Clinical Trials /

Cord Blood Fucosylation to Enhance Homing and Engraftment in Patients With Hematologic Malignancies

NCT01471067

Description:

The goal of this clinical research study is to learn if it is safe and feasible to transplant changed cord blood for patients with leukemia or lymphoma. Researchers also want to learn if this can help to control the disease. The cord blood will be changed to make use of sugar that is found in small amounts in blood cells. It plays a role in signaling where in the body the transplanted cells should go to. Adding more sugars to the cord blood cells in the laboratory is designed to help the cord blood cells find their way faster to the bone marrow. This may help your blood counts to recover faster. This process is called fucosylation. Anti-thymocyte globulin (ATG) is a protein that removes immune cells that cause damage to the body. Clofarabine is designed to interfere with the growth and development of cancer cells. Fludarabine is designed to interfere with the DNA (genetic material) of cancer cells, which may cause the cancer cells to die. This chemotherapy is also designed to block your body's ability to reject the donor's bone marrow cells. Melphalan and busulfan are designed to bind to the DNA of cells, which may cause cancer cells to die. Mycophenolate mofetil (MMF) and tacrolimus are designed to block the donor cells from growing and spreading in a way that could cause graft versus host disease (GVHD -- a condition in which transplanted tissue attacks the recipient's body). This may help to prevent GVHD. Rituximab is designed to attach to cancer cells, which may cause them to die.

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

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cord Blood Fucosylation to Enhance Homing and Engraftment in Patients With Hematologic Malignancies
  • Official Title: Cord Blood Fucosylation to Enhance Homing and Engraftment in Patients With Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2010-0658
  • SECONDARY ID: NCI-2011-03742
  • SECONDARY ID: 2R01CA06158
  • SECONDARY ID: 5P01CA148600
  • NCT ID: NCT01471067

Conditions

  • Blood And Marrow Transplantation
  • Leukemia
  • Lymphoma
  • Transplantation Infection
  • Transplantation, Bone Marrow

Interventions

DrugSynonymsArms
MelphalanAlkeranFludarabine + Melphalan
FludarabineFludarabine Phosphate, FludaraFludarabine/Clofarabine/Busulfan/Rituximab/TBI
Mycophenolate mofetilMMF, CellCeptFludarabine/Clofarabine/Busulfan/Rituximab/TBI
TacrolimusPrografFludarabine/Clofarabine/Busulfan/Rituximab/TBI
RituximabRituxanFludarabine/Clofarabine/Busulfan/Rituximab/TBI
ATGAntithymocyte Globulin, ThymoglobulinFludarabine/Clofarabine/Busulfan/Rituximab/TBI
BusulfanBu, Myleran, BusulfexFludarabine/Clofarabine/Busulfan/Rituximab/TBI
ClofarabineClofarex, ClolarFludarabine/Clofarabine/Busulfan/Rituximab/TBI

Purpose

The goal of this clinical research study is to learn if it is safe and feasible to transplant changed cord blood for patients with leukemia or lymphoma. Researchers also want to learn if this can help to control the disease. The cord blood will be changed to make use of sugar that is found in small amounts in blood cells. It plays a role in signaling where in the body the transplanted cells should go to. Adding more sugars to the cord blood cells in the laboratory is designed to help the cord blood cells find their way faster to the bone marrow. This may help your blood counts to recover faster. This process is called fucosylation. Anti-thymocyte globulin (ATG) is a protein that removes immune cells that cause damage to the body. Clofarabine is designed to interfere with the growth and development of cancer cells. Fludarabine is designed to interfere with the DNA (genetic material) of cancer cells, which may cause the cancer cells to die. This chemotherapy is also designed to block your body's ability to reject the donor's bone marrow cells. Melphalan and busulfan are designed to bind to the DNA of cells, which may cause cancer cells to die. Mycophenolate mofetil (MMF) and tacrolimus are designed to block the donor cells from growing and spreading in a way that could cause graft versus host disease (GVHD -- a condition in which transplanted tissue attacks the recipient's body). This may help to prevent GVHD. Rituximab is designed to attach to cancer cells, which may cause them to die.

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, and the cord blood transplant will
      be given by vein through your CVC. Blood samples will also be drawn through your CVC. The CVC
      will remain in your body for about 2-5 months.

      Study Plans:

      If you agree to take part in this study, your doctor will choose one of the following 2 study
      plans based on the disease and your age and medical history.

