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Natural Killer Cells Before and After Donor Stem Cell Transplant in Treating Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia

NCT01904136

Description:

This phase I/II studies the side effects and best dose of natural killer cells before and after donor stem cell transplant and to see how well they work in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia. Giving chemotherapy with or without total body irradiation before a donor peripheral blood stem cell or bone marrow 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 Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: NK Cells to Prevent Disease Relapse for Patients High Risk Myeloid Malignancies
  • Official Title: A Phase I/II Clinical Trial of Natural Killer (NK) Cells Administration to Prevent Disease Relapse for Patient With High-Risk Myeloid Malignancies Undergoing Haploidentical Stem-Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2012-0708
  • SECONDARY ID: NCI-2013-02183
  • SECONDARY ID: RP110553 05-07-04832
  • SECONDARY ID: P01 - 5P01
  • NCT ID: NCT01904136

Conditions

  • Leukemia
  • Myeloproliferative Diseases

Interventions

DrugSynonymsArms
MelphalanAlkeranExpanded Natural Killer (NK) Cells
FludarabineFludarabine phosphate, FludaraExpanded Natural Killer (NK) Cells
MesnaMesnexExpanded Natural Killer (NK) Cells
CyclophosphamideCytoxan, NeosarExpanded Natural Killer (NK) Cells
TacrolimusPrografExpanded Natural Killer (NK) Cells
Mycophenolate mofetilMMF, CellCeptExpanded Natural Killer (NK) Cells
G-CSFFilgrastim, NeupogenExpanded Natural Killer (NK) Cells

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 about the safety of giving a kind of immune cells called "natural killer" (NK) cells with standard chemotherapy and an allogeneic stem cell transplant (using cells from a donor). Researchers also want to learn the highest tolerable dose of NK cells that can be given. Immune system cells (such as NK cells) are made by the body to attack foreign or cancerous cells. Researchers believe that the NK cells you receive from the donor may react against the leukemia cells in your body, help eliminate leukemia, and prevent disease relapse. This is an investigational study. The study drugs are FDA approved and commercially available for the treatment of blood cancers and/or stem cell transplant. The way the researchers process the NK cells and the infusion of them is investigational and is not FDA approved. Up to 45 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Dose Levels:

      If you agree to take part in this study, you will be assigned to a dose level of NK cells
      based on when you joined this study. 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 for up to 6 dose levels, until the
      highest tolerable dose of NK cells is found.

      The day you receive the stem cell transplant is called Day 0. The days before you receive
      your stem cell transplant are named with a minus sign (-). The days after you receive the
      stem cell transplant are named with a plus sign (+).

      You will receive 1 of 2 chemotherapy treatments that will be chosen by your doctor. The
      treatment will be selected based on your age and health. The types include a high-dose
      regimen and a reduced-intensity regimen.

      Study Drug Administration (High Dose Regimen):

      On Day -8, you will be admitted to the hospital and given fluids by vein.

      On Day -7, you will receive melphalan by vein over 30 minutes.

      On Days -7 through -4, you will receive fludarabine by vein over 1 hour. Fludarabine and
      melphalan are 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 -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 or Day -1, you will receive NK cells by vein over 30 minutes.

      On Day -1, you will "rest" (not receive chemotherapy).

      On Day 0, you will receive the donor's stem cells by vein. The infusion will last anywhere
      from about 30 minutes to several hours.

      On Days +3 and +4, you will receive 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 donor NK and stem cells, attacks the
      tissues of the recipient's body). You will also receive mesna by vein over 30 minutes every 4
      hours for a total of 10 mesna doses on Days +3 and +4. Mesna is given to lower the risk of
      side effects to the bladder caused by cyclophosphamide.

      Starting on Day +5, you will receive tacrolimus and mycophenolate mofetil (MMF) to help lower
      the risk of GVHD. Tacrolimus will be given by vein non-stop for about 2 weeks. After the 2
      weeks of taking tacrolimus by vein, you will take tacrolimus by mouth as a pill for at least
      4 months after the transplant. MMF will be given by mouth, 3 times a day, usually for about
      6-7 months.

      Starting on Day +7, you will receive filgrastim-sndz as an injection under the skin 1 time a
      day, until your blood cell levels are high enough. Filgrastim-sndz is designed to help with
      the growth of a type of healthy white blood cells that fight infection.

      On Day +7 (+/- 1 day) and once about 3-12 weeks later, you will receive NK cells by vein over
      30 minutes.

      You will be given standard drugs to help decrease the risk of side effects. You may ask the
      study staff for information about how the drugs are given and their risks.

      Study Drug Administration (Reduced Intensity Regimen) If your study doctor thinks it is
      needed due to illness or your age, you will receive a reduced intensity regimen.

