Clinical Trials /

NK Cells in Cord Blood Transplantation

NCT01619761

Description:

This phase I trial studies the side effects and best way to give natural killer cells and donor umbilical cord blood transplant in treating patients with hematological malignancies. Giving chemotherapy with or without total body irradiation before a donor umbilical cord blood transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Double-Hit Lymphoma
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Natural Killer (NK) Cells in Cord Blood Transplantation
  • Official Title: Natural Killer Cells In Allogeneic Cord Blood Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2011-0493
  • SECONDARY ID: NCI-2012-02071
  • SECONDARY ID: 13369
  • NCT ID: NCT01619761

Conditions

  • Leukemia
  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
LenalidomideCC-5013, RevlimidCB NK + Chemotherapy
Fludarabine monophosphateFludarabine phosphate, FludaraCB NK + Chemotherapy
MelphalanAlkeranCB NK + Chemotherapy
TacrolimusPrografCB NK + Chemotherapy
Mycophenolate mofetilCellCept, MMFCB NK + Chemotherapy
RituximabRituxanCB NK + Chemotherapy
CyclophosphamideCytoxan, NeosarCB NK + Chemotherapy

Purpose

Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant. The goal of this clinical research study is to learn if giving cells called natural killer (NK) cells after receiving a chemotherapy treatment and a UCB transplant can improve response in patients with leukemia, lymphoma, or MM. The safety of this treatment and whether NK cells can lessen the risk of graft vs. host disease (GVHD) will also be studied. Patients with a disease that is CD20-positive will also receive rituximab on this study. The first 3 patients enrolled on this study will not receive NK cells but will receive a cord blood transplant. UCB and NK cells may be able to kill leukemia, lymphoma, or myeloma cells that remain in your body after chemotherapy treatment. The UCB cells are also designed to increase blood production and strengthen your immune system. This is an investigational study. Cyclophosphamide, fludarabine, melphalan, lenalidomide, and the UCB transplant procedure are all FDA approved and commercially available for the treatment of CLL. Cyclophosphamide is approved for the treatment of CLL. Fludarabine is approved for treatment of refractory CLL. Melphalan is approved for the treatment of multiple myeloma (MM) but has been used in transplant conditioning regimens. Lenalidomide is approved for the treatment of low risk myelodysplastic syndromes and for MM. Rituximab is approved for the treatment of CD20 positive B-cell lymphomas and chronic lymphocytic leukemia (in combination with chemotherapy). The use of NK cells in patients is investigational. Up to 13 participants will be enrolled in this study. All will be enrolled at MD Anderson.

Detailed Description

      Pregnancy Tests:

      If you are able to become pregnant, you will have a blood (1 teaspoon) pregnancy test within
      10-14 days and 24 hours before taking lenalidomide, and then 28 days after your last dose of
      lenalidomide. Lenalidomide must be discontinued right away if you miss a period, have an
      abnormal pregnancy test, or have abnormal menstrual bleeding.

      Study Drug Administration and Study Procedures:

      Two (2) UCB units have been selected to give to you. If you are enrolled after the third
      patient is enrolled, one of the selected units will have NK cells separated out from it. The
      NK cells are separated from the UCB unit using a machine called the CliniMACS system. This
      machine uses certain kinds of cells and antibody-coated magnetic beads to separate the NK
      cells. The separated NK cells will then be "grown" to increase their numbers before they are
      given to you. The drug aldesleukin (interleukin-2) will be added to the NK cells in attempt
      to improve their function. The aldesleukin will be washed out of the NK cells before they are
      given to you. The second UCB unit will be given to you without any NK cell separation.

      For UCB transplant schedules, the days before the transplant are called minus days (Day -2,
      Day -1, etc.). The day of the transplant is called Day 0. The days after the transplant are
      called plus days (Day +1, Day +2, etc.).

      You will receive 1 of 2 chemotherapy treatments that will be chosen by your doctor. The
      treatment will be selected based on your disease status.

      Treatment Plan #1:

      On Day -8, you will be admitted to the hospital and you will begin receiving fluids by vein
      to hydrate you. The fluids will be given as a continuous (non-stop) infusion until you leave
      the hospital. If your disease is CD20-positive, you will be admitted to the hospital on Day
      -9. Your study doctor will discuss this with you.

