Fucosylated T Cells for Graft Versus Host Disease (GVHD) Prevention
Condition: Leukemia; Lymphoma
MeSH terms: Graft vs Host Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential
      participant.

      T-cells are white blood cells that are important to the immune system. The T cells for this
      study (called regulatory T-cells, or Tregs) will be from a donor who is not related to you.
      Before the Tregs are given to you, they may be changed in the laboratory to make use of sugar
      that is found in small amounts in blood cells through a process called fucosylation. They are
      then called fucosylated Tregs. Adding more sugars to the Tregs in the laboratory is designed
      to help the Tregs find their way faster to the bone marrow, which may help low blood counts
      to recover faster.

      The goal of this clinical research study is to learn if it is safe and practical to give
      fucosylated Tregs to patients who will receive a matched related donor (MRD), a matched
      unrelated donor (MUD), or cord blood transplant. Researchers also want to learn if these
      Tregs may prevent or reduce the effects of graft-versus host disease (GVHD). GVHD can result
      from a reaction of the transplanted cord blood cells against certain tissues in the body.

      This is an investigational study. Fucosylation of Tregs is not an FDA-approved process. It is
      currently being used for research purposes only. Fludarabine, melphalan, cyclophosphamide and
      rituximab are FDA approved and commercially available to be given to patients with leukemia
      or lymphoma having a cord blood transplant. Total body irradiation is delivered using
      FDA-approved and commercially available methods.

      Up to 47 patients will take part in this study. All will be enrolled at MD Anderson.
    

Detailed description: 
      Central Venous Catheter Placement:

      You will first have a central venous catheter (CVC) placed. A CVC is a sterile flexible tube
      that will be placed into a large vein while you are under local anesthesia. Your doctor will
      explain this procedure to you in more detail, and you will be required to sign a separate
      consent form for it.

      The chemotherapy, some of the other drugs in this study, the Tregs, and the MRD, MUD or cord
      blood transplant will be given by vein through your CVC. Some blood samples will also be
      drawn through your CVC. The CVC will remain in your body for about 2-5 months.

      Study Treatments:

      If you are found to be eligible to take part in this study, you will be assigned to a dose
      level of Tregs based on when you joined this study. You may receive fucosylated or
      non-fucosylated Treg cells. Two dose levels of fucosylated Tregs will be tested. Up to 3
      participants will be enrolled in Dose Level 1, and up to 17 will be in Dose Level 2. The
      first group of participants will receive the lower dose level. The next group will receive a
      higher dose than the first group, if no intolerable side effects were seen.

      The next 10 participants will receive non-fucosylated Tregs at Dose Level 2.

      The last 34 patients enrolled in the study will be will be randomly assigned (as in the flip
      of a coin) to 1 of 2 study groups and will have an equal chance of receiving either
      fucosylated or non-fucosylated Treg cells.

      You will receive 1 of 2 preparative regimens before your transplant. These regimens are used
      to prepare your body to receive the transplant. Your study doctor will decide which regimen
      is best for you.

      Regimen #1:

      On Day -12, you will receive rituximab by vein over 4-6 hours, if you are receiving it. This
      will depend on the disease that you have.

      On Day -9, you will be admitted to the hospital and given fluids by vein to hydrate you.

      On Day -8, you will receive fludarabine and cyclophosphamide by vein over 1 hour. You will
      also receive mesna by vein over 30-60 minutes before the cyclophosphamide dose and then every
      4 hours for a total of 5 doses. Mesna is given to lower the risk of side effects to the
      bladder caused by cyclophosphamide.

      On Days -7, -6, and -5, you will receive fludarabine by vein over 1 hour.

      On Day -4, you will receive a single treatment of low-dose total body irradiation as part of
      the standard of care for stem cell transplants. You will receive a separate consent form that
      describes this procedure and its risks.

      On Day -1, you will receive the Tregs by vein over 30-60 minutes.

      On Day 0, you will receive your stem cell transplant through the CVC over about 30 minutes to
      several hours depending on the donor type of stem cell transplant you receive.

      Regimen #2:

      On Day -12, you will receive rituximab by vein over 4-6 hours, if you are receiving it. This
      will depend on the disease that you have.

      On Day -6, you will be admitted to the hospital and given fluids by vein to hydrate you.

      On Days -5, -4, -3 and -2, you will receive fludarabine by vein over 1 hour.

      On Day -2, you will receive melphalan by vein over 30 mins.

      On Day -1, you will receive the Tregs by vein over 30-60 minutes.

      On Day 0, you will receive your stem cell transplant through the CVC over about 30 minutes to
      several hours depending on the donor type of stem cell transplant you receive.

      Supportive Drugs:

      You will be given standard drugs to help decrease the risk of side effects. You may ask the
      study staff about how the drugs are given and their risks.

      Starting on Day -3, you will receive sirolimus by mouth once a day. You will receive
      mycophenolate mofetil (MMF) as a tablet by mouth 3 times a day.

