A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints

Area of Science:

• Oncology
• Clinical Trial Design
• Biostatistics

Background:

• Integrated Phase I/II oncology trials are gaining traction for molecularly targeted agents (MTAs).
• Challenges include complex dose-efficacy relationships and MTA combinations.
• Existing designs often overlook continuous efficacy endpoints, limiting information extraction.

Purpose of the Study:

• To extend an information-theoretic design for Phase I/II oncology trials to accommodate continuous efficacy endpoints.
• To investigate the performance of this novel design in single-agent and dual-agent settings.
• To assess the design's robustness to missing data and correlated endpoints.

Main Methods:

• Proposed an extension of an existing information-theoretic design.
• Utilized a logistic transformation for continuous outcomes.
• Employed an information-theoretic approach to guide trial progression.
• Evaluated performance in single-agent and dual-agent trial simulations.

Main Results:

• The novel design demonstrated substantial improvements in operating characteristics compared to a model-based alternative.
• These improvements were particularly evident under nonmonotonic dose/combination-efficacy relationships.
• The design showed robustness when handling missing/delayed efficacy responses and correlated toxicity/efficacy endpoints.

Conclusions:

• The proposed information-theoretic design offers a valuable advancement for integrated Phase I/II oncology trials with continuous efficacy endpoints.
• This approach enhances efficiency and provides more informative results, especially for complex scenarios involving molecularly targeted agents.
• The design's robustness makes it a practical tool for real-world clinical trial applications.