      On Day -9, you will be admitted to the hospital and given fluids by vein.

      On Day -8, you will receive melphalan by vein over 30 minutes.

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

      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 or Day -1, you will receive NK cells by vein over 30 minutes.

      On Day -1, you will "rest" (not receive chemotherapy).

      On Day 0, you will receive the donor's stem cells by vein. The infusion will last anywhere
      from about 30 minutes to several hours.

      On Days +3 and +4, you will receive cyclophosphamide by vein over 3 hours. You will also
      receive mesna by vein over 30 minutes every 4 hours for a total of 10 mesna doses on Days +3
      and +4. Mesna is given to lower the risk of side effects to the bladder.

      Starting on Day +5, you will receive tacrolimus and MMF to help lower the risk of GVHD.
      Tacrolimus will be given by vein non-stop for about 2 weeks. After the 2 weeks of taking
      tacrolimus by vein, you will take tacrolimus by mouth as a pill for at least 4 months after
      the transplant. MMF will be given by mouth, 3 times a day, usually for about 6-7 months.

      Starting on Day +7, you will receive filgrastim-sndz as an injection under the skin 1 time a
      day, until your blood cell levels are high enough. Filgrastim-sndz is designed to help with
      the growth of white blood cells.

      On Day +7 (+/- 1 day) and once about 3-12 weeks later, you will receive NK cells by vein over
      30 minutes.

      You will be given standard drugs to help decrease the risk of side effects. You may ask the
      study staff for information about how the drugs are given and their risks.

      Study Testing:

      Before you are sent home from the hospital and/or clinic, you will receive additional written
      instructions. These instructions will include how often you will come to the hospital/clinic,
      which standard drugs you will take at home, and what side effects you may have and what to do
      for them.

      After finishing the chemotherapy and cell infusion, your follow-up care will be routine
      standard of care follow-up that all patients receiving allogeneic stem cell transplantation
      receive. At each visit, you will have a physical exam. You will be asked about any side
      effects you may have had. Blood (about 1 tablespoon) will be drawn 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 aspirate, an area of the hip or other site is numbed with
      anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

      Blood (up to about 4 tablespoons) will be drawn to test the genetic makeup and function of
      the infused NK cells and to check the status of the disease about once a week for the first 4
      weeks after the transplant, before the 3rd NK cell infusion and about 1 week later, and then
      about 3, 6, and 12 months after the transplant, if possible. This may be repeated, if your
      doctor thinks it is needed.

      Length of Treatment:

      Your active participation in this study will be over 12 months after the transplant. You will
      be off study 2 years after the transplant. Between Years 1 and 2 after the transplant, the
      study staff may check your medical record to see how you are doing. You may be taken off
      study early if the doctor thinks it is in your best interest, if the disease gets worse or
      comes back requiring further treatment, if intolerable side effects occur, if not enough NK
      cells can be collected, or if you are unable to follow study directions.

      If for any reason you want to leave the study early, you must talk to the study doctor. It
      may be life-threatening to leave the study after you have started to receive the study drugs
      but before you receive the stem cell transplant because your blood cell counts will be
      dangerously low.
    

Trial Arms

NameTypeDescriptionInterventions
Expanded Natural Killer (NK) CellsExperimentalMelphalan 140 mg/m^2 by vein on Day -7. Fludarabine 40 mg/m^2 by vein daily on Days -7 to -4. Escalating doses of NK cells used, between 1x10^5/kg and 1x10^8/kg CD3- CD56+ cells/kg. First infusion of expanded NK cells on Day -2 and the other 2 infusions use cryopreserved expanded NK cells. Bone marrow transplant on Day 0. Mesna 10 mg/kg by vein on Day +3 and +4, repeated every 4 hours for total of ten doses. Cyclophosphamide 50 mg/kg by vein on Day +3 and +4. Tacrolimus 0.015 mg /kg by vein daily starting on Day +5 and continued by mouth for at least 4 months post transplant. Mycophenolate mofetil (MMF) 15 mg/kg by mouth starting on Day +5. It is recommended start tapering at Day +180, unless otherwise indicated, weekly over at least 3 weeks. Day +7 and Day +28 second and third NK infusions. G-CSF 5 mcg/kg/day subcutaneously once a day daily starting on Day +7 until neutrophil recovery. All patients receive total body irradiation (TBI) 200 cGy administrated on Day -3.
  • Melphalan
  • Fludarabine
  • Mesna
  • Cyclophosphamide
  • Tacrolimus
  • Mycophenolate mofetil
  • G-CSF

Eligibility Criteria

        Inclusion Criteria:

          1. Patients age 18 to 65 years old. Eligibility for pediatric patients will be determined
             in conjunction with an MDACC pediatrician. Patients age 2-17 years old may be enrolled
             after at least 4 adults (ages 18-65 years old) have been treated without toxicity, as
             defined in the Statistical Considerations section.