      Fludarabine/Clofarabine/Busulfan/Rituximab/Total Body Irradiation:

      If you are between 1 and 55 years of age and can receive high-dose chemotherapy, or you are
      between 55 and 65 years old and your doctor agrees, you will receive fludarabine,
      clofarabine, busulfan, ATG, total body irradiation, and possibly rituximab.

      You will receive a test dose of busulfan by vein over 60 minutes as an outpatient. If the
      test dose cannot be given as an outpatient, you will be admitted to the hospital on Day -10
      for intravenous (IV) fluids and will receive the busulfan test dose on Day -9. This low-level
      "test" dose of busulfan is to check how the level of busulfan in your blood changes over
      time. This information will be used to decide the next dose needed to reach the target blood
      level that matches your body size.

      About 11 samples of blood will be drawn for pharmacokinetic (PK) testing of busulfan. PK
      testing measures the amount of study drug in the body at different time points. These blood
      samples will be drawn at various timepoints starting before the busulfan infusion and
      continuing over about the next 11 hours. The blood samples will be repeated again with the
      first day of high-dose busulfan treatment. Each sample will be about 1 teaspoon of blood. A
      temporary heparin lock will be placed in your vein to lower the number of needle sticks
      needed for these draws. If it is not possible for the PK tests to be performed for technical
      or scheduling reasons, you will receive the standard fixed dose of busulfan.

      If you will receive the test dose as an outpatient, you will be admitted to the hospital on
      Day -8 and will receive fluids by vein. If appropriate for the disease, you will receive
      rituximab by vein over 4-6 hours on Day -8.

      If you will receive the test dose as an inpatient, you will be admitted on Day -10 and will
      receive fluids by vein. If appropriate for the disease, you will receive rituximab by vein
      over 4-6 hours on Day -10.

      On Days -7 through -4, you will receive fludarabine by vein over 1 hour, clofarabine by vein
      over 1 hour, and busulfan by vein over 3 hours. You will receive ATG on Days -4 and -3. On
      Day -3, you will receive a single treatment of low-dose total body irradiation. You will
      "rest" (not receive chemotherapy drugs) on Days -2 and -1. Day 0 is the day of the cord blood
      transplant, so the negative day numbers are used to label the treatment days before the
      transplant.

      All chemotherapy drugs, fluids, and other drugs that must be given by vein will be infused
      through the catheter. Once the back-up cells are collected, all participants will be admitted
      to the hospital as indicated by their assigned treatment plan schedule.

      Fludarabine/Melphalan:

      If your doctor chooses fludarabine and melphalan, you will have the following schedule:

        -  On Day -6 (6 days before your transplant), you will be admitted to the hospital and will
           receive fluids by vein.

        -  On Days -5, -4, and -3, you will receive fludarabine by vein over 30 minutes.

        -  On Days -4 and -3, you will receive ATG by vein over 4 hours.

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

        -  On Day -1, you will not receive any drugs.

        -  On Day 0, you will receive your cord blood transplant through the CVC.

      Supportive Drugs:

      Starting on Day -3, you will receive mycophenolate mofetil as a tablet by mouth 2 times a
      day. 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 after your cord blood transplant, the
      dose of MMF will be gradually lowered. If you have GVHD, MMF may be stopped 7 days after the
      GVHD is controlled.

      Starting on Day -2, you will receive tacrolimus by vein as a continuous (nonstop) 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 gradually lowered if you do not
      have GVHD. Your doctor will discuss this with you.

      Starting on Day 0, you will receive filgrastim (G-CSF) through a needle under the skin 1 time
      a day every day until your white blood count begins to recover. Filgrastim is designed to
      help cells in the bone marrow to divide, which helps raise white blood cells counts more
      quickly, lower fever, and decrease the risk of infection.

      Study Visits:

      At 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 CMV antibodies,
           and for genetic tests to learn if the donor's cells have "taken". The routine blood
           tests will be repeated as often as the doctor thinks is needed.

        -  If the doctor thinks it is needed, you will have a bone marrow aspiration to check the
           status of the disease.

      You will need to stay in the hospital for about 4 weeks. After you leave the hospital, you
      will continue as an outpatient in the hospital area, which means you will have to stay close
      enough to be able to come back for any visits for about 100 days after the transplant.

      Length of Participation:

      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 the cord blood is infected and cannot be
      transplanted, if you are unable to follow study directions, or if your doctor thinks it is in
      your best interest.

