Clinical Trial Simulation to Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation


Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation (HCT), suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant endpoint, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m2 ) to either covariate-based or therapeutic drug monitoring (TDM)-guided-dosing with potential outcomes being non-relapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (OS, covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of endpoints and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided-dosing to current practice with NRM as primary outcome (n=70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible.

CPT Pharmacometrics & Systems Pharmacology