Phase I-II clinical trial design: A state-of-the-art paradigm for dose finding

Abstract

Background

Conventional phase I algorithms for finding a phase-2 recommended dose (P2RD) based on toxicity alone is problematic because the maximum tolerated dose (MTD) is not necessarily the optimal dose with the most desirable risk-benefit trade-off. Moreover, the increasingly common practice of treating an expansion cohort at a chosen MTD has undesirable consequences that may not be obvious.

Patients and methods

We introduce the phase I-II paradigm and the EffTox design, which utilizes both efficacy and toxicity to choose optimal doses for successive patient cohorts and find the optimal P2RD. We conduct computer simulation study to compare the performance of the EffTox design with the traditional 3 + 3 design and the continuous reassessment method.

Results

By accounting for the risk-benefit trade-off, the EffTox phase I-II design overcomes the limitations of conventional toxicity-based phase I designs. Numerical simulations show that the EffTox design has higher probabilities of identifying the optimal dose and treats more patients at the optimal dose.

Conclusions

Phase I-II designs, such as the EffTox design, provide a coherent and efficient approach to finding the optimal P2RD by explicitly accounting for risk-benefit trade-offs underlying medical decisions.