TY - JOUR
T1 - Time-to-event Bayesian optimal interval design to accelerate phase I trials
AU - Yuan, Ying
AU - Lin, Ruitao
AU - Li, Daniel
AU - Nie, Lei
AU - Warren, Katherine E.
N1 - Funding Information:
The authors thank the editor and three reviewers for their constructive comments and suggestions. Y. Yuan's research is partially supported by NCI award P50CA098258.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10/15
Y1 - 2018/10/15
N2 - Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose-escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients' toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose-escalation/ deescalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target dose-limiting toxicity (DLT) rate and has higher accuracy to identify the MTD. Compared with the more complicated model-based timeto- event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. As the TITE-CRM is more aggressive in dose escalation, it is less likely to underdose patients. When there are no pending data, the TITE-BOIN seamlessly reduces to the BOIN design. Numerical studies show that the TITE-BOIN design supports continuous accrual without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate earlyphase drug development.
AB - Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose-escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients' toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose-escalation/ deescalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target dose-limiting toxicity (DLT) rate and has higher accuracy to identify the MTD. Compared with the more complicated model-based timeto- event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. As the TITE-CRM is more aggressive in dose escalation, it is less likely to underdose patients. When there are no pending data, the TITE-BOIN seamlessly reduces to the BOIN design. Numerical studies show that the TITE-BOIN design supports continuous accrual without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate earlyphase drug development.
UR - http://www.scopus.com/inward/record.url?scp=85054997726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054997726&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-0246
DO - 10.1158/1078-0432.CCR-18-0246
M3 - Article
C2 - 29769209
AN - SCOPUS:85054997726
SN - 1078-0432
VL - 24
SP - 4921
EP - 4930
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -