Probability-of-Decision Designs to Accelerate Dose-Finding Trials

• Activity Number: 584 - Innovations and Breakthroughs in Oncology Dose Finding Designs for Time-to-Event Monitoring and Trial Acceleration in the New Age of Immunotherapy and Cell Therapy
• Type: Topic Contributed
• Date/Time: Thursday, August 6, 2020 : 3:00 PM to 4:50 PM
• Sponsor: Section on Risk Analysis
• Author(s): Tianjian Zhou* and Yuan Ji
• Companies: University of Chicago and University of Chicago
• Keywords: Clinical trial design; Decision theory; Late-onset toxicity; Maximum tolerated dose; Phase I trial

Abstract

Cohort-based enrollment can slow down phase I dose-finding trials since the outcomes of the previous cohort must be fully evaluated before the next cohort can be enrolled. This results in frequent suspension of patient enrollment. We propose a class of probability-of-decision (POD) designs to accelerate dose-finding trials, which enable dose assignments in real-time in the presence of pending toxicity outcomes. With uncertain outcomes, the dose assignment decisions are treated as random variables, and we calculate the posterior distribution of the decisions. The posterior distribution reflects the variability in the pending outcomes and allows a direct and intuitive evaluation of the confidence of all possible decisions. Optimal decisions are calculated based on the 0-1 loss, and extra safety rules are constructed to enforce sufficient protection from exposing patients to risky doses. A new and useful feature of POD designs is that they allow investigators and regulators to balance the trade-off between enrollment speed and making risky decisions by tuning a pair of intuitive design parameters. The performances of POD designs are evaluated through numerical studies.