Tacrolimus, Bortezomib, & Thymoglobulin in Preventing Low Toxicity GVHD in Donor Blood Stem Cell Transplant Patients

PRIMARY OBJECTIVES:

I. To determine a composite end point of alive and severe acute GVHD free at 6 months
following human leukocyte antigen (HLA) matched related or unrelated donor hematopoietic
peripheral blood transplant in patients with hematologic malignancies who receive the
immunosuppressive combination tacrolimus, bortezomib, anti-thymocyte globulin (TBT) as GVHD
prophylaxis.

II. To determine the safety of this combination in the first six months post-transplant.

SECONDARY OBJECTIVES:

I. To determine the cumulative incidence of grade III-IV aGVHD.

II. To determine incidence and severity of chronic GVHD.

III. To determine disease relapse or progression overall and disease free survival at one
year.

OUTLINE:

Patients receive tacrolimus intravenously (IV) on day -3 through day 180. Patients may
receive tacrolimus orally (PO) later at the doctor's discretion. Patients receive
anti-thymocyte globulin IV on days -3, -2, and -1 and bortezomib IV on day 0 and day 3.
Patients undergo allogeneic bone marrow transplant on day 0.

After completion of study treatment, patients are followed up for 6 months and then
periodically for up to 2 years.

Inclusion Criteria:

- Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative
disorder and myelodysplasia with no circulating blasts and with less than 5% blasts in
the bone marrow within 4 weeks of the start of transplant conditioning regimen

- Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma; follicular,
marginal zone, diffuse large B-cell or mantle cell lymphoma with chemo-sensitive
disease at time of transplant

- Patients must have a related or unrelated peripheral blood stem cell donor; sibling
donor must be a 6/6 match for human leukocyte antigen (HLA)-A and -B at intermediate
(or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid
(DNA)-based typing, and must be willing to donate peripheral blood stem cells and meet
institutional criteria for donation; unrelated donor must be 8/8 match at HLA-A, -B,
-C and -DRB1 at high resolution using DNA-based typing; unrelated donor must be
willing to donate peripheral blood stem cells and be medically eligible to donate stem
cells according to National Marrow Donor Program (NMDP) criteria

- Cardiac function: ejection fraction > 40%

- Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault
formula and actual body weight)

- Pulmonary function: carbon monoxide diffusing capability test (DLCO) ≥ 40% (adjusted
for hemoglobin) and forced expiratory volume in 1 second (FEV1) ≥ 50%

- Total bilirubin < 1.5 x the upper limit of normal; patients who have been diagnosed
with Gilbert's disease are allowed to exceed the defined bilirubin value of 1.5 x the
upper limit of normal

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper
normal limit

- Female subjects (unless postmenopausal for at least 1 year before the screening visit,
or surgically sterilized), agree to practice two effective methods of contraception or
agree to completely abstain from heterosexual intercourse from the time of signing the
informed consent through 12 months post-transplant

- Male subjects (even if surgically sterilized), of partners of women of childbearing
potential must agree to practice effective barrier contraception or abstain from
heterosexual intercourse from the time of signing the informed consent through 12
months post-transplant

- Signed informed consent

Exclusion Criteria:

- Prior allogeneic transplant

- Karnofsky performance score < 70%

- Active central nervous system (CNS) involvement by malignant cells

- Patients with uncontrolled bacterial, viral, or fungal infections (currently taking
medication and with progression or no clinical improvement) at time of enrollment

- Patients with transformed lymphoma (e.g., Richter's transformation arising in
follicular lymphoma or chronic lymphocytic leukemia)

- Patients seropositive for the human immunodeficiency virus (HIV)

- Patient with active hepatitis B or C

- Patients with hypersensitivity to bortezomib, boron, or mannitol

- Patients with > grade 2 sensory peripheral neuropathy

- Myocardial infarction within 6 months prior to enrollment or New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiography (ECG) abnormality at screening must be documented by the
investigator as not medically relevant

- Female patients who are lactating or pregnant

- Patients with a serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Patients with prior malignancies, except resected basal cell carcinoma or treated
cervical carcinoma in situ; cancer treated with curative intent > 5 years previously
will be allowed; cancer treated with curative intent < 5 years previously will not be
allowed unless approved by the protocol officer or one of the protocol chairs