Exposure Adjusted Continual Reassessment Method (EACRM) for Phase I Oncology Dose-Finding Studies

• Activity Number: 350
• Type: Contributed
• Date/Time: Tuesday, August 5, 2014 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Xin Qi*+ and Wijith Munasinghe and Balakrishna Hosmane and Yi-Lin Chiu and Kyle Holen
• Companies: Michigan State University and AbbVie and AbbVie and AbbVie and AbbVie
• Keywords: Adaptive Designs ; Accelerated Failure Time Model ; Maximum Tolerated Dose ; Dose Limiting Toxicity ; Phase I

Abstract

Finding the maximum tolerated dose (MTD) is a common primary objective for Phase I oncology studies. The drug exposure and toxicity events are the two most important components required for the characterization of the MTD. Improvements to conventional adaptive dose finding designs to include information on the extent of exposure and the time to event, may allow for a more dynamic enrollment and increase the efficiency, accuracy and safety of identifying the MTD. The EACRM dynamically extends the conventional adaptive dose finding designs by incorporating dose limiting toxicity (DLT) as well as at-the-event information from each patient. An Accelerated Failure Time model with some modifications to update the time to DLT for subjects who did not complete the entire DLT assessment period at particular time point was developed. Simulations, under a variety of assumptions, have indicated that the EACRM performed equal or better than the traditional 3+3 design in identifying MTD and other important operating characteristics such as length of study, total number of subjects and probability of a certain dose being MTD.