A Model-based Approach in the Estimation of the Maximum Tolerated Dose in Phase I Cancer Clinical Trials

• Activity Number: 305
• Type: Contributed
• Date/Time: Wednesday, August 11, 2004 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Weili He*+ and Jun Liu and Bruce Binkowitz and Hui Quan
• Companies: Merck & Co., Inc. and Rutgers University and Merck & Co., Inc. and Merck & Co., Inc.
• Keywords: maximum tolerated dose ; dose-limiting toxicity ; model-based approach ; traditional algorithm-based designs ; traditional 3+3 designs

Abstract

The primary aim of a phase I cancer clinical trial is to determine the maximum tolerated dose (MTD) of a new agent. The MTD is determined at the highest dose level of a therapeutic agent in which the patients have experienced an acceptable level of dose-limiting toxicity (DLT). The standard methods for conducting phase I cancer trials has been the traditional algorithm-based designs. These designs begin with the selection of a starting dose based on animal studies, and the dose escalation usually follows a modified Fibonacci scheme. Due to practical simplicity, the algorithm-based designs are still widely used. Most often, the traditional "3+3" design is used. Our simulation studies show that the "3+3" designs cannot provide reasonable estimates of the MTD due to their intrinsic design limitations. We propose a model-based approach in the estimation of the MTD following a "3+3" design. Our simulations found that our approach produces less biased estimates of the MTD than the estimates obtained from the "3+3" designs. We conclude that our proposed method provides much improved estimates of the MTD. Further, our model can be easily modified to extend to any traditional A+B designs.