Clinical Trials /

Personalized NK Cell Therapy After Chemotherapy and Cord Blood Transplant in Treating Patients With Myelodysplastic Syndrome, Leukemia, Lymphoma or Multiple Myeloma

NCT02727803

Description:

This phase II clinical trial studies how well personalized natural killer (NK) cell therapy works after chemotherapy and umbilical cord blood transplant in treating patients with myelodysplastic syndrome, leukemia, lymphoma or multiple myeloma. This clinical trial will test cord blood (CB) selection for human leukocyte antigen (HLA)-C1/x recipients based on HLA-killer-cell immunoglobulin-like receptor (KIR) typing, and adoptive therapy with CB-derived NK cells for HLA-C2/C2 patients. Natural killer cells may kill tumor cells that remain in the body after chemotherapy treatment and lessen the risk of graft versus host disease after cord blood transplant.

Related Conditions:
  • Acute Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Personalized Natural Killer (NK) Cell Therapy in Cord Blood Transplantation (CBT)
  • Official Title: Personalized Natural Killer (NK) Cell Therapy in Cord Blood Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2015-0313
  • SECONDARY ID: NCI-2016-00584
  • SECONDARY ID: 1R01CA211044-01
  • NCT ID: NCT02727803

Conditions

  • Leukemia
  • Lymphoma
  • Myeloma
  • Myeloproliferative Diseases

Interventions

DrugSynonymsArms
BusulfanBusulfex, MyleranTreatment Plan #1
FludarabineFludarabine phosphate, FludaraTreatment Plan #1
ClofarabineClofarex, ClolarTreatment Plan #1
Rabbit ATGATG (Rabbit), Rabbit Antithymocyte Globulin, Rabbit Antilymphocyte Globulin, rATG, ThymoglobulinTreatment Plan #1
RituximabRituxanTreatment Plan #2
CyclophosphamideCytoxan, NeosarTreatment Plan #2
MelphalanAlkeranTreatment Plan #3
MesnaMesnexTreatment Plan #2

Purpose

The goal of this clinical research study is to learn if giving cells called natural killer (NK) cells after receiving 1 of 3 pre-treatment plans and a UCB transplant can improve response in patients with MDS, leukemia, lymphoma, or MM. The safety of this treatment and whether NK cells can lessen the risk of graft versus host disease (GVHD) will also be studied. If the disease is CD20 positive, you will also receive rituximab on this study in addition to what is described above. CD20 is a type of marker for white blood cells. White blood cells help protect the body from infections. 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. Based on your genes, your NK cells may not recover as quickly after transplant. Before the transplant, blood will be collected for genetic testing as part of standard screening tests. If the genetic test shows that your NK cells will not recover as quickly after transplant, you will receive the NK cell infusion. This is an investigational study. Busulfan, fludarabine, clofarabine, ATG, rituximab, cyclophosphamide, mesna, and melphalan are FDA approved and commercially available for the treatment of blood cancers and/or for use in stem cell transplant. The way the researchers process the NK cells and the way they are infused is not FDA approved. These processes are currently being used for research purposes only. Up to 100 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      The days before you receive the UCB transplant are called minus (-) days. The day you receive
      the UCB transplant is called Day 0. The days after you receive the UCB transplant are called
      plus (+) days.

      Before you receive your UCB transplant, you will receive 1 of 3 chemotherapy treatments that
      will be chosen by your doctor. The treatment will be selected based on your age and health.
      Each plan is described in detail below.

      Treatment Plan #1:

      If you are assigned to this plan, you will receive busulfan, fludarabine, clofarabine, and
      antithymocyte globulin (ATG) by vein, as well as total body irradiation (TBI), according to
      the following schedule.

      Before Day -10, you will receive a low-level "test" dose of busulfan by vein over about 45
      minutes to 1 hour. Test doses are used to study how your body breaks down busulfan and decide
      the dose of busulfan that you will receive. You may receive the test dose before Day -10 as
      an outpatient in the clinic, or on Day -9 as an inpatient in the hospital.

