Cord Blood Natural Killer (NK) Cells in Leukemia/Lymphoma
Condition: Leukemia
MeSH terms: Leukemia
Study type: Interventional
Phase: Phase 1

Summary: 
      The goal of this clinical research study is to find the highest tolerable dose of immune
      cells called natural killer (NK) cells that can be given with chemotherapy to patients with
      CLL. Researchers want to learn if adding NK cells will be effective in treating the disease.
      The safety of this will also be studied.

      NK cells may kill cancer cells that remain in your body after your last chemotherapy
      treatment. The NK cells will be separated from umbilical cord blood. The device used in the
      laboratory to separate the NK cells is called a CliniMACS. These separated NK cells will then
      be grown in the lab to increase the number of NK cells that can be given to you by vein.

      This is an investigational study. Rituximab, fludarabine, and cyclophosphamide are FDA
      approved and commercially available for the treatment of CLL. Cytarabine, filgrastim, and
      lenalidomide are FDA approved and commercially available for the treatment of other types of
      cancer. The use of cytarabine, filgrastim, and lenalidomide for the treatment of CLL is
      investigational.

      The use of NK cells is investigational. The NK cell process is not FDA approved or
      commercially available. It is currently being used for research purposes only.

      Up to 44 patients will take part in this study. All will be enrolled at MD Anderson.
    

Detailed description: 
      Central Venous Catheter:

      The chemotherapy, some of the other drugs in this study, and the NK cells will be given by
      vein through your central venous catheter (CVC). A CVC is a sterile flexible tube and needle
      that will be placed into a large vein while you are under local anesthesia. Blood samples
      will also be drawn through your CVC. The CVC will remain in your body during treatment. Your
      doctor will explain this procedure to you in more detail, and you will be required to sign a
      separate consent form.

      NK Cell Dose Levels:

      You will be assigned to a dose level of NK cells based on when you joined this study. Up to 5
      dose levels of NK cells will be tested. The first group of participants will receive the
      lowest dose level. Each new group will receive a higher dose than the group before it, if no
      intolerable side effects were seen. This will continue until the highest tolerable dose of NK
      cells is found.

      If not enough NK cells can be produced in the laboratory for your assigned dose level, you
      will still receive the NK cells that were produced. If you are infused with a lower number of
      NK cells than had been originally planned, the CLL may not respond. Researchers do not know
      what number of NK cells is needed for a response.

      Chemotherapy and NK Cell infusion:

      The days before you receive the NK cells are called minus days. The day you receive the NK
      cells is called Day 0. The days after you receive the NK cells are called plus days.

      You will receive 1 of 3 study drug plans. Your doctor will decide which plan you will receive
      based on your age, prior treatment, diagnosis, and health status. You will receive 1 of the 3
      options as explained below.

      Option #1:

      On Day -2 through Day +14, you will take lenalidomide by mouth once a day at about the same
      time each day. If you are able to do so, you will take aspirin or another drug as instructed
      by your doctor on these days to help prevent blood clots. You will be asked to complete a
      study drug diary and bring it to each study visit. The study staff will tell you more about
      this.

      On Day -5, you will receive fludarabine by vein over 1 hour and cyclophosphamide by vein over
      3 hours. If you have a B-cell cancer, you will receive rituximab by vein over 3-6 hours.
      Rituximab and fludarabine are given to treat the cancer and lower the immune system in order
      to lower the risk of the body rejecting the NK cells. Cyclophosphamide is given to lower the
      immune system in order to lower the risk of graft-versus-host disease (GVHD -- when
      transplanted immune tissue, such as cord blood NK cells, attacks the tissues of the
      recipient's body).

      On Day -4 and -3, you will receive fludarabine by vein over 1 hour and cyclophosphamide by
      vein over 3 hours.

      On Days -2 and -1, you will rest.

      On Day 0, you will receive NK cells by vein.

      Option #2:

      On Day -2 through Day +14, you will take lenalidomide by mouth once a day at about the same
      time each day. If you are able to do so, you will take aspirin or another drug as instructed
      by your doctor on these days to help prevent blood clots. You will be asked to complete a
      study drug diary and bring it to each study visit. The study staff will tell you more about
      this.

      On Day -6, you will receive fludarabine by vein over 1 hour. Fludarabine is given to treat
      the cancer and lower the immune system in order to lower the risk of the body rejecting the
      NK cells.

      On Day -5, and -4, you will receive fludarabine by vein over 1 hour and cyclophosphamide by
      vein over 3 hours. Cyclophosphamide is given to lower the immune system in order to lower the
      risk of graft-versus-host disease (GVHD -- when transplanted immune tissue, such as cord
      blood NK cells, attacks the tissues of the recipient's body).

