Pharmacokinetics-based Mycophenolate Mofetil Dosing for GVHD Prevention

Study Overview
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Brief Summary
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Bone marrow transplantation (BMT) is used to successfully treat high-risk forms of leukemia, lymphoma, and other childhood cancers that were once considered incurable. A major barrier to the application of this life-saving treatment is acute graft-versus-host disease (GVHD) which develops in approximately 30-80% of patients and is a leading cause of death from transplant complications. Current GVHD prevention methods are not very efficacious and lead to unacceptable side effects. Mycophenolate mofetil (MMF), an anti-rejection medication used in solid organ transplants, has shown great promise in BMT recipients. The effectiveness of MMF depends on blood levels of mycophenolic acid (MPA, the active form of MMF). Different patients have been found to have different blood levels of MPA when they are given the same dose of MMF. The purpose of this study is to study a novel method of giving MMF based on its metabolism (pharmacokinetics) to achieve desired blood levels of MPA for prevention of GVHD. Non-invasive ways of monitoring the drug exposure will also be studied. The ultimate goal of this study is to improve approaches to GVHD prevention and improve outcomes of BMT in children.

Detailed Description
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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.

Official Title
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A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation

Conditions
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Allogeneic Blood and Marrow Transplantation (BMT), Graft Versus Host Disease

Intervention / Treatment
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* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be between 6 months and 21 years of age. Recipients of an allogeneic blood and marrow transplant (BMT). Stem cell sources should be bone marrow or umbilical cord blood. Bone marrow or cord blood unit: Sibling should be HLA matched at A, B and DRB1 loci. Unrelated cord blood unit should be at a minimum 4/6 matched at allele level on HLA A, B and DRB1 loci. Unrelated donor should be HLA allele level matched at A, B, C and DRB1 loci. Minimum prefreezing nucleated cell dose for cord blood units: 3x10^7/kg for malignant diseases and 5x10^7/kg for nonmalignant diseases. Conditioning regimen must be myeloablative in intensity. Examples include but are not limited to Cy/TBI, BuCy 200, etc. Patients ≥ 16 years old must have a Karnofsky score ≥ 70%, and patients < 16 years old must have a Lansky score ≥ 70%. Renal: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2. Hepatic: Total bilirubin ≤ 2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase < 5 x upper limit of normal (ULN) for age. Cardiac: Left ventricular ejection fraction at rest > 40%, or shortening fraction > 26%, by echocardiogram or radionuclide scan. Pulmonary: FEV1, FVC, and DLCO (diffusion capacity) > 50% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% of room air. Exclusion Criteria: Patients with a known hypersensitivity to MMF. Prior autologous or allogeneic BMT < 12 months prior to enrollment. Mismatched related donor. Mismatched unrelated marrow donor. Peripheral blood stem cell source. Reduced intensity conditioning. Uncontrolled bacterial, viral, fungal or other infection. Evidence of HIV infection or HIV positive serology. Requirement of supplemental oxygen. Patients who are pregnant (B-hCG positive) or breastfeeding. All females of 11 years of age or older and/or who have begun menstruating will be screened for hCG by either urinalysis or a blood sample in order to screen for pregnancy status, as per institutional BMT policy.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate mofetil<br>Pharmacokinetics-based targeting of mycophenolate mofetil | Drug: Mycophenolate mofetil<br>* Based on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade ≥3 Toxicities Scored According to the CTCAE Version 4.0. |  | 100 days | 
| Number of Participants With Acute Grade II-IV GVHD, Acute Grade III-IV GVHD, and Chronic GVHD. | Acute GVHD will be graded according to the Modified Glucksberg Staging Criteria. Chronic GVHD will be graded according to NIH Chronic GVHD Consensus Guidelines. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Neutrophil and Platelet Engraftment. | Neutrophil and platelet engraftment definitions as defined by the CIBMTR Data Management Manual. | 100 days | 
| Number of Participants Who Experienced Relapse. |  | 1 year | 
| Number of Participants Who Experienced Nonrelapse Mortality. |  | 1 year | 
| Number of Participants in Overall Survival. |  | 1 year | 
| Pharmacokinetic Analysis of MMF AUC to Evaluate MMF Dose Relationships to Drug Exposure. | Pharmacokinetic analysis includes, but is not limited to, area under the plasma concentration versus time curve (AUC). | 100 days | 
| Pharmacokinetic Analysis of MMF Clearance to Evaluate MMF Dose Relationships to Drug Exposure. | Pharmacokinetic analysis includes, but is not limited to, clearance. | 100 days | 
| Pharmacokinetic Analysis of MMF Steady State Concentration to Evaluate MMF Dose Relationships to Drug Exposure. | Pharmacokinetic analysis includes, but is not limited to, steady-state concentrations. | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic blood and marrow transplantation (BMT), Graft versus host disease, Mycophenolate mofetil, Pharmacokinetics