TY - JOUR
T1 - TOP
T2 - Time-to-Event Bayesian Optimal Phase II Trial Design for Cancer Immunotherapy
AU - Lin, Ruitao
AU - Coleman, Robert L.
AU - Yuan, Ying
N1 - Funding Information:
YY is funded by National Institutes of Health grants 5P50CA098258, 1P50CA217685, and CA016672. RLC is funded by Cancer Prevention Research Institute of Texas grant RP120214, the Judy Reis/Al Pisani, MD, Ovarian Cancer Research Fund, and the Ann Rife Cox Chair in Gynecology.
Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Background: Immunotherapies have revolutionized cancer treatment. Unlike chemotherapies, immune agents often take longer to show benefit, and the complex and unique mechanism of action of these agents renders the use of multiple endpoints more appropriate in some trials. These new features of immunotherapy make conventional phase II trial designs, which assume a single binary endpoint that is quickly ascertainable, inefficient and dysfunctional. Methods: We propose a flexible and efficient time-to-event Bayesian optimal phase II (TOP) design. The TOP design is efficient in that it allows real-time "go/no-go" interim decision making in the presence of late-onset responses by using all available data and maximizes statistical power for detecting effective treatments. TOP is flexible in the number of interim looks and capable of handling simple and complicated endpoints under a unified framework. We conduct simulation studies to evaluate the operating characteristics of the TOP design. Results: In the considered trial settings, compared to some existing Bayesian designs, the TOP design shortens the trial duration by 4-10 months and improves the power to detect effective treatment up to 90%, with well-controlled type I errors. Conclusions: The TOP design is transparent and easy to implement, as its decision rules can be tabulated and included in the protocol prior to the conduct of the trial. The TOP design provides a flexible, efficient, and easy-to-implement method to accelerate and improve the development of immunotherapies.
AB - Background: Immunotherapies have revolutionized cancer treatment. Unlike chemotherapies, immune agents often take longer to show benefit, and the complex and unique mechanism of action of these agents renders the use of multiple endpoints more appropriate in some trials. These new features of immunotherapy make conventional phase II trial designs, which assume a single binary endpoint that is quickly ascertainable, inefficient and dysfunctional. Methods: We propose a flexible and efficient time-to-event Bayesian optimal phase II (TOP) design. The TOP design is efficient in that it allows real-time "go/no-go" interim decision making in the presence of late-onset responses by using all available data and maximizes statistical power for detecting effective treatments. TOP is flexible in the number of interim looks and capable of handling simple and complicated endpoints under a unified framework. We conduct simulation studies to evaluate the operating characteristics of the TOP design. Results: In the considered trial settings, compared to some existing Bayesian designs, the TOP design shortens the trial duration by 4-10 months and improves the power to detect effective treatment up to 90%, with well-controlled type I errors. Conclusions: The TOP design is transparent and easy to implement, as its decision rules can be tabulated and included in the protocol prior to the conduct of the trial. The TOP design provides a flexible, efficient, and easy-to-implement method to accelerate and improve the development of immunotherapies.
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U2 - 10.1093/jnci/djz049
DO - 10.1093/jnci/djz049
M3 - Article
C2 - 30924863
AN - SCOPUS:85074003675
SN - 0027-8874
VL - 112
SP - 38
EP - 45
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
ER -