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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 review 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 a 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.

SUBMITTER: Yan F

PROVIDER: S-EPMC5888967 | biostudies-literature |

REPOSITORIES: biostudies-literature

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