      Blood (about 1 teaspoon each time) will then be drawn for pharmacokinetic (PK) testing up to
      11 times over the 11 hours after the busulfan test dose. PK testing measures the amount of
      busulfan in the body at different time points. The study staff will tell you more about the
      PK testing schedule.

      A heparin lock line (a special kind of IV that has heparin in it to prevent clotting) will be
      placed in your vein before the PK testing to help lower the number of needle sticks needed
      for these draws. This will allow the study staff to draw blood from the heparin lock line
      instead of sticking you with needles multiple times. If for any reason it is not possible for
      the PK tests to be performed, you will receive the standard dose of busulfan.

      On Day -10, you will be admitted to the hospital and given fluids by vein to hydrate you.

      On Days -9 and -8, you will receive ATG by vein over 4 hours. ATG is designed to weaken your
      immune system in order to lower the risk that your body will reject the transplant.

      On Days -7 through -4, you will receive fludarabine by vein over 1 hour, then clofarabine by
      vein over 1 hour, and then busulfan by vein over 3 hours.

      On Day -3, you will receive 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 Days -2 and -1, you will rest.

      On Day 0, you will receive a UCB transplant by vein. This will consist of 2 CB units infused
      separately.

      Between Day +30 and +180, if the cord blood selected for your transplant matches your genetic
      makeup, you may receive NK cells by vein.

      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.

      Treatment Plan #2:

      If you are assigned to this plan, you will receive rituximab, fludarabine, cyclophosphamide,
      mesna, and ATG by vein, as well as total body irradiation (TBI), according to the following
      schedule.

      On Day -10, if the disease is CD20 positive, you will be admitted to the hospital and given
      fluids by vein to hydrate you, and then on Day -9, you will receive rituximab by vein over
      about 6 hours.

      On Day -9, if the disease is not CD20 positive, you will be admitted to the hospital and
      given fluids by vein to hydrate you. You will not receive rituximab.

      On Days -8 and -7, you will receive ATG by vein over 4 hours. ATG is designed to weaken your
      immune system in order to lower the risk that your body will reject the transplant.

      On Day -6, you will receive fludarabine by vein over 1 hour and cyclophosphamide by vein over
      3 hours. You will also receive mesna by vein after cyclophosphamide to help lower the risk of
      side effects to the bladder.

      On Days -5 through -3, you will receive fludarabine by vein over 1 hour.

      On Day -2, you will rest.

      On Day -1, 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 0, you will receive a UCB transplant by vein. This will consist of 2 CB units infused
      separately.

      Between Day +30 and +180, if the cord blood selected for your transplant matches your genetic
      makeup, you may receive NK cells by vein. This will consist of 2 CB units infused separately.

      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.

      Treatment Plan #3:

      If you are assigned to this plan, you will receive fludarabine, ATG, and melphalan by vein
      according to the following schedule.

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

      On Days -7 and -6, you will receive ATG by vein over 4 hours. ATG is designed to weaken your
      immune system in order to lower the risk that your body will reject the transplant.

      On Days -5 through -2, you will receive fludarabine by vein over 1 hour.

      On Day -2, you will receive melphalan by vein over 30 minutes.

      On Day -1, you will rest.

      On Day 0, you will receive an UCB transplant by vein. This will consist of 2 CB units infused
      separately.

      Between Day +30 and +180, if the cord blood selected for your transplant matches your genetic
      makeup, you will receive NK cells by vein.

      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 Visits:

      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 daily until Day +100. Blood tests may be performed
      more often, if the doctor thinks it is needed.

      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 2 times each week. At each visit, blood (about 2
      teaspoons) will be drawn for routine tests, to check your kidney and liver function, and to
      check the level of tacrolimus (a drug that is part of your standard care outside of this
      study) in your blood. Once a week, your blood will also be tested for cytomegalovirus (CMV)
      infection.

