Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) Initial Salvage Therapy for Induction Failure Acute Myeloid Leukemia (AML)
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      Objectives:

      Primary Objectives:

        1. To determine the safety and feasibility of allogeneic hematopoietic stem cell
           transplantation (AHSCT) as initial salvage treatment for patients with primary induction
           failure (PIF) acute myeloid leukemia (AML).

        2. To determine efficacy of AHSCT following decitabine, clofarabine, idarubicin, and
           cytarabine (DCIA) salvage chemotherapy evaluated by overall response rate (RR), defined
           as complete response (CR) or CR without platelet recovery (CRp) or CR with insufficient
           hematological recovery (CRi).

      Secondary Objectives:

        1. To determine the percentage of patients with PIF AML eligible for AHSCT after up to 2
           courses of induction chemotherapy.

        2. To determine the early treatment-related mortality (TRM) (within first 4 weeks of first
           salvage chemotherapy regimen with DCIA and day 100 TRM after AHSCT.

        3. To determine the efficacy DCIA regimen as salvage chemotherapy for patients with PIF AML
           (% of patients who achieve </=5% bone marrow blasts prior to AHSCT.

        4. To determine the TRM at 1 year, relapse rate (RR), overall survival (OS) and event-free
           survival (EFS) for patients with PIF AML treated with DCIA followed by early AHSCT.
    

Detailed description: 
      Salvage Chemotherapy Before Transplant:

      Study Drug Administration:

      On Days 1-5, you will receive decitabine 1 time each day by vein over about 1-3 hours.

      On Days 6-10:

        -  You will receive cytarabine 1 time a day by vein over about 1-3 hours.

        -  On Days 6-8 only, you will receive idarubicin 1 time a day by vein over about 30
           minutes.

        -  On Days 6-9 only, you will receive clofarabine 1 time a day by vein over about 1-2
           hours.

      Study Visits:

      After your last study drug dose:

        -  Blood (about 2 teaspoons) will be drawn to check your kidney and liver function.

        -  You will have an echocardiogram (ECHO) or multigated acquisition (MUGA) scan to check
           your heart function.

        -  You will have a lung function test.

      On Day 21 (+/- 7 days), you will have a bone marrow biopsy/aspirate to check the status of
      the disease. To collect a bone marrow biopsy/aspirate, an area of the hip is numbed with
      anesthetic, and a small amount of bone and bone marrow is withdrawn through a large needle.

      If the results of your bone marrow biopsy/aspirate, blood tests, and heart and lung function
      tests show that you are eligible to receive an allogeneic stem cell transplant, you will be
      asked to sign a separate informed consent for the transplant.

      If the results of your bone marrow aspirate/biopsy, blood tests, and heart and lung function
      tests show that you are not eligible to receive an allogeneic stem cell transplant you will
      not receive it. The study staff will call you and ask how you are feeling and about any other
      drugs you may be taking every 3 months for 2 years after your last study drug dose. These
      calls should last about 5 minutes each.

      If you are found to NOT be eligible to receive an allogeneic stem cell transplant, your
      doctor will discuss other treatment options with you.

      Stem Cell Transplant:

      Study Drug Administration, Pharmacokinetic (PK) Testing, and Stem Cell Transplant:

      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 45 minutes to 1 hour as an outpatient
      or as an inpatient on Day -8. With the first busulfan infusion, blood (about 1 teaspoon each
      time) will be drawn for pharmacokinetic (PK) testing about 11 times over 11 hours before and
      after you receive your first dose of busulfan. PK testing measures the amount of study drug
      in the body at different time points. The study staff will tell you the blood testing
      schedule. Test doses are used to study how your body breaks down busulfan and decide the dose
      of busulfan that you will receive on Days -6 through -3.

      A heparin lock line will be placed in your vein before the PK testing to lower the number of
      needle sticks needed for these draws. 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 -7, you will rest.

      On Days -6 through -3, you will receive fludarabine by vein over 1 hour, clofarabine by vein
      over 1 hour, and then busulfan by vein over 3 hours.