          2. Patient with no matched related donor who has a related haploidentical donor
             identified (</= 7/8 allele match at the A, B, C,DR loci) who is willing to undergo a
             bone marrow harvest and an NK cell collection approximately 2 weeks of the recipient's
             admission for transplant. The donor must be 16 years of age or older and weigh at
             least 110 pounds.

          3. Patients with one of the following diseases: Acute myeloid leukemia (AML): a. First
             complete remission with high-risk features defined as: (i) Greater than 1 cycle of
             induction therapy required to achieve remission; (ii) Preceding myelodysplastic
             syndrome (MDS); (iii) Presence of FLT3 mutations or internal tandem duplication or
             other mutations associated with poor-risk AML (e.g. DNMT3A, TET2); (iv) FAB M6 or M7
             classification; (v) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities
             involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 abnormalities]; (vi)
             Treatment-related AML, or b. Second or greater remission; patients beyond second
             remission have to be in CR at transplant to be eligible, or c. Primary induction
             failure with partial response to therapy who achieve adequate cytoreduction.

          4. Patients with myelodysplastic syndromes (MDS): a. De novo MDS with intermediate or
             high-risk IPSS scores. Patients with intermediate-1 features should have failed to
             respond to hypomethylating agent therapy, or b. Patients with treatment-related MDS.

          5. Chronic myeloid leukemia (CML): a. Failed to achieve cytogenetic remission or have
             cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or b.
             Accelerated phase or blast phase at any time.

          6. Performance score of at least 70% by Karnofsky or 0 to 1 by ECOG (age >/= 12 years),
             or Lansky Play-Performance Scale of at least 70% or greater (age <12 years).

          7. Adequate major organ system function as demonstrated by: Serum creatinine clearance
             equal or more than 50 ml/min (calculated with Cockcroft-Gault formula).

          8. Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease. ALT or AST equal
             or less than 200 IU/ml for adults. Conjugated (direct) bilirubin less than 2x upper
             limit of normal.

          9. Left ventricular ejection fraction equal or greater than 40%.

         10. Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50% predicted
             corrected for hemoglobin. For children </= 7 years of age who are unable to perform
             PFT, oxygen saturation >/= 92% on room air by pulse oximetry.

         11. Patient or patient's legal representative, parent(s) or guardian should provide
             written informed consent. Assent of a minor if participant's age is at least seven and
             less than eighteen years.

        Exclusion Criteria:

          1. HIV positive; active hepatitis B or C.

          2. Uncontrolled infections; PI is the final arbiter of this criterion.

          3. Liver cirrhosis.

          4. CNS involvement within 3 months.

          5. Positive pregnancy test in a woman with child bearing potential defined as not
             post-menopausal for 12 months or no previous surgical sterilization.

          6. Inability to comply with medical therapy or follow-up.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Expanded Natural Killer (NK) Cells
Time Frame:70 days after stem cell transplant
Safety Issue:
Description:Dose-finding, "toxicity" defined as any of the events (i) death, (ii) grade 4 infusion reaction, (iii) grade 4 organ toxicity (not including mucositis or myelosuppression) (iv) graft failure, or (v) severe (grade 3 or 4) graft-versus-host disease (GVHD) within the 72-day window occurring between day -2 (the time of the first NK cell dose) and day 70 post stem cell transplant (SCT). Patient outcome is time of occurrence of toxicity or, if toxicity has not yet occurred by an observation time prior to day +70, the outcome will be the patient's follow up time (starting at day -2) without toxicity.

Secondary Outcome Measures

Measure:Treatment Related Mortality
Time Frame:100 days after stem cell transplant
Safety Issue:
Description:Treatment related mortality defined as death due to any cause without disease recurrence within 100 days post stem cell transplant (SCT)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Myeloproliferative Diseases
  • Blood And Marrow Transplantation
  • High Risk Myeloid Malignancies
  • Acute myeloid leukemia
  • AML
  • Myelodysplastic syndrome
  • MDS
  • Chronic myeloid leukemia
  • CML
  • Haploidentical Stem-cell Transplantation
  • HaploSCT
  • Expanded natural killer cells
  • NK
  • Melphalan
  • Alkeran
  • Mesna
  • Mesnex
  • Cyclophosphamide
  • Cytoxan
  • Neosar
  • Tacrolimus
  • Prograf
  • Mycophenolate mofetil
  • MMF
  • CellCept
  • G-CSF
  • Filgrastim
  • Neupogen
  • Fludarabine
  • Fludarabine phosphate
  • Fludara

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