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

Abstract

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.Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for a variety of malignant and benign hematological disorders. Unfortunately, nonrelapse mortality (NRM; 10-40%) and disease relapse (20-50%) remain major causes of therapy failure, 1 thus further treatment optimization is potentially life-saving.The conditioning regimen prior to HCT consists of a combination of cytotoxic agents (chemotherapy and serotherapy) administered to eradicate recipient's bone marrow and immune system. Minimizing the toxicity while maintaining the efficacy of such regimens is one of the key strategies to reduce NRM. 2 Fludarabine combined with busulfan and rabbit antithymocyte globulin (rATG) is a frequently used conditioning regimen for HCT. Variability in exposure has been shown to predict variable outcome for all these agents. [3][4][5] Given that exposure-targeted dosing of busulfan through therapeutic drug monitoring (TDM) is widely applied and has been proven superior over fixed dosing in a randomized

Therapeutic Drug Monitoring of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation: A Pilot Single-Center Study in Taiwan

“…Recently, Punt et al developed an LC–MS/MS method for the simultaneous quantitation of busulfan, clofarabine, and fludarabine in plasma [ 28 ]. This method has been applied to study the population PKs of fludarabine and clofarabine [ 33 , 34 , 35 ]. The combination of busulfan and fludarabine, with or without clofarabine, is currently emerging as an HCT conditioning regimen [ 36 ].…”

Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety

“…with respect to enrolment numbers (e.g. phase I studies) (9)(10)(11)32). Dickinson et al demonstrated the utility of virtual pharmacogenetic trials using the example of warfarin and CYP2C9 polymorphisms, though without power analyses (33).…”

“…In contrast, the latter non-model-based approaches conventionally only consider one single time point of the concentration-or effect-time profile (8). The utility of clinical trial simulations and model-based data analysis methods to inform the design of clinical studies has been demonstrated across various therapeutic fields (9)(10)(11). In pharmacogenomics, pharmacometric models have foremost been used to enhance the understanding of the impact of genetic variants on drug exposure and various outcomes rather than for clinical trial design.…”

Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in paediatric patients

“…The decrease in clofarabine clearance relating to renal function is a gradual process and even an eGFR below 120 mL/min/1.73 m 2 is associated with a decrease in clofarabine clearance and concomitant higher exposures, 4 which makes a dose algorithm, taking renal function into account, more suitable to decide which dose should be administered. This approach has been described previously for other drugs, for example carboplatin and fludarabine 25–27 . Such a dosing algorithm for clofarabine was derived from this PK model (Equation 5); however, a target AUC is needed to calculate the conventional clofarabine dose.…”

“…This approach has been described previously for other drugs, for example carboplatin and fludarabine. 25 , 26 , 27 Such a dosing algorithm for clofarabine was derived from this PK model (Equation 5 ); however, a target AUC is needed to calculate the conventional clofarabine dose. A target AUC for clofarabine during conditioning prior to HCT has not yet been determined.…”