Clinical Trials /

Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

NCT01471444

Description:

The goal of this clinical research study is to learn if combining busulfan with clofarabine and fludarabine can help control the disease better than the previous standard method (using busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination therapy will also be studied.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
  • Official Title: A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined With Intervenous Busulfan Followed by Allogeneic Hemopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: 2011-0628
  • SECONDARY ID: NCI-2012-00038
  • NCT ID: NCT01471444

Conditions

  • Disorder Related to Bone Marrow Transplantation
  • Leukemia
  • Transplantation Infection

Interventions

DrugSynonymsArms
FludarabineFludarabine Phosphate, FludaraFlu + Bu
ClofarabineClofarex, ClolarFlu +Clo + Bu
BusulfanBusulfex, MyleranFlu + Bu
ThymoglobulinATG, Antithymocyte GlobulinFlu + Bu
TacrolimusPrografFlu + Bu
MethotrexateFlu + Bu

Purpose

The goal of this clinical research study is to learn if combining busulfan with clofarabine and fludarabine can help control the disease better than the previous standard method (using busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination therapy will also be studied.

Detailed Description

      Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells),
      which may cause cancer cells to die. Busulfan is commonly used in stem cell transplantation.

      Clofarabine is designed to interfere with the growth and development of cancer cells.

      Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer
      cells to die.

      Study Groups:

      You will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups.

        -  Group 1 will receive busulfan, fludarabine, and clofarabine.

        -  Group 2 will receive busulfan and fludarabine.

      Both groups will have a stem cell transplant. The stem cells will be given by vein. The cells
      will travel to your bone marrow where they are designed to make healthy, new blood cells
      after several weeks.

      For a stem cell transplant, the days before you receive your stem cells are called minus
      days. The day you receive the stem cells is called Day 0. The days after you receive the stem
      cells are called plus days.

      Study Drug Administration and Procedures:

      Both groups will receive a "test" dose of busulfan by vein over about 45 minutes to 1 hour.
      This low-level test dose of busulfan is to check how fast busulfan is processed by your body
      and cleared from your blood. This information will determine the amount of busulfan you will
      receive. You may receive the busulfan test dose as an outpatient during the week before you
      are admitted to the hospital or as an inpatient 8 days before your stem cell transplant.

      About 11 samples of blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK)
      testing. PK testing measures the amount of study drug in the body at different time points
      and will also help determine your dose of busulfan. These blood samples will be drawn at
      various times before you receive busulfan and over the next 11 hours. These blood draws will
      be repeated again on the first day of high-dose busulfan treatment (Day -6, which is 6 days
      before the transplant).

      A heparin lock line 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.

      On Days -6 through -3, you will receive fludarabine by vein over 1 hour, then clofarabine (if
      you are in Group 1) by vein over 1 hour, then busulfan by vein over 3 hours.

      After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive
      (lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host
      disease (GvHD), a reaction of the donor's immune cells against the recipient's body.

      If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor,
      you will also receive antithymocyte globulin (ATG) by vein over 4 hours on the 3 days before
      the transplant. This drug is designed to further weaken your immune system to reduce the risk
      of rejecting of the transplant.

      You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
      after the transplant, until your blood cell levels return to normal. Filgrastim is designed
      to help with the growth of white blood cells.

      While you are in the hospital, you will be checked for any side effects as part of your
      standard of care. Blood (about 2 teaspoons) will be drawn every day to check for side
      effects, for routine tests, to check your blood counts, kidney and liver function, and to
      check for infections.

      As part of standard care, you will remain in the hospital for about 3-4 weeks after
      transplant. After you are released from the hospital, you must remain in the Houston area to
      be monitored for infections and other transplant side effects until about 3 months after
      transplant. During this time, you will return to the clinic at least 1 time each week. 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.

      Around 14-30 days after the transplant (when the transplant "engrafts", or "takes"), you will
      have a bone marrow aspirate to check the status of the disease.

      Around Day 30, and about 3, 6, and 12 months after the transplant, the following tests and
      procedures will be performed:

        -  You will have a physical exam, including measurement of your vital signs (blood
           pressure, heart rate, temperature, and breathing rate).

        -  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 to see how well the transplant has taken.

        -  You will have a bone marrow aspiration to check the status of the disease. To collect a
           bone marrow aspiration, 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.

      Length of Study:

      You will be taken off study 5 years after the end of treatment. You may be taken off study
      early if the disease gets worse, if you have any intolerable side effects, of if you are
      unable to follow study directions.

      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 transplant doctor decides it is needed.

      It may be life-threatening to leave the study after you have begun to receive the study drugs
      but before you receive the stem cells.

