Clinical Trials /

Allogeneic Transplantation Using Timed Sequential Busulfan and Fludarabine Conditioning

NCT01572662

Description:

The goal of this clinical research study is to learn if giving busulfan and fludarabine before a stem cell transplant can help control the disease better than the standard method in patients with leukemia, lymphoma, multiple myeloma, MDS, or MPD. In this study, 2 doses of busulfan will be given 2 weeks before a stem cell transplant followed by 4 doses of busulfan and fludarabine during the week before the stem cell transplant, rather than the standard method of giving 4 doses of busulfan and fludarabine only during the week before the stem cell transplant. The safety of this combination therapy will also be studied. 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 transplants. Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer cells to die.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Allogeneic Transplantation Using Timed Sequential Busulfan and Fludarabine Conditioning
  • Official Title: Phase II Study of Timed Sequential Busulfan in Combination With Fludarabine in Allogeneic Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 2011-0958
  • SECONDARY ID: NCI-2012-00573
  • NCT ID: NCT01572662

Conditions

  • Leukemia
  • Acute Myeloid Leukemia
  • Acute Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Myeloproliferative Diseases
  • Non-Hodgkins Lymphoma
  • Hodgkins Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Fludarabine monophosphateFludarabine Phosphate, FludaraFludarabine + Busulfan
BusulfanBusulfex, MyleranFludarabine + Busulfan
TacrolimusPrografFludarabine + Busulfan
MethotrexateFludarabine + Busulfan
G-CSFFilgrastim, NeupogenFludarabine + Busulfan

Purpose

The goal of this clinical research study is to learn if giving busulfan and fludarabine before a stem cell transplant can help control the disease better than the standard method in patients with leukemia, lymphoma, multiple myeloma, MDS, or MPD. In this study, 2 doses of busulfan will be given 2 weeks before a stem cell transplant followed by 4 doses of busulfan and fludarabine during the week before the stem cell transplant, rather than the standard method of giving 4 doses of busulfan and fludarabine only during the week before the stem cell transplant. The safety of this combination therapy will also be studied. 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 transplants. Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer cells to die.

Detailed Description

      Central Venous Catheter:

      If you choose to take part in this study, the chemotherapy, some of the other drugs in this
      study, and the stem cell transplant will be given by vein through your central venous
      catheter (CVC). A CVC is a sterile flexible tube and needle that will be placed into a large
      vein while you are under local anesthesia. Blood samples will also be drawn through your CVC.
      The CVC will remain in your body during treatment. Your doctor will explain this procedure to
      you in more detail, and you will be required to sign a separate consent form.

      Study Drug Administration and Procedures:

      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.

      You will receive a dose of busulfan by vein over about 3 hours on Day -13 and Day -12. With
      the Day -13 busulfan infusion, about 11 samples of blood (about 1-2 teaspoons each time) will
      be drawn for pharmacokinetic (PK) testing at various time points before and after you receive
      your first dose of busulfan. The study staff will tell you the blood testing schedule. PK
      testing measures the amount of study drug in the body at different time points. The PK
      testing will help the doctor decide your dose of busulfan for Days -6 through -3. If needed,
      PK blood testing may also be done on Day -6 during your dose of Busulfan. You may receive the
      Day -13 and Day -12 busulfan dose either as an outpatient in the clinic or as an inpatient in
      the hospital.

      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
      reasons, you will be taken off study and receive the standard fixed dose of busulfan.

      On Days -13 and -12, you will receive busulfan by vein over 3 hours.

      On Days -11 through -7, you will rest.

      On Days -6 through -3, you will receive fludarabine by vein over 1 hour, then busulfan by
      vein over 3 hours.

      On Days -2 and -1, you will rest.

      On Day 0, you will receive the stem cell transplant by vein.

      After the transplant, you will receive tacrolimus, methotrexate, or other drugs to weaken the
      immune system 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.

