Arzneimitteldesign: Offener Zugang
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Abstrakt

Exposure Adjusted Continuous Reassessment Method (EACRM) - an Adaptive Design Incorporating Time to Toxicity Event for Phase I Dose Finding Studies.

Qi X, Munasinghe W, Hosmane B, Chiu Y and

Finding the maximum tolerated dose (MTD) is the most important primary objective for Phase I oncology studies. The drug exposure and the toxicity event are the two components required for characterization of the MTD. Phase I trials currently require multiple subjects treated at numerous dose levels, with many of these subjects receiving doses of drug at less than predicted efficacious exposures. Further, these studies employ predefined, step-wise increments in doses that can result in inaccurate predictions of the MTD. Improvements to conventional adaptive dose finding designs to attain more accurate information on the extent of exposure and the time to event, with a more dynamic enrollment to facility better decision making are needed and have been the focus of previous published efforts. The EACRM dynamically extends the conventional adaptive dose finding designs by incorporating dose limiting toxicity (DLT) events as well as at-the-event information from each patient. An Accelerated Failure Time model with some tweaking 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 the MTD and also outperformed the 3+3 design in other important operating characteristics such as the length of study, the number of subjects treated at above the MTD, and the total number of subjects.