Determining a maximum-tolerated schedule of a cytotoxic agent

Area of Science:

• Clinical Pharmacology
• Biostatistics
• Oncology

Background:

• Phase I clinical trials traditionally determine maximum-tolerated dose (MTD) based on short-term toxicity.
• Repeated administration of agents necessitates evaluating long-term and cumulative toxicity.
• Current methods often use binary toxicity outcomes, not accounting for the timing of adverse events.

Purpose of the Study:

• To propose a novel statistical method for phase I clinical trials with repeated drug administrations.
• To determine a maximum-tolerated schedule (MTS) by modeling time-to-toxicity.
• To provide a framework for continuous data monitoring and decision-making in dose-finding studies.

Main Methods:

• Developed a statistical model based on time-to-toxicity rather than a binary outcome.
• Modeled the overall hazard of toxicity as a sum of hazards associated with each administration.
• Applied the method to an allogeneic bone marrow transplantation (BMT) trial for graft-versus-host disease (aGVHD) prophylaxis.

Main Results:

• The proposed method accounts for the entire sequence of drug administrations and cumulative toxicity.
• Demonstrated the application of the time-to-toxicity model in a simulated BMT trial setting.
• Facilitates continuous monitoring and adaptive decision-making throughout the trial.

Conclusions:

• The new method offers a more comprehensive approach to dose-finding for agents requiring repeated administration.
• Determining a maximum-tolerated schedule (MTS) is crucial for managing cumulative toxicity in clinical trials.
• This approach enhances patient safety by continuously monitoring toxicity over the treatment course.