      You will receive tacrolimus by vein as a nonstop infusion until you are able to take it by
      mouth to help lower the risk of GVHD. You will then take tacrolimus by mouth 2 times a day
      for about 3 months. After that, your tacrolimus dose may be lowered if you do not have GVHD.
      Your doctor will discuss this with you. On Days 1, 3, and 6, if your stem cells are from a
      related or matched unrelated donor, you will receive methotrexate over 30 minutes each day by
      vein to help lower the risk of GVHD. Participants receiving a matched unrelated donor will
      also receive methotrexate on Day 11 after 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.

      Study Testing:

      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 the
      transplant. After you are sent home from the hospital, you must remain in the Houston area to
      be checked 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.

      About 1, 3, 6, and 12 months after the transplant:

        -  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 5 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, if your
           doctor thinks it is needed. 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 3 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 follow-up visits after the
      transplant, 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. The investigational part of this study is the addition of 2 more
      doses of busulfan.

      Up to 200 patients will take part in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Fludarabine + BusulfanExperimentalFludarabine administered by vein at dose of 40 mg/m2 in 100 ml of normal saline (NS) on Days -6 through -3. First two doses of Busulfan, 80 mg/m2 administered as an outpatient or as an inpatient to facilitate for this pharmacokinetically directed therapy. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -13 and -12) systemic exposure of 20,000 ± 12% µMol-min based on the pharmacokinetic studies.
  • Fludarabine monophosphate
  • Busulfan
  • Tacrolimus
  • Methotrexate
  • G-CSF

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with high-risk hematologic malignancies with anticipated poor prognosis with
             non transplant therapy, including those in remission or with induction failure and
             after treated or untreated relapse. Diagnoses to be included a) Acute myeloid
             leukemia; b) Acute lymphocytic leukemia; c) Chronic myeloid leukemia; d) Chronic
             lymphocytic leukemia; e) Myelodysplastic syndrome; f) Myeloproliferative syndromes; g)
             Non-Hodgkins lymphoma; h) Hodgkins Lymphoma; i) Multiple myeloma.

          2. Patients must have a histocompatible stem cell donor. An HLA-identical related donor
             or a 8/8 matched unrelated donor.

          3. Age 5 to 75 years old.

          4. Performance score of >/= 70 by Karnofsky/Lansky or PS 0 to 1 (ECOG </=1).

          5. Left ventricular ejection fraction at least 40%.

          6. Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of expected corrected for
             hemoglobin and/or volume. Children unable to perform pulmonary function tests (e.g.,
             less than 7 years old) pulse oximetry of >/= 92% on room air

          7. Creatinine clearance (calculated creatinine clearance is permitted) should be >40
             ml/min.

          8. Bilirubin </= 2 x the upper limit of normal (except Gilbert's Syndrome). SGPT (ALT) <
             200.

          9. 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.

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

        Exclusion Criteria:

          1. HIV seropositivity.

          2. Uncontrolled infections.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:5 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Non-Relapse Mortality Rate (NRM)
Time Frame:100 days
Safety Issue:
Description:Bayesian monitoring rules monitor the 100-day NRM rate. Proportion of patients with NRM reported for each treatment arm, along with 95% Bayesian credible intervals. Bone marrow aspiration to check status of the disease around Day 30, and about 3, 6, and 12 months after the transplant.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Day 30
Safety Issue:
Description:Progression-free survival calculated from the time of transplant by the method of Kaplan and Meier. Cox proportional hazards regression analysis used to assess the association between these survival parameters and clinical and treatment covariates of interest.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Acute myeloid leukemia
  • Acute lymphocytic leukemia
  • Chronic myeloid leukemia
  • Chronic lymphocytic leukemia
  • Myeloproliferative Diseases
  • Non-Hodgkins Lymphoma
  • Hodgkins lymphoma
  • Multiple myeloma
  • Myelodysplastic syndrome
  • MDS
  • Fludarabine monophosphate
  • Fludarabine phosphate
  • Fludara
  • Busulfan
  • Busulfex
  • Myleran
  • Tacrolimus
  • Prograf
  • Methotrexate
  • G-CSF
  • Filgrastim
  • Neupogen
  • Stem cell transplant
  • Allogeneic Transplantation

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