Open AccessClinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation
Author(s) -
Langenhorst Jurgen B.,
Dorlo Thomas P.C.,
Kesteren Charlotte,
Maarseveen Erik M.,
Nierkens Stefan,
Witte Moniek A.,
Boelens Jaap Jan,
Huitema Alwin D.R.
Publication year - 2020
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12486
Subject(s) - dosing , fludarabine , medicine , randomized controlled trial , transplantation , hematopoietic cell , clinical trial , concomitant , intensive care medicine , hematopoietic stem cell transplantation , haematopoiesis , chemotherapy , stem cell , biology , genetics , cyclophosphamide
Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, 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 end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m 2 ) to either covariate‐based or therapeutic drug monitoring (TDM)‐guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm ( n ) required to achieve 80% power was calculated for all combinations of end points 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.