      If you are not able to take the MMF tablet by mouth, you will receive MMF by vein over 2
      hours. If you do not have GVHD at Day 100, the dose of MMF will be gradually lowered. If you
      have GVHD, MMF may be stopped 7 days after the GVHD is controlled. If you do not have GVHD at
      Day 180 after your transplant, the dose of sirolimus will be gradually lowered. Your doctor
      will discuss this with you.

      You will receive filgrastim as an injection under the skin 1 time a day, starting on Day 0
      for cord blood transplant or Day 7 for a matched related or MUD transplant, until your blood
      cell levels return to normal. Filgrastim is designed to help with the growth of white blood
      cells.

      Study Visits:

      As part of standard care, you will remain in the hospital for about 4 weeks after the
      transplant. After you are released from the hospital, you will continue as an outpatient in
      the Houston area to be monitored for infections and transplant-related complications.

      On Days -10, -1, 0, +1, +3, +7, +14, +21, and then at 1, 2, 3, 6, and 12 months after the
      transplant, blood (about 3 tablespoons) will be drawn to check your immune function, response
      to the T cells, inflammatory responses, and for GVHD markers. If possible, the blood will be
      collected during standard of care blood draws so that no additional needle sticks will be
      needed.

      About 1, 3, 6, and 12 months after the transplant:

        -  You will have a physical exam.

        -  You will be checked for possible reactions to the transplant and study drugs, including
           GVHD.

        -  Blood (about 4 teaspoons) will be drawn for routine tests, to check for cytomegalovirus
           (CMV), and for genetic tests to learn if your body has accepted the donor cells.

      Urine will be collected for routine tests.

        -  If the doctor thinks it is needed, you will have a bone marrow aspiration to check the
           status of the disease. To collect a bone marrow aspiration/biopsy, an area of the hip or
           other site is numbed with anesthetic, and a small amount of bone marrow and bone is
           withdrawn through a large needle.

        -  If you have lymphoma or Hodgkin's Disease and the doctor thinks it is needed, you will
           have a CT scan of your neck, chest, abdomen, and pelvis to check the status of the
           disease.

      Length of Study:

      You will be on study for up to 1 year. You will be taken off study early if the disease gets
      worse, if intolerable side effects occur, if not enough T cells can be created, if you are
      unable to follow study directions, or if your doctor thinks it is in your best interest.
    

Intervention name(s): Rituximab; Fludarabine; Cyclophosphamide; Total Body Radiation; Fucosylated Regulatory T Cells; Cord Blood Infusions; Mycophenolate mofetil; Sirolimus; Bone Marrow Aspiration; G-CSF; Non-Fucosylated Regulatory T Cells
Intervention type(s): Drug; Drug; Drug; Radiation; Procedure; Procedure; Drug; Drug; Procedure; Drug; Procedure
Intervention description(s): 375 mg/m2 by vein on Day -12 for for participants with CD20+ malignancies.; 40 mg/m2 by vein on Days -8 to -5.; 50 mg/kg by vein on Day -8.; 2 Gy delivered on Day -4.; Phase I: Participants treated at cell dose level 1: 1 x 10^6/kg Fucosylated T-reg cells on Day -1.
Phase II: Participants treated at cell dose level 2: 1 x 10^7/kg Fucosylated T-reg cells on Day -1.; Cord blood transplant, MRD, or MUD infused on Day 0.; 15 mg/kg (actual body weight with a maximum dose of 1 gram twice daily) by vein or mouth from Day -3 to Day +100 in the absence of GVHD.; 12 mg by mouth load followed by 4 mg by mouth daily from Day -3 to Day +180 in the absence of GVHD.; Bone marrow aspiration performed at 1, 3, 6, and 12 months after transplant to check status of disease.; 5 mcg/kg/day subcutaneously beginning on D+0, and continuing until absolute neutrophil count (ANC) is > 500 x 10/L for 3 consecutive days.; Phase I: Participants treated at cell dose level 1: 1 x 10^7/kg Non-Fucosylated T-reg cells on Day -1.
Phase II: Participants treated at cell dose level 2: 1 x 10^7/kg Non-Fucosylated T-reg cells on Day -1.
Other intervention name(s): Rituxan; Fludarabine Phosphate; Fludara; Cytoxan; Neosar; Radiation Therapy; XRT; TBI; Tregs; MMF; CellCept; Rapamune; Filgrastim; Neupogen; Tregs
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia; Lymphoma; Advanced hematologic malignancies; Graft versus host disease; GVHD; Fucosylated umbilical cord blood Regulatory T cells; CB; Tregs; T cells; Cord blood transplant; Total body radiation; TBI; Radiation therapy; XRT; Rituximab; Rituxan; Fludarabine; Fludarabine phosphate; Fludara; Cyclophosphamide; Cytoxan; Neosar; Mycophenolate; Mycophenolate mofetil; MMF; CellCept; Sirolimus; Rapamune; G-CSF; Filgrastim; Neupogen