An adaptive phase I design for identifying a biologically optimal dose for dual agent drug combinations

Area of Science:

• Clinical Trial Design
• Pharmacology
• Biostatistics

Background:

• Traditional dose-finding trials for chemotherapeutic drug combinations prioritize maximum tolerated dose (MTD) and safety.
• Target-based agents present challenges due to unknown dose-efficacy curves and minimal dose-toxicity relationships, necessitating alternative designs.
• Existing methods are insufficient for optimizing dual-agent combinations with complex dose-response profiles.

Purpose of the Study:

• To propose an extension of an adaptive single-agent dose-finding design for dual-agent combination trials.
• To develop a method that incorporates both toxicity and efficacy of individual agents to identify an optimal dosing region for the combination.
• To evaluate the operating characteristics of the proposed design through simulation studies.

Main Methods:

• Generalization of the continuation ratio model to define separate toxicity and efficacy curves for each agent in a dual-agent combination.
• Generation of a dose-success surface for the drug combination.
• Implementation of a continual reassessment method with a dose selection criterion based on accumulated patient data.

Main Results:

• Simulation studies demonstrated favorable operating characteristics for the proposed design.
• The design showed favorable experimentation and recommendation rates.
• The average sample size was found to be efficient across various scenarios.

Conclusions:

• The proposed adaptive design effectively incorporates individual agent toxicity and efficacy for identifying optimal combination dosing regions.
• This novel approach offers an improvement over traditional methods for dose-seeking trials with targeted agents.
• The method warrants further consideration for its application in clinical trials involving dual-agent drug combinations.