      At the time of engraftment, and then about Days 30, 60, and 100 days after the transplant,
      blood (about 2 teaspoons) will be drawn for chimerism testing, which looks to see how much
      the blood cells and tissue are mixed between the donor and recipient. This test shows how
      well the transplant has "taken."

      About 2 months after the transplant:

        -  Blood (about 2 teaspoons) will be drawn for chimerism testing.

        -  You will have a bone marrow biopsy to check the status of the disease. 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.

      Blood (up to 7 tablespoons each time) will be drawn to check the function of NK cells:

        -  Before and after the NK cell infusion

        -  On Days +1, +7, +14, +28, +45, +60, and +100

        -  At Months 6, 9, and 12 after the NK cell infusion

      Follow-Up Visits:

      You will have routine tests that are part of transplant follow-up care, as often as your
      doctor thinks it is needed.

      Length of Study:

      You will be on study for 2 years but then will be followed yearly as part of your regular
      care. You may be taken off study early if the disease gets worse, if you have graft failure,
      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. 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 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 leave the study, your test results and information cannot be removed from the study
      records.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment Plan #1ExperimentalParticipants with ALL, AML, NHL, CLL, CML, HD, and MM who are >/= 18 and </= 55 years old receive myeloablative regimen #1. Patients > 55 but < 65 years who have a Performance Status of 0 or 1 and no comorbidities may receive the Myeloablative Regimen 1 at the discretion of the investigator(s). Participants receive busulfan, fludarabine, clofarabine, and antithymocyte globulin (ATG) by vein, as well as total body irradiation (TBI).
  • Busulfan
  • Fludarabine
  • Clofarabine
  • Rabbit ATG
Treatment Plan #2ExperimentalParticipants with AML, ALL, NHL, CLL, CML, HD and MM who are > 55 and </= 80 years old or of any age with co-morbid condition that in the opinion of the investigators would preclude myeloablative therapy receive Nonmyeloablative Regimen #2. Participants receive rituximab (only for those with CD20+ malignancies) or no rituximab (without CD20+ malignancies), fludarabine, cyclophosphamide, mesna, and ATG by vein, as well as total body irradiation (TBI).
  • Fludarabine
  • Rabbit ATG
  • Rituximab
  • Cyclophosphamide
  • Mesna
Treatment Plan #3ExperimentalParticipants with AML, ALL, NHL, CLL, CML, and HD who are >/= 18 and </= 80 years old that in the opinion of the investigator(s) would preclude myeloablative therapy receive Reduced Intensity Regimen #3. Participants receive fludarabine, ATG, and melphalan by vein.
  • Fludarabine
  • Rabbit ATG
  • Melphalan

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 including complex karyotype, abn(3q),
             -5/5q-, -7/7q-, abn(12p), abn(17p), MLL gene re-arrangement and t (6;9)47, flt3
             mutation positive and/or evidence of minimal residual disease by flow cytometry),
             secondary leukemia from prior chemotherapy and/or arising from MDS, any disease beyond
             first remission.

          2. Myelodysplastic Syndrome (MDS): Primary or therapy related, including patients that
             will be considered for transplant. These include any of the following categories: 1)
             revised IPSS intermediate and high risk groups, 2) MDA with transfusion dependency, 3)
             failure to respond or progression of disease on hypomethylating agents, 4) refractory
             anemia with excess of blasts, 5) transformation to acute leukemia, 6) chronic
             myelomonocytic leukemia, 7) atypical MDS/myeloproliferative syndromes, 8) complex
             karyotype, abn(3g), -5/5g-, -7/7g-, abn(12p), abn(17p).

          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 translocations 9;22 or 4;11, hypodiploidy,
             complex karyotype, secondary leukemia developing after cytotoxic drug exposure, and/or
             evidence of minimal residual disease4 or acute biphenotypic leukemia, or double hit
             non-Hodgkin's lymphoma.