      On Days -8 through -2, you will take lenalidomide by mouth 1 time a day. The capsules should
      be taken at around the same time every day with a cup (8 oz. ) of water. Do not break, chew,
      or open the lenalidomide capsules. If you miss a dose of lenalidomide, take it as soon as you
      remember on the same day. If you miss taking your dose for the entire day, take your regular
      dose the next scheduled day. Do not double your regular dose to make up for the missed dose.
      If you take more than the prescribed dose of lenalidomide, you should seek emergency medical
      care if needed and contact the study staff right away.

      If your disease is CD20-positive, you will receive rituximab by vein over about 6 hours on
      Day -8.

      On Days -7 through -4, you will receive fludarabine by vein over about 1 hour.

      On Day -4, you will receive melphalan by vein over about 30 minutes.

      On Day -2, you will receive the NK cells by vein over about 30 minutes (first 3 patients will
      not receive the NK cells).

      On Day -1, you will not receive any study drugs or NK cells.

      On Day 0, you will receive the UCB transplant.

      Treatment Plan #2:

      On Day -8, you will be admitted to the hospital and you will begin receiving fluids by vein
      to hydrate you. The fluids will be given as a continuous (non-stop) infusion until you leave
      the hospital. If your disease is CD20-positive, you will be admitted to the hospital on Day
      -9. Your study doctor will discuss this with you.

      If your disease is CD20-positive, you will receive rituximab by vein over about 6 hours on
      Day -8.

      On Days -7 through -4, you will receive fludarabine by vein over about 1 hour.

      On Day -7, you will receive cyclophosphamide by vein over 3 hours and mesna by vein over 30
      minutes. Mesna is given to lower the risk of side effects to the bladder caused by
      cyclophosphamide.

      On Days -7 through -2, you will take lenalidomide by mouth 1 time a day. The capsules should
      be taken at around the same time every day with a cup (8 oz. ) of water. Do not break, chew,
      or open the lenalidomide capsules. If you miss a dose of lenalidomide, take it as soon as you
      remember on the same day. If you miss taking your dose for the entire day, take your regular
      dose the next scheduled day. Do not double your regular dose to make up for the missed dose.
      If you take more than the prescribed dose of lenalidomide, you should seek emergency medical
      care if needed and contact the study staff right away.

      On Day -3, you will receive total body irradiation (TBI). TBI involves the delivery of high
      doses of radiation designed to destroy cancer cells and/or lower the immune system in order
      to lower the risk of the body rejecting the new stem cells.

      On Day -2, you will receive the NK cells by vein over about 30 minutes (first 3 patients will
      not receive the NK cells).

      On Day -1, you will not receive any study drugs or NK cells.

      On Day 0, you will receive the UCB transplant.

      Supportive Drugs:

      You will be given drugs to help prevent side effects. The study staff will tell you about
      these drugs, how they will be given, and the possible risks.

      Starting on Day 0, you will begin receiving filgrastim (G-CSF) through a needle under the
      skin 1 time every day until your white blood count begins to recover. Filgrastim is designed
      to make white blood cells grow. This may help to fight infections.

      Starting on Day -2, you will begin receiving tacrolimus by vein as a non-stop infusion until
      you are able to take it by mouth. You will then take tacrolimus by mouth 2 times a day for
      about 6 months. After that, your tacrolimus dose may be reduced if you do not have GVHD. Your
      doctor will discuss this with you.

      Starting on Day -3, you will begin taking mycophenolate mofetil (MMF) by mouth 3 times a day
      with food. If you are not able to take the tablet by mouth, you will receive MMF by vein over
      2 hours, 2 times a day. If you do not have GVHD at Day 100, the dose of MMF will be reduced.
      If you miss a dose of MMF you should tell your study doctor. You should not try to make up
      the dose later.

      Study Tests:

      You will stay in the hospital for about 2-4 weeks after the UCB transplant. While you are in
      the hospital, you will be checked for any side effects you may have and blood (about 2
      teaspoons) will be drawn for routine tests whenever the doctor feels it is necessary.

