Conditions: Leukemia
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
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief 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.

Arms:
arm 1: Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Test dose Busulfan 32 mg/m2 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. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Stem cell infusion performed on Day 0. arm 2: Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: 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. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Total body irradiation (TBI) delivered at 2Gy on Day -2. Stem cell infusion performed on Day 0. 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. arm 3: Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: 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. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2. Stem cell infusion performed on Day 0.

Interventions: intervention 1: Busulfan intervention 2: Fludarabine intervention 3: Clofarabine intervention 4: Total Body Irradiation (TBI) intervention 5: Thymoglobulin intervention 6: Stem Cell Infusion intervention 7: Cyclophosphamide intervention 8: Tacrolimus intervention 9: Mycophenolate mofetil intervention 10: Decitabine intervention 11: Cytarabine intervention 12: Idarubicin
Intervention descriptions: intervention 1: Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3. intervention 2: Fludarabine 10 mg/m2 by vein on Days -6 to -3. intervention 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. intervention 4: Total body irradiation (TBI) delivered at 2Gy on Day -2. intervention 5: Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2. intervention 6: 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. intervention 7: Cyclophosphamide 50 mg/kg by vein on Days +3 and +4. intervention 8: Tacrolimus 0.015 mg/kg/day by vein or mouth on Day +5. intervention 9: Mycophenolate mofetil 15 mg/kg/dose by vein or by mouth three times a day from Day +5 to Day+100. intervention 10: 20 mg/m2 by vein on Days 1 - 5. intervention 11: 1 g/m2 by vein on Days 6 - 10. intervention 12: 10 mg/m2 by vein on Days 6 - 8.

Protocol document:
Prot_SAP_000.pdf: 
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