Determining a maximum tolerated cumulative dose: dose reassignment within the TITE-CRM

Area of Science:

• Clinical Pharmacology
• Biostatistics
• Oncology Drug Development

Background:

• Traditional phase I clinical trials face challenges in dose escalation, particularly when dose duration is a key factor.
• The time-to-event continual reassessment method (TITE-CRM) is a statistical approach for dose-finding studies.
• Determining the maximum tolerated cumulative dose (MTCD) is crucial for patient safety in early-phase drug trials.

Purpose of the Study:

• To present a modified TITE-CRM phase I design suitable for trials where dose represents duration of drug administration.
• To develop an adaptive study design that adjusts doses both between and within subjects during the trial.
• To optimize the identification of the maximum tolerated cumulative dose (MTCD) while minimizing patient exposure to excessive toxicity.

Main Methods:

• The proposed design modifies the TITE-CRM by Cheung and Chappell.
• Subjects are enrolled at the estimated MTCD, and doses are reassessed and modified as data becomes available.
• Simulations were conducted to evaluate the operating characteristics of the new design.

Main Results:

• Simulations demonstrate that the modified TITE-CRM design maintains excellent operating characteristics, comparable to the original TITE-CRM.
• The adaptive nature of the design effectively adjusts doses within subjects, improving MTCD estimation.
• The design successfully minimizes the number of subjects exposed to doses exceeding the MTCD.

Conclusions:

• The modified TITE-CRM offers an effective and safe adaptive phase I design for dose-duration studies.
• This approach is particularly beneficial in settings like bone marrow transplant studies, using recombinant human keratinocyte growth factor as an example.
• The design balances the need for efficient dose-finding with the imperative of patient safety and minimizing toxicity.