Clinical trial NCT01518153
Conditions: Leukemia Lymphoma Myeloma Myeloproliferative Diseases
Keywords: Blood and Marrow Transplantation Lymphoma Myeloma Myeloproliferative Diseases Leukemia Myelodysplastic syndrome MDS Hodgkin disease Multiple myeloma Fludarabine Fludarabine Phosphate Fludara Melphalan Alkeran Tacrolimus Prograf Methotrexate G-CSF Filgrastim NeupogenTM Donor Lymphocyte Infusion DLI Allogeneic Stem Cell Transplantation Graft-vs-host disease GvHD T-lymphocytes T-cells Alemtuzumab CAMPATH-1H Campath
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-02-01; Completion date: 2014-08-01
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn what dose of a kind of immune cell called T-lymphocytes (T-cells) given as a donor infusion about 8-9 weeks after a stem cell transplant has the best results. The safety of this treatment will also be studied. This will be tested in patients with leukemia, MDS, lymphoma, Hodgkin disease, and multiple myeloma. These results are measured as helping to control the disease without severe graft-versus-host disease (GvHD). GvHD is when transplanted donor tissue attacks the tissues of the recipient's body.

Fludarabine, melphalan, and alemtuzumab are commonly given before stem cell transplants:

* Fludarabine is designed to interfere with the DNA (genetic material) of cancer cells, which may cause the cancer cells to die.
* Melphalan is designed to bind to the DNA of cells, which may cause cancer cells to die.
* Alemtuzumab is designed to weaken the immune system and reduce the risk of rejection of the transplant and graft-vs-host disease (GvHD).

The donor infusion of T-cells is designed to help restore the immune system after the transplant, cause an immune reaction against the cancer, and reduce the risk of the cancer coming back.

Detailed description:
Study Groups:

If you agree to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups involving the dose of T-cells in the donor lymphocyte infusion.

* Group 1 will receive a low dose of donor T-cells.
* Group 2 will receive a higher dose of donor T-cells than Group 1.

Both you and your study doctor will know which group you are in. 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.

Study Drug Administration:

Patients receive fludarabine, melphalan and alemtuzumab to kill malignant cells and suppress immunity to prevent rejection of the stem cell transplant. The day you receive the stem cells is called Day 0. The days before you receive your stem cells are called minus days. The days after you receive the stem cells are called plus days.

On Day -7, you will be admitted to the hospital and given fluids by vein to hydrate you.

On Days -6 through -3, you will receive fludarabine by vein over 1 hour each day.

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

On Day -1, you will receive alemtuzumab by vein over 2 hours.

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

After the transplant, you will receive tacrolimus and methotrexate. At first, you will receive tacrolimus 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 5 weeks and then your doctor will tell you how to taper it off (gradually stop taking it). On Days 1, 3, and 6 after the transplant, you will receive methotrexate by vein over 30 minutes.

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.

Between Day +56 and +64, if you are in stable medical condition and have not developed GvHD, you will receive a donor lymphocyte infusion containing T-cells by vein over 10-30 minutes. You will receive Benadryl (diphenhydramine) by vein over 15 minutes before the infusion to lower the risk of an allergic reaction.

Study Visits:

Before the T-cell infusion:

* 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 and biopsy to check the status of the disease, if your doctor thinks it is needed. To collect a bone marrow aspiration/biopsy, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

After the T-cell infusion, you will have a physical exam every week for at least 6 weeks.

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

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about how you are feeling and about any side effects you may be having.
* Blood (about 4 tablespoons) will be drawn for routine tests and to check the level of the infused T-cells, for immune function tests, and to check the status of the disease.
* You will have a bone marrow aspiration, blood tests and CT scans as medically necessary to check the status of the disease, if your doctor thinks it is needed.

During the study, you will have blood draws (about 2 teaspoons) and urine will be collected for routine tests, to check your blood counts, kidney and liver function, and/or to check for infections as often as the doctor thinks is needed during this time.

Length of Treatment:

You will be off study after your 12-month follow-up visit. You will be taken off study early if you have graft failure (the donor cells did not "take") or if the cancer comes back and needs another treatment.

This is an investigational study. Melphalan, fludarabine, and alemtuzumab are FDA approved and commercially available for the treatment of blood cancers. Donor T-cell infusions are commonly used to treat blood cancers that come back after a stem cell transplant. The investigational part of this study is to find the best dose of T-cells that are given with the goal of helping to prevent the cancer from coming back.

Up to 56 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Fludarabine 40 mg/m\^2 by vein on Day -6 to -3. Melphalan 140 mg/m\^2 by vein on Day -2. Alemtuzumab 50 mg by vein on Day -1. Reduced intensity stem cell transplant on Day 0. Planned Donor Lymphocyte Infusion CD3+ cells: 3 \* 106 CD3+ cells/kg between Day +56 and +64. Tacrolimus 0.015 mg/kg by vein as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml (target is 10 ng/ml). Tacrolimus is changed to oral dosing when tolerated. Tapering should start on approximately Day +24 with intention to be completely off drug by approximately Day +35. Methotrexate 5 mg/m2 dosed based on actual body surface area and administered intravenously on days +1, +3, +6. G-CSF 5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until absolute neutrophil count (ANC) is \> 500 \* 10/L for 3 consecutive days. arm 2: Fludarabine 40 mg/m\^2 by vein on Day -6 to -3. Melphalan 140 mg/m\^2 by vein on Day -2. Alemtuzumab 50 mg by vein on Day -1. Reduced intensity stem cell transplant on Day 0. High Dose Donor T-Cells Planned Donor Lymphocyte Infusion CD3+ cells: 1 \* 107 CD3+ cells/kg between Day +56 and +64. Tacrolimus 0.015 mg/kg by vein as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml (target is 10 ng/ml). Tacrolimus is changed to oral dosing when tolerated. Tapering should start on approximately Day +24 with intention to be completely off drug by approximately Day +35. Methotrexate 5 mg/m2 dosed based on actual body surface area and administered intravenously on days +1, +3, +6. G-CSF 5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until absolute neutrophil count (ANC) is \> 500 \* 10/L for 3 consecutive days.
Interventions: intervention 1: Fludarabine intervention 2: Melphalan intervention 3: Alemtuzumab intervention 4: Stem Cell Infusion intervention 5: Tacrolimus intervention 6: Methotrexate intervention 7: G-CSF intervention 8: Low Dose Donor T-Cells intervention 9: High Dose Donor T-Cells
Intervention descriptions: intervention 1: 40 mg/m\^2 by vein on Day -6 to -3. intervention 2: 140 mg/m\^2 by vein on Day -2. intervention 3: 50 mg by vein on Day -1. intervention 4: Reduced intensity stem cell transplant on Day 0. intervention 5: 0.015 mg/kg by vein as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml (target is 10 ng/ml). Tacrolimus is changed to oral dosing when tolerated. Tapering should start on approximately Day +24 with intention to be completely off drug by approximately Day +35. intervention 6: 5 mg/m2 dosed based on actual body surface area and administered intravenously on days +1, +3, +6. intervention 7: 5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until absolute neutrophil count (ANC) is \> 500 \* 10/L for 3 consecutive days. intervention 8: Planned Donor Lymphocyte Infusion CD3+ cells: 3 \* 106 CD3+ cells/kg between Day +56 and +64. intervention 9: Planned Donor Lymphocyte Infusion CD3+ cells: 1 \* 107 CD3+ cells/kg between Day +56 and +64.

Protocol documents: