ATLCEP: A New Integrated Design that Encompasses the Safety and Efficacy Objectives of Phase I/II Trials

Abstract

Several designs, such as designs to find the optimal biological dose, the Eff-Tox design and seamless Phase I/II designs, have been proposed to evaluate both drug toxicity and efficacy as alternatives to the traditional paradigm of a stepwise drug development approach. Here, we first examine the effect of sample and cohort size on the accuracy of dose selection in early phase oncology designs and then propose a design that is large enough to allow accurate dose selection for toxicity and that incorporates Bayesian decision rules at the end to select an optimal dose for toxicity and efficacy. We propose the Accelerated Titration Large Cohort Early Phase (ATLCEP) design, a moderately large, simple rule-based integrated Phase I/II trial design that evaluates both safety and efficacy. This design incorporates stopping rules within dose levels to allow more flexible decision-making. Finally, we compare the operating characteristics of this design with other Phase I/II strategies, via simulations. Our simulations of the ATLCEP design yield a mean sample size of approximately 42 patients for the true DLT and response rates and stopping rules considered and show that with this sample size the design can robustly pick a dose that is optimal for efficacy and safety. In our simulations, it performs as well as or better than the Eff-Tox or the Optimal Biological Dose (OBD) Isotonic design. It also performs better than a 3+3 Phase I design followed by a standard Phase II design.