Pharmacokinetics-based Mycophenolate Mofetil Dosing for GVHD Prevention
Condition: Allogeneic Blood and Marrow Transplantation (BMT); Graft Versus Host Disease
MeSH terms: Graft vs Host Disease
Intervention: Mycophenolate mofetil
Intervention description: Based on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure
Intervention MeSH terms: Mycophenolic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 6 Months
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Allogeneic blood and marrow transplantation (BMT); Graft versus host disease; Mycophenolate mofetil; Pharmacokinetics

Summary:

      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.
    

Eligibility criteria:

        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.