Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)

BACKGROUND:

Stem cell transplantation is a standard therapy for acute and chronic leukemias and
myelodysplastic disorders. A common problem that may occur after a stem cell transplant is a
condition known as GVHD. The purpose of this study is to compare two combinations of
medications to see which is better at preventing GVHD. The combinations of medications in
this study are:

- Sirolimus and tacrolimus

- Methotrexate and tacrolimus

Doctors want to know if one combination is better than the other or if they both have the
same result.

DESIGN NARRATIVE:

Participants will receive one of the two conditioning regimens described in the protocol, at
the discretion of the transplant physician. The transplant physician must choose among these
regimens prior to the participant's assignment to the GVHD prophylaxis treatment.
Conditioning regimens will vary by center, but will be the same for all participants at each
center. Stem cell donors will donate peripheral blood stem cells according to local
institutional practices. Peripheral blood stem cells will not be manipulated or T-depleted
prior to administration. Standard post-transplant care will be administered. Participants
will be randomly assigned to one of two GVHD prophylaxis regimens and will be followed for
the endpoints of interest.

Participants will be followed for 114 days post-randomization for evaluation of the primary
endpoint, with additional follow-up for 2 years after transplantation for evaluation of
secondary endpoints.

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.