STEIN-NETS: A Simple Toxicity and Efficacy Interval Design with Normalized Equivalent Toxicity Score

Music City Center 

Traditional early-phase dose-finding methods rely solely on toxicity to select the MTD. These methods can be insufficient for targeted therapies, which may not always exhibit a monotonically increasing dose-efficacy curve. FDA's Project Optimus advocates selecting safe and efficacious doses, aiming to identify the OBD, thus maximizing the risk-benefit tradeoff. Many model-assisted designs, such as BOIN12, BOIN-ET, and STEIN, have been proposed for this purpose. However, these designs only use binary toxicity and efficacy outcomes, leading to significant information loss in the dosing decision-making process. To tackle this, a normalized equivalent toxicity score was proposed to treat toxicity as a quasi-continuous variable. We propose a new approach integrating the NETS with the STEIN design while incorporating a Gaussian-distributed efficacy to evaluate potential doses. Extensive simulation studies show that the proposed design improves trial efficiency compared to other existing designs by: 1) improving OBD selection rates with better patient allocation and 2) exhibiting higher probabilities of early trial termination with smaller sample sizes due to futility or over-toxicity.

Normalized Equivalent Toxicity Score

Bayesian Adaptive Design

Dose Finding

Phase I/II Clinical Trials 

Biopharmaceutical Section