      After you are released from the hospital, you must remain in the Houston area to be monitored
      for infections and other transplant-related side effects until about Day 100. During this
      time, you will return to the clinic 1 time each week and the following tests and procedures
      will be performed:

        -  You will be asked about how you are feeling and about any side effects you may be
           having.

        -  Blood (about 2 teaspoons) will be drawn for routine tests.

      About 4 weeks after the transplant (around Day 42), the following tests and procedures will
      be performed:

        -  You will have a physical exam.

        -  You will be asked about how you are feeling and about any side effects you may be
           having.

        -  Blood (about 4 teaspoons) will be drawn for routine tests and to check for side effects,
           including GVHD. The blood will also be used to check how the UCB is being "received" by
           your body.

      At about 3, 6, and 12 months after the UCB transplant, the following tests and procedures
      will be performed:

        -  You will have a physical exam.

        -  Blood (about 4 teaspoons) and urine will be drawn for routine tests and to check for
           side effects, including GVHD. The blood will also be used to check how the UCB is being
           "received" by your body.

        -  You will be asked about how you are feeling and about any side effects you may be
           having.

        -  You may have a bone marrow biopsy to check the status of the disease if the doctor
           thinks it is necessary. To collect a bone marrow 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.

      Length of Study:

      Your participation on this study will be over after you have completed the 12-month study
      visit.

      You will be taken off study if the disease gets worse, if intolerable side effects occur, if
      your doctor thinks it is in your best interest, or if you are unable to follow the study
      directions. You will also be taken off study if you are unable to receive the UCB transplant,
      if you need medical treatment that is not allowed in this study, or if you have any
      infections.

      You must talk to the study doctor if you want to leave the study early. It may be
      life-threatening to leave the study after you have started receiving study drugs but before
      you have had the UCB transplant.
    

Trial Arms

NameTypeDescriptionInterventions
CB NK + ChemotherapyExperimentalLenalidomide 10 mg by mouth day -8 to -2. Fludarabine 40 mg/m2 intravenous (IV) from day -7 to -4. Melphalan 140 mg/m2 IV on day -4. The NK cell infusion administered intravenously on day -2 over a period of 30 minutes. The NK dose infused will be 5x 10^6/kg. Remaining cells discarded if not needed for laboratory studies. On Day 0, unmanipulated products (smaller cord blood unit and remnant of the larger unit) infused. Tacrolimus 0.03 mg/kg or 0.015 mg/kg (ideal body weight) by vein starting on Day -2 and tapered around Day +180 if no GvHD is present. Mycophenolate mofetil 15 mg/kg (actual body weight with a maximum dose of 1 gram twice daily) by vein or by mouth Days -3 to Day +100 in the absence of GvHD. CD20 positive participants admitted to hospital on day -9 to start hydration, receive rituximab 375 mg/m2 by vein on day -8, receive the designated preparative regimen on days -8 through -4. CD20 negative participants will not receive rituximab and admitted on day -8.
  • Lenalidomide
  • Fludarabine monophosphate
  • Melphalan
  • Tacrolimus
  • Mycophenolate mofetil
  • Rituximab
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have one of the following hematologic malignancies: Acute Myelogenous
             Leukemia (AML), induction failure, high-risk for relapse first remission (with
             intermediate-risk or high-risk cytogenetics, FLT3 mutation positive and/or evidence of
             minimal residual disease by flow cytometry), secondary leukemia from prior
             chemotherapy and/or arising from myelodysplastic syndrome, any disease beyond first
             remission.

          2. Myelodysplastic Syndrome (MDS): Primary or therapy related.

          3. Acute Lymphoblastic Leukemia (ALL): induction failure, primary refractory to treatment
             (do not achieve complete remission after first course of therapy) or are beyond first
             remission including second or greater remission or active disease. Patients in first
             remission are eligible if they are considered high risk, defined as any of the
             following detected at any time: with t(9;22) or t(4;11), hypodiploidy, complex
             karyotype, secondary leukemia developing after cytotoxic drug exposure, and/or
             evidence of minimal residual disease, or acute biphenotypic leukemia, or double hit
             non-Hodgkin's lymphoma.

          4. Non-Hodgkin's Lymphoma (NHL) in second or third complete remission, refractory NHL, or
             relapsed NHL (including relapse post autologous hematopoietic stem cell transplant).
             Double hit lymphomas in first remission or more advanced disease.

