Adaptive Estimation of Personalized Maximum Tolerated Doses in Cancer Phase I Clinical Trials According to All Toxicities and Individual Characteristics

• Activity Number: 490
• Type: Contributed
• Date/Time: Wednesday, August 3, 2016 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Zhengjia Chen* and Zheng Li and Ying Yuan and Michael Kutner and Taofeek Owonikoko and Walter J. Curran and Jeanne Kowalski
• Companies: Emory University and Penn State University and MD Anderson Cancer Center and Emory University and Emory University and Emory University and Emory University
• Keywords: Phase I Clinical Trial ; Biomarkers ; Covariates ; Personalized MTD ; EWOC-NETS

Abstract

Many biomarkers have recently been found to play a significant role in cancer therapy. Estimation of personalized maximum tolerated doses (pMTDs) is a critical step toward personalized medicine, which aims to maximize the therapeutic effect of a treatment for individual patients. In this manuscript, we propose to further utilize patient biomarkers that can predict susceptibility to specific adverse events and response as covariates to estimate pMTDs based on a cutting-edge cancer Phase I clinical trial design called escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS), which fully utilizes all toxicities. The methodology of incorporating patient biomarker information in the estimation of pMTDs for novel cancer therapeutic agents is fully elaborated and the design operating characteristics are evaluated with extensive simulations. Simulation studies demonstrate that utilization of biomarkers in EWOC-NETS can estimate pMTDs while maintaining its original merits, such as ethical constraint of overdose control and full utilization of all toxicity information, to improve the accuracy and efficiency of the pMTD estimation.