TY - JOUR
T1 - Accuracy and Safety of Novel Designs for Phase I Drug-Combination Oncology Trials
AU - Liu, Rong
AU - Yuan, Ying
AU - Sen, Suman
AU - Yang, Xin
AU - Jiang, Qi
AU - Li, Xiaoyun
AU - Lu, Chengxing
AU - Gönen, Mithat
AU - Tian, Hong
AU - Zhou, Heng
AU - Lin, Ruitao
AU - Marchenko, Olga
N1 - Funding Information:
Ying Yuan’s research was partially supported by Award Numbers P50CA217685, P50CA127001, and P50CA221707 from the National Cancer Institute. Ruitao Lin’s research was supported in part by the grants 1R01CA261978, P30CA016672, and P50CA221703 from the National Cancer Institute. We would like to thank the Editor, the Associate Editor, and the two reviewers for their valuable comments and suggestions, with special thanks to the reviewer whose dedicated and meticulous effort has led to a much-improved version of our article.
Publisher Copyright:
© 2022 American Statistical Association.
PY - 2022
Y1 - 2022
N2 - Despite numerous innovative designs having been published for phase I drug-combination dose finding trials, their use in real applications is rather limited. As a working group under the American Statistical Association Biopharmaceutical Section, our goal is to identify the unique challenges associated with drug combination, share industry’s experiences with combination trials, and investigate the pros and cons of the existing designs. Toward this goal, we review seven existing designs and distinguish them based on the criterion of whether their primary objectives are to find a single maximum tolerated dose (MTD) or the MTD contour (i.e., multiple MTDs). Numerical studies, based on either industry-specified fixed scenarios or randomly generated scenarios, are performed to assess their relative accuracy, safety, and ease of implementation. We show that the algorithm-based 3 + 3 design has poor performance and often fails to find the MTD. The performance of model-based combination trial designs is mixed: some demonstrate high accuracy of finding the MTD but poor safety, while others are safe but with compromised identification accuracy. In comparison, the model-assisted designs, such as BOIN and waterfall designs, have competitive and balanced performance in the accuracy of MTD identification and patient safety, and are also simple to implement, thus offering an attractive approach to designing phase I drug-combination trials. By taking into consideration the design’s operating characteristics, ease of implementation and regulation, the need for advanced infrastructures, as well as the risk of regulatory acceptance, our article offers practical guidance on the selection of a suitable dose-finding approach for designing future combination trials.
AB - Despite numerous innovative designs having been published for phase I drug-combination dose finding trials, their use in real applications is rather limited. As a working group under the American Statistical Association Biopharmaceutical Section, our goal is to identify the unique challenges associated with drug combination, share industry’s experiences with combination trials, and investigate the pros and cons of the existing designs. Toward this goal, we review seven existing designs and distinguish them based on the criterion of whether their primary objectives are to find a single maximum tolerated dose (MTD) or the MTD contour (i.e., multiple MTDs). Numerical studies, based on either industry-specified fixed scenarios or randomly generated scenarios, are performed to assess their relative accuracy, safety, and ease of implementation. We show that the algorithm-based 3 + 3 design has poor performance and often fails to find the MTD. The performance of model-based combination trial designs is mixed: some demonstrate high accuracy of finding the MTD but poor safety, while others are safe but with compromised identification accuracy. In comparison, the model-assisted designs, such as BOIN and waterfall designs, have competitive and balanced performance in the accuracy of MTD identification and patient safety, and are also simple to implement, thus offering an attractive approach to designing phase I drug-combination trials. By taking into consideration the design’s operating characteristics, ease of implementation and regulation, the need for advanced infrastructures, as well as the risk of regulatory acceptance, our article offers practical guidance on the selection of a suitable dose-finding approach for designing future combination trials.
KW - Clinical trial
KW - Dose finding
KW - Drug combination
KW - Maximum tolerated dose
KW - Toxicity
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U2 - 10.1080/19466315.2022.2081602
DO - 10.1080/19466315.2022.2081602
M3 - Article
C2 - 37275462
AN - SCOPUS:85135228419
SN - 1946-6315
VL - 14
SP - 270
EP - 282
JO - Statistics in Biopharmaceutical Research
JF - Statistics in Biopharmaceutical Research
IS - 3
ER -