      This is an investigational study. Fucosylation is not an FDA-approved process. It is
      currently being used for research purposes only. Fludarabine, busulfan, clofarabine,
      melphalan, mycophenolate mofetil, tacrolimus, 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 50 patients will be enrolled in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Fludarabine/Clofarabine/Busulfan/Rituximab/TBIExperimentalMyeloablative Regimen: Rituxan 375 mg/m^2 (B cell malignancy) by vein (IV) on Day -10; Busulfan AUC 4,000 IV either as an outpatient prior to admission or as an inpatient on Day -9; Clofarabine 30 mg/m^2 IV Day -7 to Day -4; ATG 1.25 mg/Kg by vein on Day -4 and 1.75 mg/Kg by vein on Day -3; Fludarabine 10 mg/m^2 IV on Days -7 to -4; Total Body Irradiation (TBI) 2 Gy on Day -3; with Cord Blood infusions on Day 0.
  • Fludarabine
  • Mycophenolate mofetil
  • Tacrolimus
  • Rituximab
  • ATG
  • Busulfan
  • Clofarabine
Fludarabine + MelphalanExperimentalReduced Intensity: Fludarabine 40 mg/m^2 IV on Days -5 to -2; Melphalan 140 mg/m^2 IV on Day -2; ATG 1.25 mg/Kg by vein on Day -4 and 1.75 mg/Kg by vein on Day -3; with Cord Blood infusions on Day 0.
  • Melphalan
  • Fludarabine
  • Mycophenolate mofetil
  • Tacrolimus
  • ATG

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 MDS, Langerhan's cell histiocytosis, any disease
             beyond first remission; or,

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

          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 disease, or acute biphenotypic leukemia, or double hit
             non-Hodgkin's lymphoma; or,

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

          5. Small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL) with
             progressive disease following standard therapy; or,

          6. CML second chronic phase or accelerated phase; or,

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

          8. Patients Age Criteria: Age >/= 1 and </= 80 years old. Eligibility for pediatric
             patients will be determined in conjunction with an MDACC pediatrician.

          9. Performance score of at least 80% by Karnofsky or PS < 3 (ECOG) (age >/= 12 years), or
             Lansky Play-Performance Scale of at least 60% or greater (age <12 years).

         10. Adequate major organ system function as demonstrated by: a. Left ventricular ejection
             fraction of at least 40-45% b. Pulmonary function test (PFT) demonstrating a diffusion
             capacity of least 50% predicted. For children </= 7 years of age who are unable to
             perform PFT, oxygen saturation >/= 92% on room air by pulse oximetry. c. Creatinine <
             1.6 mg/dL. d. SGPT/bilirubin </= to 2.0 x normal.

         11. Negative Beta HCG test in a woman with child bearing potential defined as not
             post-menopausal for 12 months or no previous surgical sterilization and willing to use
             an effective contraceptive measure while on study.

         12. 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 10^7 total nucleated cells/Kg recipient body weight (pre-thaw).

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

        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 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.

          5. Positive beta HCG in female of child-bearing potential defined as not post-menopausal
             for 12 months or no previous surgical sterilization or breast-feeding.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with engraftment within 42 days
Time Frame:42 days
Safety Issue:
Description:Engraftment is defined as the evidence of donor derived cells (more than 95%) by chimerism studies in the presence of neutrophil recovery by day 28 post stem cell infusion.

Details

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

Trial Keywords

  • Blood And Marrow Transplantation
  • Leukemia
  • Lymphoma
  • Pediatrics
  • Cord blood transplant
  • Cord Blood Fucosylation
  • Hematologic Malignancies
  • Acute Myelogenous Leukemia
  • AML
  • Myelodysplastic Syndrome
  • MDS
  • High-risk cytogenetics
  • Secondary leukemia from prior chemotherapy
  • Langerhan's cell histiocytosis
  • Acute Lymphoblastic Leukemia
  • ALL
  • complete remission
  • Philadelphia chromosome
  • translocation 4;11
  • Hypodiploidy
  • Chronic Myeloid Leukemia
  • CML
  • Non-Hodgkin's Lymphoma
  • NHL
  • Hodgkin's Disease
  • HD
  • Chronic Lymphocytic Leukemia
  • CLL
  • Melphalan
  • Alkeran
  • Thiotepa
  • Fludarabine
  • Fludarabine Phosphate
  • Fludara
  • Mycophenolate Mofetil
  • MMF
  • CellCept
  • Tacrolimus
  • Prograf
  • Rituximab
  • Rituxan
  • ATG
  • Antithymocyte Globulin
  • Thymoglobulin

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