TITE-STEIN: Time-to-event simple toxicity and efficacy interval design to accelerate phase I/II trials

Area of Science:

• Clinical Trials
• Biostatistics
• Pharmacology

Background:

• Oncology trials are transitioning from maximum-tolerated dose (MTD) to optimal biological dose (OBD) selection.
• Novel therapies like immunotherapies require methods that account for complex dose-efficacy relationships.
• Existing designs face challenges with delayed toxicity/efficacy onset and rapid patient accrual.

Purpose of the Study:

• To introduce TITE-STEIN, a time-to-event extension of the STEIN design for adaptive oncology dose finding.
• To address limitations of current designs regarding timely dose decisions and patient safety.
• To improve the accuracy and efficiency of OBD selection in clinical trials.

Main Methods:

• Extending the Simple Toxicity and Efficacy Interval (STEIN) design to incorporate time-to-event (TITE) data.
• Integrating an optimal biological dose (OBD) verification step into the dose selection process.
• Conducting extensive simulations to compare TITE-STEIN with existing time-to-event designs.

Main Results:

• TITE-STEIN significantly reduces trial duration compared to the original STEIN design.
• The integrated OBD verification procedure effectively prevents patient exposure to inadmissible doses.
• TITE-STEIN demonstrates superior performance in accurate OBD selection and overdose control compared to other TITE designs.

Conclusions:

• TITE-STEIN offers a more efficient and safer approach to adaptive dose finding in oncology.
• The design is particularly beneficial for novel therapies with delayed toxicity or efficacy.
• TITE-STEIN improves upon existing time-to-event designs by enhancing accuracy and patient safety.