TSNP

TSNP implements a two-stage nonparametric Phase I/II clinical trial framework that integrates toxicity and efficacy outcomes to identify the optimal biological dose (OBD) for immunotherapy.

Key Features:

• Two-Stage Design: A Phase I/II structure with stage one focused on exploring dose-specific toxicity profiles and stage two focused on selecting the OBD that maximizes efficacy under acceptable toxicity.
• Nonparametric Approach: Derives closed-form estimates for joint toxicity–efficacy response probabilities using a nonparametric strategy subject to a monotonic increasing constraint on toxicity.
• Utility Function Integration: Incorporates a utility function that jointly evaluates toxicity and efficacy to guide OBD identification by optimization of therapeutic benefit versus adverse effects.
• Superior Operating Characteristics: Simulation studies reported that the TSNP design outperforms existing Bayesian parametric designs in operating characteristics for dose-finding.

Scientific Applications:

• Immunotherapy Dose-Finding: Identifying OBDs in immunotherapy clinical trials by jointly considering toxicity and efficacy outcomes.
• Phase I/II Trial Design: Application in early-phase trials where balancing safety and therapeutic effect is critical for dose selection.

Methodology:

Derivation of closed-form joint toxicity–efficacy probability estimates under a monotonic increasing toxicity constraint within a two-stage Phase I/II nonparametric framework, selection of OBD via a utility-based optimization, and evaluation of operating characteristics by simulation studies comparing to Bayesian parametric designs.