期刊
ANNALS OF ONCOLOGY
卷 29, 期 3, 页码 694-699出版社
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdx795
关键词
dose finding; phase I-II trials; risk-benefit tradeoff; adaptive design; immunotherapy; molecularly targeted agents
类别
资金
- National Social Science of China [16BTJ021]
- National Institutes of Health [R01 CA83932, P50CA098258]
- NATIONAL CANCER INSTITUTE [ZIDBC011642, P30CA016672, P50CA098258] Funding Source: NIH RePORTER
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. 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. 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. 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.
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