Standard of Care vs. Bortezomib in Graft-Versus Host Disease After Hematopoietic Stem Cell Transplant
Condition: Graft Versus Host Disease
MeSH terms: Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      This research study is a Phase II clinical trial. Phase II clinical trials test the
      effectiveness of an investigational drug to learn whether the drug works in treating a
      specific cancer. "Investigational" means that the drug is still being studied and that
      research doctors are trying to find out more about it-such as the safest dose to use, the
      side effects it may cause, and if the drug is effective for treating different types of
      cancer. It also means that the FDA has not yet approved bortezomib to treat or prevent
      graft-versus-host disease. Bortezomib is approved by the FDA to treat other human
      malignancies.

      Bortezomib is a drug that has an anti-cancer effect that involves inhibiting cell growth and
      causing cell death. This drug has been used in other research studies, and information from
      thos other research studies suggests that bortezomib may help to lower the risk of GVHD after
      allogeneic stem cell transplantation in patients who have matched unrelated, unmatched
      related or unrelated donors in this research study.

      Allogeneic stem cell transplantation is a procedure in which selected blood cells taken from
      your sibling or unrelated donor are given to you. Lower doses of chemotherapy drugs are given
      before the donor cells are infused in a process known as reduced-intensity conditioning. Stem
      cell transplant destroys cancer in two ways: The conditioning regimen destroys cancer cells
      and teh immune cells from the donor can recognize cancer cells and kill them.

      A common problem after stem cell transplant is graft-versus-host disease (GVHD). The word
      "graft" refers to the donor blood cells that you will receive during your transplant. The
      word "host" refers to the person (in this case, you) receiving the cells. GVHD is a
      complication of transplantation where the donor graft attacks and damages some of your
      tissues. GVHD can cause skin rash, intestinal problems such as nausea, vomiting or diarrhea.
      GVHD may also damage your liver and cause hepatitis or jaundice. GVHD may also increase your
      risk of infection.

      After stem cell transplant, all patients receive prophylactic medications against GVHD. In
      this research study we are studying the safety and effectiveness of preventing GVHD using
      bortezomib treatment in combination with other drugs versus standard of care prophylaxis
      (tacrolimus + methotrexate). If you take part in this study, there is a 33% chance you will
      receive any one of the following GVHD prevention treatments:

        -  tacrolimus + methotrexate (standard of care GVHD prophylaxis)

        -  bortezomib + tacrolimus + methotrexate

        -  bortezomib + sirolimus + tacrolimus Sirolimus, tacrolimus and methotrexate are drugs
           that suppress the immune system to try to prevent GVHD.
    

Detailed description: 
      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.
    

Intervention name(s): Tacrolimus; Methotrexate; Bortezomib; Sirolimus
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Sirolimus; Methotrexate; Bortezomib; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment