Two-Stage Design Sample Size Determination for Two Doses in Oncology Phase II Trials
Pub. online: 11 April 2025
Type: Methodology Article
Open Access
Open Access
Area: Biomedical Research
1
The author is currently employed by the US Food and Drug Administration (FDA). Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Accepted
24 January 2025
24 January 2025
Published
11 April 2025
11 April 2025
Abstract
In oncology therapy development, Simon’s two-stage design is commonly employed in early-phase clinical trials to assess the preliminary efficacy of a single dose, typically the maximum tolerable dose (MTD) or the maximum assessed dose (MAD). In this design, a dose may be terminated at the first stage if the anti-tumor activity is insufficient or it may proceed to the second stage for further evaluation with more subjects. To enhance the design for better benefit-risk profile dose selection and to meet the increasing needs for study designs that explore dose-response relationships, we extend Simon’s two-stage design to evaluate two doses and to include early termination for success in addition to futility. The proposed method derives decision rules and sample sizes for optimal study designs that minimize the expected or overall sample sizes while controlling type I error and meeting desired power.
References
Bartroff, J., Lai, T. L. and Narasimhan, B. (2014). A new approach to designing phase I-II cancer trials for cytotoxic chemotherapies. Statistics in medicine 33(16) 2718–2735. https://doi.org/10.1002/sim.6124. MR3256534
Crippa, A., Discacciati, A., Bottai, M., Spiegelman, D. and Orsini, N. (2019). One-stage dose–response meta-analysis for aggregated data. Statistical methods in medical research 28(5) 1579–1596. https://doi.org/10.1177/0962280218773122. MR3941095
Lin, Y. and Shih, W. J. (2004). Adaptive two-stage designs for single-arm phase IIA cancer clinical trials. Biometrics 60(2) 482–490. https://doi.org/10.1111/j.0006-341X.2004.00193.x. MR2067004
Liu, S. and Yuan, Y. (2015). Bayesian optimal interval designs for phase I clinical trials. Journal of the Royal Statistical Society: Series C: Applied Statistics 507–523. https://doi.org/10.1111/rssc.12089. MR3325461
US Food and Drug Administration (2022). Expansion cohorts: use in first-in-human clinical trials to expedite development of oncology drugs and biologics. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expansion-cohorts-use-first-human-clinical-trials-expedite-development-oncology-drugs-and-biologics Accessed 2023-12-01.
US Food and Drug Administration (2023). Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases Accessed 2023-12-01.
Whitehead, J. (2014). One-stage and two-stage designs for phase II clinical trials with survival endpoints. Statistics in medicine 33(22) 3830–3843. https://doi.org/10.1002/sim.6196. MR3260663
Zohar, S. and Chevret, S. (2003). Phase I (or phase II) dose-ranging clinical trials: proposal of a two-stage Bayesian design. Journal of Biopharmaceutical Statistics 13(1) 87–101. https://doi.org/10.1002/sim.6338. MR3286234
