Dose-finding design driven by efficacy in onco-hematology phase I/II trials

Area of Science:

• Clinical Trials
• Biostatistics
• Pharmacology

Background:

• Phase I/II clinical trials often assess both drug efficacy and toxicity.
• Traditional methods focus on maximum tolerated dose or the most successful dose (efficacy without toxicity).
• A gap exists in methods that balance efficacy and safety under a specific toxicity threshold.

Purpose of the Study:

• To develop an adaptive, model-based dose-finding procedure for Phase I/II trials.
• To propose a novel definition of treatment success based on efficacy and controlled toxicity.
• To evaluate the performance of the proposed method using simulations and a real-world case study.

Main Methods:

• The study employs an adaptive model-based approach for dose escalation.
• A joint statistical model is utilized to simultaneously estimate probabilities of efficacy response and toxicity.
• Dose selection is guided by the probability of dose-limiting toxicity remaining below a predefined threshold.

Main Results:

• Simulations demonstrated the procedure's ability to identify effective and safe dose levels.
• The proposed method offers a more nuanced approach compared to traditional maximum tolerated dose strategies.
• Retrospective analysis of a chronic lymphocytic leukemia trial showcased the method's practical applicability.

Conclusions:

• The presented adaptive model provides a robust framework for dose finding in early-phase trials.
• This approach enhances the balance between therapeutic efficacy and patient safety.
• The method is suitable for trials where both efficacy and toxicity data are concurrently collected.