Flexible, rule-based dose escalation: The cohort-sequence design.

Area of Science:

• Oncology
• Clinical Trial Design
• Biostatistics

Background:

• Phase I oncology trials are crucial for assessing novel treatment safety.
• Current rule-based designs, like the 3+3, are often inflexible and inefficient.
• There is a need for improved designs to optimize dose escalation and patient enrollment.

Purpose of the Study:

• To introduce and evaluate a novel rule-based design, the "cohort-sequence" design, for Phase I oncology trials.
• To address the limitations of traditional designs in terms of efficiency and flexibility.
• To enable rapid and accurate identification of the maximum tolerated dose (MTD).

Main Methods:

• The proposed cohort-sequence design utilizes a sequence of increasing cohort sizes and critical values.
• The design escalates through planned doses, increasing cohort size upon observing toxicities.
• Parameter selection (J and θ) allows for efficient identification of a target toxicity rate and potential dose expansion.

Main Results:

• The cohort-sequence design generally identifies the MTD more rapidly than the 3+3 design.
• This approach avoids unnecessary patient enrollment at lower doses with likely low toxicity and response rates.
• Simulations demonstrated the design's efficiency across various toxicity scenarios.

Conclusions:

• The cohort-sequence design offers a more efficient and flexible alternative to the 3+3 design for Phase I oncology trials.
• This method optimizes patient enrollment and accelerates the identification of the MTD.
• The design is available as an R package, facilitating its implementation in clinical research.