and Drug Administration (FDA) rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a variation of the MF-UD, known as accelerated titration (AT) design. This event motivated us to perform an extensive simulation study comparing the operating characteristics of AT and EWOC. We show that the AT design has poor operating characteristics relative to three versions of EWOC under several practical scenarios. From the clinical investigator's perspective, lower bias and mean square error make EWOC designs preferable than AT designs without compromising safety. From a patient's perspective, uniformly higher proportion of patients receiving doses within an optimal range of the true MTD makes EWOC designs preferable than AT designs.
Source: Entropy
DOI: 10.3390/e17085288
Institution: Cedars-Sinai Medical Center
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,137
Funders: National Computational Infrastructure, Erika Glazer Family Foundation, National Institutes of Health, U.S. Food and Drug Administration, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: Design of Cancer Phase I/II Clinical Trials Using Drug Combinations of Cytotoxic and Biologic Agents, G1120375403, UCLA Clinical and Translational Science Institute, G2027279726, Reliable Evaluation of Coronary Artery Disease using Myocardial BOLD MRI with CO2, G2168128885, G2417647834, G2663518188, Prostate Cancer Bone Metastasis Biology and Targeting, G2989067737, UCLA Clinical and Translational Science Institute, Quantitative Prediction of Disease and Outcomes from Next Generation SPECT and CT, TGF Beta Signals in Prostate Stromal-Epithelial Interactions, G7806704164, G8047847897, Treatment of pituitary Cushing disease with a selective CDK inhibitor, R-roscovit
OpenAlex ID: W1581010861