MLN9708 for the Prophylaxis of Chronic Graft-versus-host Disease in Patient Undergoing Allogeneic Transplantation

Inclusion Criteria

• Patients with a history of a hematological malignancy or bone marrow failure syndrome undergoing (or status post) a peripheral blood allogeneic HCT.
• Patients aged ≥18 are eligible.
• All patients must have received or plan to receive an allograft from a suitable human leukocyte antigens (HLA) -matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate donor).
• Voluntary written consent must be given before patient registration and performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Bilirubin ≤ 2 x the upper limit of normal (ULN). For patients with Gilbert's syndrome or suspected mild veno-occlusive disease, bilirubin ≤ 3 x ULN is permitted.
• Creatinine clearance of ≥ 30 mL/min calculated by Cockcroft-Gault equation.
• Karnofsky performance status > 60.
• A negative pregnancy test will be required for all women of child bearing potential. Females of child bearing potential should agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug and must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.). Breast feeding is not permitted.
• Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment.
• No known active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.

Exclusion Criteria

• Patients with active ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period will be excluded.
• Patients with history of allergy and/or intolerance to MLN9708 are not eligible.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing is not permitted.
• Patients receiving (or status post) a cord blood or a haplo-identical allograft will not be eligible.
• Patients undergoing (or status post) a T-cell depleted allogeneic transplantation will not be eligible.
• Patients receiving (or status post) conditioning regimens containing antithymocyte globulin, and/or campath, one receiving post-HCT planned cyclophosphamide will not be eligible.
• Method of stem-cell collection from the donor will be at the discretion of the treating physician. Although it is anticipated that majority of patients will receive allograft mobilized with Granulocyte- colony stimulating factor (CSF) alone; however donors receiving allografts mobilized with experimental agents (e.g. plerixafor) will remain eligible for the study.
• Patients experiencing disease relapse (for those in complete remission at the time of HCT) or progression (for those in partial remission, stable or refractory disease at the time of HCT) will be excluded.
• Donor lymphocyte infusions between day zero of HCT and first dose of MLN9708 are not