BE-BOIN: A Dose Optimization Design Accommodating Backfill and Late-Onset Toxicity

Area of Science:

• Clinical Pharmacology
• Biostatistics
• Oncology Drug Development

Background:

• The US Food and Drug Administration (FDA) issued guidance for Project Optimus to reform dose-finding trials.
• Current trials often focus on the maximum tolerated dose (MTD), which may not optimize treatment benefits.
• Late-onset toxicities and the need for robust safety and efficacy data across doses present challenges.

Purpose of the Study:

• To propose a novel clinical trial design, BE-BOIN (Backfill time-to-Event Bayesian Optimal INterval), to address challenges in dose-finding and selection.
• To optimize the identification of the optimal biological dose (OBD) for cancer therapeutics.
• To enhance the accuracy and efficiency of dose-finding trials.

Main Methods:

• The BE-BOIN design allows for patient backfilling into safe and effective dose levels during dose escalation.
• It incorporates a time-to-event model to accommodate late-onset toxicities.
• Simulation studies were conducted to evaluate the design's performance.

Main Results:

• BE-BOIN accurately identifies both the maximum tolerated dose (MTD) and the optimal biological dose (OBD).
• The design facilitates the collection of additional safety and efficacy data for improved dose selection.
• Simulation results indicate a significant reduction in overall trial duration compared to traditional methods.

Conclusions:

• The BE-BOIN design offers a robust approach to optimizing dose selection in early-phase oncology trials.
• It effectively balances the need for comprehensive safety and efficacy data with trial efficiency.
• This design supports real-time dose adjustments and more reliable OBD determination, aligning with FDA's Project Optimus goals.