Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
Conditions
Leukemia
Conditions: Keywords
Leukemia, Acute myeloid leukemia, AML, Myelodysplastic syndromes, MDS, Blood And Marrow Transplantation, Myeloproliferative Diseases, High Risk Myeloid Malignancies, Allogeneic stem cell transplant, Natural Killer Cells, NK, Immune cells, Stem cell transplant, Busulfan, Busulfex, Myleran, Interleukin-2, IL-2, Aldesleukin, Proleukin, Thymoglobulin, Antithymocyte globulin, ATG, G-CSF, Filgrastim, Neupogen, Tacrolimus, Prograf, Methotrexate
Study Type
Interventional
Study Phase
Phase 1/Phase 2
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Busulfan Type: Drug
Name: Fludarabine Type: Drug
Name: Alloreactive NK infusion Type: Procedure
Name: Interleukin-2 Type: Drug
Name: Thymoglobulin Type: Drug
Name: Stem Cell Infusion Type: Procedure
Name: G-CSF Type: Drug
Name: Tacrolimus Type: Drug
Name: Methotrexate Type: Drug
Overall Status
Recruiting
Summary
The goal of this clinical research study is to find the highest tolerable dose of immune cells called natural killer (NK) cells that can be given with chemotherapy and a stem cell transplant to patients with AML and MDS. Researchers want to learn if adding NK cells will help make the stem cell transplant more effective in treating the disease. The safety of this treatment will also be studied.

NK cells may kill cancer cells that remain in your body after your last chemotherapy treatment. The NK cells will be separated from blood from a relative of yours, from a matched unrelated donor, or from umbilical cord blood. These separated NK cells will then be grown in the lab to increase the number of NK cells that can be given to you by vein.

The chemotherapy given on this study will consist of the following drugs:

- 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.

- IL-2 (interleukin-2) is a naturally occurring protein (cytokine) that can enhance NK cell function.
Detailed Description
Central Venous Catheter:

If you choose to take part in this study, the chemotherapy, some of the other drugs in this study, the NK cells, 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.

NK Cell Dose Levels:

You will be assigned to a dose level of NK cells based on when you joined this study. Up to 4 dose levels of NK cells will be tested. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of NK cell is found.

Chemotherapy, NK Cell infusion, 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 3 hours as an outpatient within 2 weeks of your hospital admission or as an inpatient on Day -15. With the first busulfan infusion, about 11 samples of blood (about 1 teaspoon 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 -13 through -10.

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, you will receive the standard dose of busulfan.

On Days -13 through -10, you will receive fludarabine by vein over 1 hour, then busulfan by vein over 3 hours.

On Day -9, you will rest.

On Day -8, you will receive NK cells by vein over about 1 hour.

On Days -8 through -4, you will receive IL-2 as an injection under your skin.

On Days -3, -2, and -1, you will receive antithymocyte globulin (ATG) by vein over 3-4 hours. ATG is given to stop your immune system from working, so your body will not fight against the stem cell transplant. If you will receive NK cells from a matched sibling, you will not receive ATG.

Beginning on Day -2, you will receive tacrolimus nonstop by vein. This will continue until you are able to take it by mouth. Tacrolimus is given to help prevent transplant rejection.

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

On Days +1, +3, +6, and +11, you will receive methotrexate by vein over 30 minutes. Methotrexate is given to help prevent graft versus host disease (GVHD).

When you are able to take tacrolimus by mouth, you will take it 1 time or 2 times a day for about 6 months and then your doctor will tell you how to taper it off (gradually stop taking it).

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.

You will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

Study Visits:

On about Day -7 and -5, blood (about 5 tablespoons each time) will be drawn to check the level of the infused NK cells and to check your immune system. If you will receive NK cells from a matched sibling, blood (5 tablespoons) will be also drawn on Day +7 for these tests.

After you finish chemotherapy and the cell infusion, your follow-up care will be the standard of care for stem cell transplants. Before you are able to go home from the hospital, you will be given written information and be taught how often you will come to the hospital/clinic, take drugs at home, and what side effects you may have and what to do for them.

The study staff will also stay in contact with your local doctor to find out if the disease comes back and to check how you are doing.

Length of Study:

You will be on active study for up to about +30 days. You may be taken off study early if the disease gets worse, if you are unable to receive the NK cell infusion due to product contamination or insufficient cell dose, if your transplant does not "take" (graft failure), if you have any intolerable side effects, 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.

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.

If you are thinking about dropping out of this study, please tell the study doctor. The doctor can tell you about the effects of stopping treatment. You and the doctor can talk about what follow-up care and testing would help you the most.

If you leave the study, your test results and information cannot be removed from the study records.

This is an investigational study. Busulfan, fludarabine, and IL-2 are FDA approved and commercially available for the treatment of other types of cancer. Their use for the treatment of AML and MDS is investigational. The use of NK cells is investigational. The NK cell process is not FDA approved or commercially available. It is currently being used for research purposes only.

Up to 72 patients will take part in this study. All will be enrolled at MD Anderson.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: 65 Years
Minimum Age: 7 Years
Gender: Both
Criteria: Inclusion Criteria:

1. Patients with age
2. Acute myeloid leukemia who fail to achieve complete remission with one course of induction chemotherapy or after relapse. Patients must have less than 20% bone marrow or peripheral blood blasts.

3. Acute myeloid leukemia in first remission with any of the following high risk features defined as: (i) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 abnormalities] (ii) Preceding myelodysplastic or myeloproliferative syndrome; (iii) Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit; (iv) FAB M6 or M7 classification; (v) treatment-related AML. (vi) residual cytogenetic or molecular abnormalities

4. Myelodysplastic syndromes with intermediate, high or very high risk R-IPSS score, CMML or therapy related MDS.

5. CML which: (i) failed to achieve a cytogenetic remission to tyrosine kinase inhibitor treatment or has a cytogenetic relapse; or (ii) has ever been in accelerated phase or blast crisis.

6. Patient must have an identified a HLA (A,B,C,DR) compatible related or unrelated donor who is age 16 years of age or older and weighs at least 110 pounds for the stem cell donation.

7. Zubrod performance status 0 to 2 or Karnofsky of at least 60.

8. Left ventricular ejection fraction >/= 45%. No uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease.

9. FEV1, FVC and DLCO >/= 50% of expected, corrected for hemoglobin.

10. Adequate liver function: a. Bilirubin
11. Serum creatinine <1.5 mg%.

12. Patient or patient's legal representative, parent(s) or guardian able to sign informed consent. Patients aged 7 to <18 to provide assent.

13. Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have been entered without dose limiting toxicity.

Exclusion Criteria:

1. Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy. The Protocol PI is the final arbiter of eligibility.

2. Pleural/pericardial effusion or ascites >1L.

3. Patients who are known to be HIV-seropositive.

4. Pregnancy: Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.

5. Women of child bearing potential not willing to use an effective contraceptive measure while on study.

6. Patients who are known to have allergy to mouse proteins.
Location
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Status: Recruiting
Start Date
June 2013
Sponsors
M.D. Anderson Cancer Center
Source
M.D. Anderson Cancer Center
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page