Keywords: Adaptive designs, Time-to-event, Survival regression, Maximum tolerated dose, Dose limiting toxicity, Phase I
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 an interesting discussion point in the industry. The Exposure Adjusted Continual Reassessment Method (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. The EACRM is readily implementable in real clinical practice with robust methodology utilizing survival regression approach. In addition, EACRM setting can easily incorporate delayed-onset toxicities observed outside the typical toxicity assessment period. Simulations were conducted to compare performance of EACRM with traditional 3+3 design, Continual Reassessment Method with over-dose-control criteria (EWOC), Modified Toxicity Probability Interval (mTPI), and Bayesian Optimal Interval design (BOIN) in single agent setting. The operating characteristics of EACRM, under variety of assumptions, have indicated that it performed equally or better than other designs in identifying true MTD. Moreover, it generally needs less number of subjects and shorter trial duration to reach targeted MTD while allocating more than 50% of the utilized subjects at or near the true MTD.