          5. Small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL) with
             progressive disease following standard therapy. Patients with progressive CLL
             following standard therapy who meet European Bone Marrow Transplant (EBMT) consensus
             guidelines of indications for allogeneic stem cell transplantation. This includes
             patients with (1) lack of response or early relapse within 1 year of receiving a
             purine analog-containing treatment regimen, (2) disease relapse within 2 years of
             receiving a purine analog combination therapy or after other therapies such as
             autologous stem cell transplantation, and (3) CLL associated with p53 mutations or
             deletions and/or del(17p) requiring therapy. Patients must have chemosensitive disease
             with at least a PR or SD with last treatment regimen.

          6. CML second chronic phase or accelerated phase.

          7. Hodgkin's Disease (HD): Induction failures, second or third complete remission, or
             relapse (including relapse post autologous hematopoietic stem cell transplant).

          8. Multiple Myeloma: stage II or III, symptomatic, secretory Multiple Myeloma requiring
             treatment.

          9. Age </= 75 years of age.

         10. Performance score of at least 80% by Karnofsky or 0 to 2 ECOG.

         11. Adequate major organ system function as demonstrated by: a. Left ventricular ejection
             fraction greater than 45%. b. Pulmonary function test (PFT) demonstrating a diffusion
             capacity of least 45% predicted. c. Creatinine < 1.6 mg/dL. d. SGPT/bilirubin </= to
             2.0 x normal.

         12. All study participants must be registered into the mandatory Revlimid REMS program,
             and be willing and able to comply with the requirements of the Revlimid REMS program.

         13. Females of reproductive potential must adhere to the scheduled pregnancy testing as
             required in the Revlimid REMS program.

         14. Negative Beta HCG test in a woman with child bearing potential defined as not
             post-menopausal for 24 months or no previous surgical sterilization and willing to
             ongoing pregnancy testing while on treatment with lenalidomide.

         15. Woman with child bearing potential must either commit to continued abstinence from
             heterosexual intercourse or begin TWO acceptable methods of birth control, one highly
             effective method and one additional effective method AT THE SAME TIME, at least 4
             weeks before she starts taking lenalidomide.

         16. Men must agree to use a latex condom during sexual contact with females of child
             bearing potential even if they have had a successful vasectomy.

         17. Patients must have two CB units available which are matched with the patient at 4, 5,
             or 6/6 HLA class I (serological) and II (molecular) antigens. Each cord must contain
             at least 1.5 x 107 total nucleated cells/Kg recipient body weight (pre-thaw). Cord
             blood units will be procured through the NMDP (National Marrow Donor Program).

         18. Have identified a back up cells source in case of engraftment failure. The source can
             be autologous, related or unrelated.

         19. Patients who have had a prior autologous transplant are eligible.

        Exclusion Criteria:

          1. Patients with known history of HIV/AIDS.

          2. Active CNS disease in patient with history of CNS malignancy.

          3. Patients with chronic active hepatitis or cirrhosis. If positive hepatitis serology,
             the Study Chair may deem the patient eligible based on the results of liver biopsy.

          4. Patients with known hypersensitivity to lenalidomide and/or rituximab.

          5. Patients who have a matched related donor who is eligible and willing to donate stem
             cells.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Success Rate
Time Frame:3 months
Safety Issue:
Description:Success is ability to generate adequate NK cells in a patient (a minimum of 3x10e8 natural killer (NK) cells). Success Rate is number of participants achieving success divided by total participants.

Secondary Outcome Measures

Measure:Treatment-Related Mortality (TRM)
Time Frame:100 days
Safety Issue:
Description:100-day treatment-related mortality (TRM) following the methods described by Thall et al.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Chronic Lymphocytic Leukemia
  • CLL
  • Cord blood
  • CB
  • Umbilical cord blood
  • UCB
  • Natural killer cells
  • NK
  • Graft versus host disease
  • GVHD
  • Lenalidomide
  • CC-5013
  • Revlimid
  • Fludarabine
  • Fludarabine Phosphate
  • Fludara
  • Melphalan
  • Alkeran
  • Rituximab
  • Rituxan

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