      On Day -3 and -2, you will receive fludarabine by vein over 1 hour. Fludarabine is given to
      treat the cancer and lower the immune system in order to lower the risk of the body rejecting
      the NK cells.

      On Day -1, you will rest.

      On Day 0, you will receive NK cells by vein.

      Option #3:

      On Day -7, you be given fluids by vein to hydrate you.

      On Days -6 through - 2, you will receive fludarabine by vein over 1 hour and cytarabine by
      vein over 1 hour.

      On Day -2 through Day +14, you will take lenalidomide by mouth once a day at about the same
      time each day. If you are able to do so, you will take aspirin or another drug as instructed
      by your doctor on these days to help prevent blood clots. You will be asked to complete a
      study drug diary and bring it to each study visit. The study staff will tell you more about
      this.

      On Day -1, you will rest.

      On Day 0, you will receive NK cells by vein.

      Starting on Day +5, you will receive filgrastim as an injection under the skin 1 time a day
      until your blood cell levels return to normal. Filgrastim is designed to help with the growth
      of white blood cells.

      Study Visits:

      Within 7 days before starting chemotherapy:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

      Within 2 days and then about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, and 4
      months after the NK cell infusion, the following tests and procedures will be performed:

      °Blood (about 4 tablespoons) will be drawn for routine tests, tests to measure levels of
      certain proteins, to learn how your body's immune system responds to the NK cell infusion,
      and to check the level of the NK cells.

      About 1 week, 3 weeks, 1 month, and 4 months after the NK cell infusion, you will have a bone
      marrow biopsy/aspiration to check the status of the disease. To collect a bone marrow
      biopsy/aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small
      amount of bone and bone marrow is withdrawn through a large needle.

      Pregnancy Tests:

      If you can become pregnant, blood (about 1 teaspoon each time) will be drawn for a pregnancy
      test within 10-14 days and 24 hours before you are prescribed lenalidomide, at about Day +21,
      at 2 months after NK cell infusion, and then again 4 weeks after therapy is stopped. To
      continue on this study, you must not be pregnant.

      If possible, the blood needed for pregnancy tests will be collected during the above blood
      draws so that no additional needle sticks will be needed.

      Length of Study:

      You will be on study for up to about 1 year. You may be taken off study early if the disease
      gets worse, if you are unable to receive the NK cell infusion, if you have any intolerable
      side effects, if you are unable to follow study directions, if your doctor thinks it is in
      your best interest, if the study is stopped, or if you choose to leave the study early.

      You should talk to the study doctor if you want to leave the study early. If you are taken
      off study early, you still may need to return for routine post-transplant follow-up visits,
      if your doctor decides it is needed.

      If you are thinking about dropping out of this study, please tell the study doctor. The
      doctor can tell you about the effects of stopping treatment. You and the doctor can talk
      about what follow-up care and testing would help you the most.

      If you leave the study, your test results and information cannot be removed from the study
      records.
    

Intervention name(s): Lenalidomide; Rituximab; Fludarabine; Cyclophosphamide; NK Cells; Cytarabine
Intervention type(s): Drug; Drug; Drug; Drug; Procedure; Drug
Intervention description(s): 2.5 mg by mouth daily on Day -2 to Day +14.; 375 mg/m2 by vein on Day -5 for participants with B-cell cancer.; Lymphodepleting Chemotherapy Option #1: Fludarabine 25 mg/m2 by vein on Days -5 to -3.
Lymphodepleting Chemotherapy Option #2: Fludarabine 25 mg/m2 by vein over 1 hour on Day -6 to -2.
Lymphodepleting Chemotherapy Option #3: Fludarabine 30 mg/m2 by vein over 1 hour on Days -6 to -2; Lymphodepleting Chemotherapy Option #1: Cyclophosphamide 200 mg/m2 by vein on Days -5 to -3.
Lymphodepleting Chemotherapy Option #2: Cyclophosphamide 60 mg/kg by vein over 3 hours on Days -5 and -4.; Participant assigned to a dose level of NK cells based on when joined study. Starting dose level of NK cells 1 x 10^7 NK cells/kg given by vein on Day 0.
NK Cell Infusion Expansion Phase: Maximum tolerated dose of NK cells from Induction Phase.; Cytarabine 2 mg/m2 by vein on Days -6 to -2.
Other intervention name(s): CC-5013; Revlimid; Rituxan; Fludarabine Phosphate; Fludara; Cytoxan; Neosar; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride
Intervention MeSH terms: Cytarabine; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Lenalidomide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia; Chronic Lymphocytic Leukemia; CLL; Natural Killer Cells; NK; Umbilical Cord Blood; UCB; Lenalidomide; CC-5013; Revlimid; Rituximab; Rituxan; Fludarabine; Fludarabine phosphate; Fludara; Cyclophosphamide; Cytoxan; Neosar; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride