Standard of Care vs. Bortezomib in Graft-Versus Host Disease After Hematopoietic Stem Cell Transplant

You will undergo some screening tests or procedures to find out if you can be in this research study. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. Possible tests include a medical history, physical exam, laboratory tests, pulmonary function tests, cardiac ejection fraction and a pregnancy test. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in the research study.

Because no one knows which of the study options is best, you will be "randomized" into one of the study groups (described below). Randomization means that you are put into a group by chance. It is like flipping a coin. You will have an equal chance of being placed in any of the groups.

Before your transplant you will receiving conditioning therapy. The conditioning therapy for this study involves fludarabine and busulfex. These drugs will be given five, four, three and two days before your transplant (Days -5 through -2). Both these chemotherapy drugs are commonly used in allogeneic stem cell transplantation. On Day 0, you will receive selected blood cells taken from your sibling or unrelated donor.

You will receive 1 of 3 GVHD prophylaxis plans depending on which one you are randomized to:

• Arm A will receive tacrolimus + methotrexate
• Arm B will receive bortezomib + tacrolimus + methotrexate
• Arm C will receive bortezomib + sirolimus + tacrolimus

Tacrolimus (Arm A, B and C) will be started three days before your transplant (Day -3). You will be given tacrolimus initially intravenously (through a needle in a vein in your arm or through a "central line", a catheter or tube placed in the large vein under your collarbone or your neck) and later by mouth. You will continue to take tacrolimus for 3 to 6 months after your transplant. Your physician will discuss your tacrolimus dose with you.

Methotrexate (Arms A and B) will be given intravenously one, three, six and eleven days after your transplant (Days 1,3,6 and 11).

Bortezomib (Arms B and C) will be given intravenously one, four and seven days after your transplant (Days 1,4 and 7).

Sirolimus (Arm C only) will start three days before your transplant (Day -3). You will be given sirolimus initially intravenously and then later by mouth. You will need to continue to take your sirolimus for 3 to 6 months after your transplant. Your physician will discuss your sirolimus dose with you.

To help with engraftment, you will be given the drug G-CSF (Neupogen) starting the day after your transplant, until your white blood cells recover. You will receive other medications as part of standard of care to help prevent you from getting infections. You will also receive medications to help prevent seizures during your conditioning therapy.

Each week for the first four weeks and 2,3,6 and 12 months following your transplant, you will have a physical exam and you will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking. If you are taking bortezomib, you will have an exam and may be asked to fill out an additional questionnaire about potential symptoms of numbness, tingling, weakness or pain on days 1,4 and 7 after your transplant.

Each week for the first four weeks and 12 months following your transplant, you will have blood drawn (approximately 6 teaspoons) to monitor your progress and health following transplant. If you receive methotrexate and/or bortezomib, you will have an additional blood draw on those days.

Approximately 12 months following your transplant, a needle will be inserted into your hip bone and a small amount of bone marrow cells and a sample of bone are removed.

Inclusion criteria

• Histologically or cytologically confirmed advanced/aggressive hematologic malignancy unlikely to be cured by alternative therapies
• HLA matched unrelated donors or 1-locus HLA mismatched related or unrelated donors
• Adequate organ function
• Willing to use appropriate contraception

Exclusion criteria

• Pregnant or breastfeeding
• Recipient of prior allogeneic hematopoietic stem cell transplantation
• Recipient of prior abdominal radiation therapy
• HIV positive on combination anti-retroviral therapy
• Seropositive for hepatitis B or C
• Known allergy to bortezomib, boron or mannitol
• Myocardial infarction within 6 months prior to enrollment or any other cardiac dysfunction
• Uncontrolled infection
• Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes or gluthathione S-transferases
• Seizures or history of seizures
• Grade greater than or equal to 2 peripheral neuropathy within 21 days of enrollment
• Use of other investigational drugs within 21 days of enrollment
• History of another non-hematologic malignancy except if disease free for at least 5 years or cervical cancer in situ, or basal/squamous cell carcinoma of the skin
• Uncontrolled intercurrent illness