          4. Non-Hodgkin's Lymphoma (NHL) in second or third complete remission, or relapse
             (including relapse post autologous hematopoietic stem cell transplant). Relapsed
             double hit lymphomas. Patients with options for treatment that are known to be
             curative are not eligible.

          5. Small Lymphocytic Lymphoma (SLL), or Chronic lymphocytic Leukemia (CLL) with
             progressive disease following a minimum of two lines of standard therapy.

          6. CML second chronic phase or accelerated phase.

          7. Hodgkin's Disease (HD): Induction failures, after first complete remission, or relapse
             (including relapse post autologous hematopoietic stem cell transplant), or those with
             active disease.

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

          9. A person (such as a haploidentical family member) or unit of cord blood must be
             identified as a source of back-up cells source in case of engraftment failure.

         10. Patient Age Criteria: Age >/= 18 and </= 45 years (Myeloablative Regimen 1. Age >/= 18
             and </= 80 years (Nonmyeloablative Regimen 2) at the discretion of the
             investigator(s). Age >/= 18 and </= 80 years old that in the opinion of the
             investigator(s) would preclude myeloablative therapy may receive reduced intensity
             regimen 3.

         11. Performance score of at least 60% by Karnofsky

         12. Adequate major organ system function as demonstrated by: Left ventricular ejection
             fraction of at least 40% (Myeloablative Regimen 1, Reduced Intensity Regimen 3). Left
             ventricular ejection fraction of at least 30% (Nonmyeloablative Regimen 2).

         13. Pulmonary function test (PFT) demonstrating an adjusted diffusion capacity of least
             50% predicted value for hemoglobin concentration (Myeloablative Regimen 1, Reduced
             Intensity Regimen 3).

         14. Serum creatinine within normal range, or if serum creatinine outside normal range,
             then renal function (measured or estimated creatinine clearance or GFR) >
             40mL/min/1.73 m2.

         15. SGPT/bilirubin < to 2.0 x normal (Myeloablative Regimen 1), Reduced Intensity Regimen
             3. SGPT/bilirubin < to 4.0 x normal (Nonmyeloablative Regimen 2).

         16. Negative Beta HCG test in a woman with child bearing potential defined as not
             post-menopausal for 12 months.

         17. Patients with options for treatment that are known to be curative are not eligible.

        Exclusion Criteria:

          1. HIV positive. HIV results will be determined by nucleic acid testing

          2. Uncontrolled serious medical condition such as persistent septicemia despite adequate
             antibiotic therapy, decompensated congestive heart failure despite cardiac medications
             or pulmonary insufficiency requiring intubation (excluding primary disease for which
             CB transplantation is proposed), or psychiatric condition that would limit informed
             consent.

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

          4. Availability of appropriate, willing, HLA-matched related stem cell donor.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS) Time in C2C2 Participants
Time Frame:Up to 2 years
Safety Issue:
Description:For the C2C2 participants, PFS time measured from the date that NK cells are given, i.e. from the date of engraftment. PFS time monitored by using the Bayesian method of Thrall et al.

Details

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

Trial Keywords

  • Acute Myelogenous Leukemia
  • AML
  • Myelodysplastic syndrome
  • MDS
  • Multiple myeloma
  • MM
  • Umbilical cord blood transplant
  • UCB
  • Natural killer cells
  • NK
  • Busulfan
  • Busulfex
  • Myleran
  • Fludarabine
  • Fludarabine Phosphate
  • Fludara
  • Clofarabine
  • Clofarex
  • Clolar
  • Rabbit ATB
  • ATG (Rabbit)
  • Rabbit Antithymocyte Globulin
  • Rabbit Antilymphocyte Globulin
  • rATG Thymoglobulin
  • Total Body Irradiation
  • TBI
  • Radiation therapy
  • XRT
  • Rituximab
  • Rituxan
  • Cyclophosphamide
  • Cytoxan
  • Neosar
  • Melphalan
  • Alkeran

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