Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)
Condition: Leukemia, Myelocytic, Acute; Leukemia, Lymphocytic, Acute; Leukemia, Myeloid, Chronic; Myelodysplastic Syndromes
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Graft vs Host Disease
Intervention: Tacrolimus; Methotrexate; Sirolimus
Intervention description: Adults and Children: Tacrolimus will be given at a dose of 0.02 mg/kg every 24 hours as a continuous intravenous infusion beginning on Day -3. An effort will be made to convert the tacrolimus to oral dosing at 2-3 times the total 24-hour intravenous dose, split into 2 doses given every 12 hours as soon as clinically feasible.
The target serum level for tacrolimus is 5-10 ng/mL.; Methotrexate will be given at a dose of 15 mg/m2 on Day 1 after transplantation, and at a dose of 10 mg/m2 on Days 3, 6 and 11 after transplantation.; Adults: Sirolimus will be given in a loading dose of 12 mg on Day -3 followed by a daily oral dose of 4 mg per day. Doses may be repeated if the subject vomits within 15 minutes of an oral dose.
Children: Children aged < 12.0 years OR weighing < 40.0 kg will be given an oral loading dose of sirolimus of 3 mg/m2 followed by a daily oral dose of 1 mg/m2, rounded to the nearest full milligram.
The target serum level for sirolimus is 3-12 ng/mL.
Intervention MeSH terms: Sirolimus; Methotrexate; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 304.0
Sex: All
Minimum age: 2 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia

Summary:

      The study is designed as a phase III, randomized, open label, multicenter, prospective,
      comparative trial of sirolimus and tacrolimus versus tacrolimus and methotrexate as
      graft-versus-host disease (GVHD) prophylaxis after human leukocyte antigen (HLA)-matched,
      related, peripheral blood stem cell transplantation in individuals with hematologic cancer.
      Participants will be stratified by transplant center and will be randomly assigned to the
      sirolimus/tacrolimus or tacrolimus/methotrexate arms at a 1:1 ratio.
    

Eligibility criteria:

        Inclusion Criteria:

          -  6/6 HLA-matched sibling, defined by Class I (HLA-A and B) serologic typing (or higher
             resolution) and Class II (HLA-DRBI) molecular typing, who is willing to donate
             peripheral blood stem cells, and meets institutional criteria for stem cell donation.
             The donor must be medically eligible to donate stem cells, according to individual
             transplant center criteria. Pediatric patients for whom a pediatric sibling donor is
             not anticipated to be a suitable leukapheresis candidate are not eligible.

          -  Karnofsky performance status of at least 70% or Lansky performance status of at least
             70% for participants less than 16 years old

          -  For participants less than 18 years old, willing and able to take oral medications,
             per the treating physician's recommendations

        Exclusion Criteria:

          -  Prior allogeneic or autologous transplant using any hematopoietic stem cell source

          -  Seropositive for the human immunodeficiency virus (HIV)

          -  Uncontrolled bacterial, viral, or fungal infection (currently taking medication and
             progression of clinical symptoms)

          -  Pregnant (positive serum human chorionic gonadotropin [β-HCG] test) or breastfeeding
             within 4 weeks of study entry

          -  Kidney function: serum creatinine outside the normal range for age, or measured
             creatinine clearance less than 50 mL/min/1.72m^2 within 4 weeks of study entry

          -  Liver function: most recent direct bilirubin, alanine aminotransferase (ALT), or
             aspartate aminotransferase (AST) greater than two times the upper limit of normal
             within 4 weeks of study entry

          -  Lung disease: in adults, forced vital capacity (FVC) or forced expiratory volume in
             one second (FEV1) less than 60% of predicted value (corrected for hemoglobin); in
             children, overt hypoxemia, as measured by an oxygen saturation of less than 92% within
             4 weeks of study entry

          -  Cardiac ejection fraction of less than 45% in adults and children, or less than 26%
             shortening fraction in children within 4 weeks of study entry

          -  Cholesterol level greater than 500 mg/dL or triglyceride level greater than 500 mg/dL
             while being treated, or not on appropriate lipid-lowering therapy within 4 weeks of
             study entry

          -  Prior history of allergy to sirolimus

          -  Requires voriconazole at time of study entry

          -  Currently receiving another investigational drug unless cleared by the protocol
             officer or protocol chair

          -  Participants with a history of cancer, other than resected basal cell carcinoma or
             treated carcinoma in-situ. Cancer treated with curative intent for more than 5 years
             previously will be allowed. Cancer treated with curative intent for less than 5 years
             previously will not be allowed unless approved by the protocol officer or protocol
             chair.