Pharmacokinetics-based Mycophenolate Mofetil Dosing for GVHD Prevention
Allogeneic Blood and Marrow Transplantation (BMT)
Graft Versus Host Disease
Drug: Mycophenolate mofetil
|Study Design:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation|
- Number of Participants With Grade ≥3 Toxicities Scored According to the CTCAE Version 4.0. [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
- Number of Participants With Acute Grade II-IV GVHD, Acute Grade III-IV GVHD, and Chronic GVHD. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Acute GVHD will be graded according to the Modified Glucksberg Staging Criteria. Chronic GVHD will be graded according to NIH Chronic GVHD Consensus Guidelines.
- Number of Participants With Neutrophil and Platelet Engraftment. [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]Neutrophil and platelet engraftment definitions as defined by the CIBMTR Data Management Manual.
- Number of Participants Who Experienced Relapse. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Number of Participants Who Experienced Nonrelapse Mortality. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Number of Participants in Overall Survival. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Pharmacokinetic Analysis of MMF AUC to Evaluate MMF Dose Relationships to Drug Exposure. [ Time Frame: 100 days ] [ Designated as safety issue: No ]Pharmacokinetic analysis includes, but is not limited to, area under the plasma concentration versus time curve (AUC).
- Pharmacokinetic Analysis of MMF Clearance to Evaluate MMF Dose Relationships to Drug Exposure. [ Time Frame: 100 days ] [ Designated as safety issue: No ]Pharmacokinetic analysis includes, but is not limited to, clearance.
- Pharmacokinetic Analysis of MMF Steady State Concentration to Evaluate MMF Dose Relationships to Drug Exposure. [ Time Frame: 100 days ] [ Designated as safety issue: No ]Pharmacokinetic analysis includes, but is not limited to, steady-state concentrations.
|Study Start Date:||June 2010|
|Study Completion Date:||January 2016|
|Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Mycophenolate mofetil
Pharmacokinetics-based targeting of mycophenolate mofetil
Drug: Mycophenolate mofetil
Based on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure
Graft-versus-host disease (GVHD) remains a major barrier to the success of allogeneic blood and marrow transplant (BMT) therapy. Acute GVHD is seen in 30-80% of patients and once established, often responds poorly to therapy and is associated with chronic disease and increased risk of death. Although combination of methotrexate (MTX) and a calcineurin inhibitor has been the "standard of care" for more than a quarter of a century, there is little consensus on the most effective and least toxic approach to GVHD prevention. MTX use is associated with painful mucositis, delay in engraftment and potential pulmonary toxicity. For cord blood transplants, commonly, a calcineurin inhibitor is used with corticosteroids and antithymocyte globulin. Steroid therapy is frequently complicated by high rates of infection, hyperglycemia and hypertension.
Mycophenolate mofetil (MMF), whose metabolite mycophenolic acid (MPA) inhibits proliferation of lymphocytes, is approved for prevention of organ transplant rejection. MMF in combination with CsA is widely used for GVHD prevention in patients receiving reduced-intensity conditioning BMT. It has also been successfully used in primary and salvage therapy of acute GVHD. In myeloablative transplants, while the GVHD outcomes appear comparable, this regimen appears to have superior toxicity profile in comparison to CsA and MTX with faster hematopoietic engraftment and reduced severity and duration of mucositis.
One challenge with MMF use in BMT recipients is a significantly lower MPA exposure in the immediate post-conditioning period when compared to organ transplant recipients. This has been shown in a number of pharmacokinetics studies including our preliminary data on pediatric myeloablative transplants. Low total and unbound MPA trough concentrations are associated with higher rates of acute GVHD and graft rejection, and lower response rates in treatment of acute GVHD. There is also poor correlation between MPA trough concentration and area under the concentration curve (AUC). While most previous studies have used fixed MMF dosing, one recent study in adults has shown feasibility of AUC-based individualized MMF dosing.
This protocol is based on the premise that optimization of MPA exposure in the immediate post-transplant phase will lead to better acute GVHD prevention. It will study an AUC-based targeting of MMF in pediatric patients undergoing myeloablative allogeneic BMT. We propose a novel continuous infusion method for MMF administration to achieve total MPA steady state concentration. Salient findings emerging from this study will be examined and in replicate cohorts of pediatric and adult patients undergoing allo-BMT.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01487577
|United States, Pennsylvania|
|Children's Hospital of Pittsburgh of UPMC|
|Pittsburgh, Pennsylvania, United States, 15224|
|Principal Investigator:||Randy M Windreich, MD||Children's Hospital of Pittsburgh of UPMC|