A Seamless Two-Stage Phase I/II Trial Design With Backfill and Joint Monitoring for Dose Optimization.

Area of Science:

• Clinical Trials
• Oncology Drug Development
• Biostatistics

Background:

• Early-phase oncology trials require efficient evaluation of antitumor activity and patient safety.
• The U.S. Food and Drug Administration's (FDA) Project Optimus initiative promotes dose optimization.
• Robust statistical frameworks are crucial for futility monitoring in dose-finding studies.

Purpose of the Study:

• To propose a seamless two-stage Phase I/II trial design that integrates dose optimization with efficacy evaluation.
• To accelerate oncology drug development through efficient trial designs.
• To enhance patient safety by incorporating robust monitoring for efficacy and toxicity.

Main Methods:

• A two-stage design combining dose-finding with efficacy evaluation.
• Stage 1 utilizes Bayesian optimal boundaries and patient backfilling for dose selection.
• Stage 2 employs joint monitoring of efficacy and toxicity with Bayesian optimal boundaries for early decision-making.

Main Results:

• The proposed design demonstrated superior operating characteristics in simulation studies.
• The backfill strategy accelerates trial timelines by allowing sequential enrollment.
• Simultaneous monitoring of efficacy and toxicity in Stage 2 facilitates early stopping decisions.

Conclusions:

• The integrated seamless two-stage design offers an efficient and safe approach for oncology drug development.
• This design is valuable for optimizing dose selection and evaluating treatment effectiveness.
• The methodology provides robust statistical frameworks for modern clinical trial challenges.