      On Days -3 and -2, if you will receive stem cells from a matched unrelated donor, you will
      receive ATG by vein over 4 hours each day.

      On Day -2, if you will receive stem cells from a haploidentical donor, you will receive total
      body irradiation (TBI) one time. 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, you will receive tacrolimus by vein over 24 hours every day until you are able to
      take it by mouth. Tacrolimus is designed to weaken the immune system and lower the risk of
      graft-versus-host-disease (GVHD - a reaction of the donor's immune cells against your body).
      After you are able to take tacrolimus by mouth, you will take it every day for about 6
      months, or until the doctor thinks it is safe to stop.

      On Day -1, you will rest. If you will receive stem cells from a matched sibling donor, you
      will rest on Days -2 and -1.

      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.

      If you will receive stem cells from a haploidentical donor:

      After the stem cell infusion, you will receive tacrolimus 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.

      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 GVHD.

      If you receive stem cells from a matched sibling or matched unrelated donor:

      On Days +1, +3, +6, and +11, you will receive methotrexate by vein over 30 minutes.
      Methotrexate is given to help prevent GVHD.

      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 transplant, 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.

      Length of Treatment:

      After 2 years, your participation in this study will be over. You may be taken off study
      early if the disease gets worse, if your transplant does not "take" (graft failure), 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.

      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.
    

Intervention name(s): Busulfan; Fludarabine; Clofarabine; Total Body Irradiation (TBI); Thymoglobulin; Stem Cell Infusion; Cyclophosphamide; Tacrolimus; Mycophenolate mofetil; Decitabine; Cytarabine; Idarubicin
Intervention type(s): Drug; Drug; Drug; Radiation; Drug; Biological; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3.; Fludarabine 10 mg/m2 by vein on Days -6 to -3.; Salvage Chemotherapy Before Transplant: Clofarabine 15 mg/m2 by vein on Days 6 - 9.
Stem Cell Transplant: Clofarabine 40 mg/m2 by vein on Days -6 to -3.; Total body irradiation (TBI) delivered at 2Gy on Day -2.; Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2.; Fresh or cryopreserved bone marrow or peripheral blood (PB) progenitor cells infused on Day 0. Goal is to infuse 4 X 106 CD34+ cells/kg if PB or >3.0 X 108 marrow mononuclear cells/kg if bone marrow.; Cyclophosphamide 50 mg/kg by vein on Days +3 and +4.; Tacrolimus 0.015 mg/kg/day by vein or mouth on Day +5.; Mycophenolate mofetil 15 mg/kg/dose by vein or by mouth three times a day from Day +5 to Day+100.; 20 mg/m2 by vein on Days 1 - 5.; 1 g/m2 by vein on Days 6 - 10.; 10 mg/m2 by vein on Days 6 - 8.
Other intervention name(s): Busulfex; Myleran; Fludarabine Phosphate; Fludara; Clofarex; Clolar; TBI; XRT; ATG (Rabbit); Rabbit Antithymocyte Globulin; Rabbit Antilymphocyte Globulin; Rabbit ATG; rATG; Cytoxan; Neosar; Prograf; MMF; CellCept; Dacogen; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride; Idamycin
Intervention MeSH terms: Cytarabine; Mycophenolic Acid; Cyclophosphamide; Busulfan; Fludarabine; Fludarabine phosphate; Decitabine; Idarubicin; Clofarabine; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia; Acute myeloid leukemia; AML; Refractory; Allogeneic hematopoietic stem cell transplantation; AHSCT; Busulfan; Busulfex; Myleran; Fludarabine; Fludarabine Phosphate; Fludara; Clofarabine; Clofarex; Clolar; Total body irradiation; TBI; XRT; Thymoglobulin; ATG (Rabbit); Rabbit antithymocyte Globulin; Rabbit Antilymphocyte Globulin; Rabbit ATG; rATG; Stem cell infusion; Cyclophosphamide; Cytoxan; Neosar; Tacrolimus; Prograf; Mycophenolate mofetil; MMF; CellCept; Decitabine; Dacogen; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride; Idarubicin; Idamycin