      This is an investigational study. Busulfan and fludarabine are both FDA approved and
      commercially available for the treatment of AML and MDS. Clofarabine is FDA approved for
      treating other types of cancer, but is being used in AML and MDS for research only. The use
      of these study drugs together at the dose level used in this study is investigational.

      Up to 250 patients will take part in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Flu + BuExperimentalFludarabine 40 mg/m2 intravenous (IV) over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours. Both delivered for 4 consecutive days (days -6 to -3). Stem cell transplant Day 0.
  • Fludarabine
  • Busulfan
  • Thymoglobulin
  • Tacrolimus
  • Methotrexate
Flu +Clo + BuExperimentalFludarabine 10 mg/m2 over 1 hour. Clofarabine 40 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, infused over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours, immediately after Clofarabine. All delivered on 4 consecutive days (days -6 through -3). Stem cell transplant Day 0.
  • Fludarabine
  • Clofarabine
  • Busulfan
  • Thymoglobulin
  • Tacrolimus
  • Methotrexate

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have one of the following hematologic malignancies: a) Acute myeloid
             leukemia (AML) any stage and cytogenetic risk-group with the only exception being that
             patients with AML and favorable cytogenetics (t(8;21, inv 16, or t(15;17) who achieve
             complete remission with one course of induction chemotherapy are not eligible .
             Patients with treatment related AML are eligible. b) Myelodysplastic syndromes (MDS)
             with intermediate or high risk International Prognostic Scoring System score (IPSS
             scores) or treatment related MDS. Patients with low risk MDS are eligible if they fail
             to respond to hypomethylating agent therapy such as azacitidine or decitabine.

          2. Age 3-70 years old. Eligibility for pediatric patients will be determined in
             conjunction with an MDACC pediatrician.

          3. Performance score of >/= 60 by Karnofsky or PS 0 to 2 (ECOG) (age > 12 years), or
             Lansky Play-Performance Scale >/= 60 or greater (age <12 years).

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

          5. Adequate major organ system function as demonstrated by: Left ventricular ejection
             fraction of at least 40%.

          6. 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.

          7. Creatinine < 1.5 mg/dL. If question about renal function discuss with study chairman
             and do 24 hour creatinine clearance (clearance should be >50 ml/min).

          8. Bilirubin < to 2.0 x normal (except Gilbert's Syndrome). SGPT (ALT) < 200. No evidence
             of chronic active hepatitis or cirrhosis.

          9. Histocompatible stem cell donor: Patients must have an HLA matched related or
             unrelated donor (HLA A, B, C and DR) willing to donate for allogeneic hematopoietic
             transplantation. High resolution allele level typing is required for donors other than
             genotypically identical siblings.

         10. No uncontrolled infection. Protocol PI or designé will be final arbiter if there is
             uncertainty regarding whether a previous infection is controlled on appropriate
             (antibiotic) therapy.

         11. Patient or patient's legal representative, parent(s) or guardian able to sign informed
             consent.

        Exclusion Criteria:

          1. Positive for HIV, HBsAg, HCV or other viral hepatitis or cirrhosis from any cause.

          2. Prior allogeneic or autologous stem cell transplant using a myeloablative busulfan or
             total body radiation containing conditioning regimen defined as busulfan-based using a
             total dose of >/=12 mg/kg given by mouth or >/=10 mg/kg given IV; or a total-body
             irradiation (> 4 Gy).

          3. Active or prior CNS leukemia, unless in complete remission for at least 3 months.

          4. Previous therapeutic XRT to the liver as part of involved-field radiation.

          5. History of serious chronic mental disorder or drug-abuse accompanied by documented
             problems of compliance with therapeutic programs.

          6. Lack of care-giver for the early (100-day) post-transplant period.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:30 Days
Safety Issue:
Description:Progression-free survival defined as the time from date of transplant to death from any cause or disease progression. Bone marrow aspiration used for disease status.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:100 days post transplant
Safety Issue:
Description:The percentage of participants in the study who are with no Grade 3 or 4 acute graft-versus-host disease at any time during the first 100 days post transplant.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Blood And Marrow Transplantation
  • Leukemia
  • Allogeneic hematopoietic stem cell transplantation
  • Acute myeloid leukemia
  • AML
  • Myelodysplastic syndrome
  • MDS
  • Progression free survival
  • Rate of engraftment
  • Toxicity
  • Relapse rate
  • Graft-vs-host disease
  • GvHD
  • Progression-free survival
  • PFS
  • Overall survival
  • OS
  • Fludarabine
  • Fludarabine Phosphate
  • Fludara
  • Clofarabine
  • Clofarex
  • Clolar
  • Busulfan
  • Busulfex
  • Myleran
  • Thymoglobulin
  • ATG
  • Antithymocyte Globulin
  • Methotrexate
  • Tacrolimus
  • Prograf

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