Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)

GVHD is a complication that can occur after a bone marrow or stem cell transplant. The
transplant recipient's body is attacked by the newly introduced cells. Only about 40% of
patients with acute GVHD have durable responses when treated with corticosteroid therapy. A
strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an
effective approach to improve survival after allogeneic transplantation.

GVHD incidence can be decreased with various treatment plans. Early transplants were done
using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later
shown to work better than methotrexate. Then doctors discovered that the combined use of
cyclosporine and methotrexate worked even better than either agent alone. More recently,
other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic
agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been
conducted to compare available treatment combinations for related and unrelated donors. The
combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis.

However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current
clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and
bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and
tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II
clinical trial will compare each intervention arm with a Tac/MTX control.

This study will enroll people who have a cancer of the blood or lymph glands and a stem cell
transplant is a treatment option. The study will take at least two years and will include 270
participants - 90 participants in each of three treatment groups. The purpose of this study
is to compare three combinations of medications to see whether one or more of them are better
than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.

Inclusion Criteria:

1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old)

2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no
circulating blasts and with less than 5% blasts in the bone marrow.

3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular,
marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with
chemosensitive disease at time of transplantation

4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)

5. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

1. Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher)
resolution, and -DRB1 at high resolution using DNA-based typing, and must be
willing to donate peripheral blood stem cells and meet institutional criteria for
donation.

2. Unrelated donor must be a 7/8 or 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 cleared to donate stem cells
according to National Marrow Donor Program (NMDP) criteria.

6. Cardiac function: Ejection fraction at rest ≥ 45%

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

8. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40%
(adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%

9. Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine
aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit.
Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the
defined bilirubin value of 1.5x the upper limit of normal.

10. Female subjects (unless postmenopausal for at least 1 year before the screening visit,
or surgically sterilized), agree to practice two (2) effective methods of
contraception at the same time, or agree to completely abstain from heterosexual
intercourse, from the time of signing the informed consent through 12 months post
transplant (see Section 2.6.4 for definition of postmenopausal).

11. Male subjects (even if surgically sterilized), of partners of women of childbearing
potential must agree to one of the following: practice effective barrier contraception
(see Section 2.6.4 for list of barrier methods), or abstain from heterosexual
intercourse from the time of signing the informed consent through 12 months post
transplant.

12. Signed informed consent

Exclusion Criteria:

1. Prior allogeneic transplant

2. Karnofsky Performance Score < 70%

3. Active central nervous system (CNS) involvement by malignant cells

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

5. Presence of fluid collection (ascites, pleural or pericardial effusion) that
interferes with methotrexate clearance or makes methotrexate use contraindicated

6. Patients with transformed lymphoma (e.g., Richters transformation arising in
follicular lymphoma or chronic lymphocytic leukemia)

7. Patients seropositive for the human immunodeficiency virus (HIV)

8. Patient with active Hepatitis B or C determined by serology and/or nucleic acid
amplification tests (NAAT)

9. Patients with hypersensitivity to bortezomib, boron or mannitol

10. Patients with ≥ grade 2 sensory peripheral neuropathy

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

12. Female patients who are lactating or pregnant

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

14. 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.

15. Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen.

16. Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI).

17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes
(CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan
metabolism during day -5 through day +7. It is acceptable to use alternative
non-interacting medications during this period, and then resume prior medications.

18. Patients with secondary acute myeloid leukemia arising from myeloproliferative
disease, including Chronic myelomonocytic leukemia (CMML), with evidence of active
myeloproliferative features or myelofibrosis in the background.