This phase I/II trial studies the side effects and best dose of donor natural killer cells
when given together with donor stem cell transplant and to see how well they work in treating
patients with myeloid malignancies that are likely to come back or spread. Giving
chemotherapy, such as busulfan and fludarabine phosphate, before a donor peripheral blood
stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's
immune system from rejecting the donor's stem cells. When the healthy stem cells and natural
killer cells from a donor are infused into the patient they may help the patient's bone
marrow make stem cells, red blood cells, white blood cells, and platelets.
- Brief Title: Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
- Official Title: Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
Clinical Trial IDs
- ORG STUDY ID:
- SECONDARY ID:
- SECONDARY ID:
- NCT ID:
|Busulfan||Busulfex, Myleran||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
|Fludarabine||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
|Interleukin-2||IL-2, Aldesleukin, Proleukin||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
|G-CSF||Filgrastim, Neupogen||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
|Tacrolimus||Prograf||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
|Methotrexate||+ Chemotherapy + NK Cell infusion + Stem Cell Transplant|
Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential
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 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
- 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
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.
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 Day -3, you will rest.
On Day 0, you will receive the stem cell transplant by vein.
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 graft-versus-host disease
(GVHD -- when transplanted immune tissue, such as donor NK and stem cells, attacks the
tissues of the recipient's body). You will also receive mesna by vein over 30 minutes every 4
hours for a total of 10 mesna doses on Days +3 and +4. Mesna is given to lower the risk of
side effects to the bladder caused by cyclophosphamide.
Beginning on Day +5, 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.
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
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.
On about Days -7, -5, and +7, blood (about 5 tablespoons each time) will be drawn to check
the level of the infused NK cells and to check your immune system.
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
|+ Chemotherapy + NK Cell infusion + Stem Cell Transplant||Experimental||Busulfan "test dose" of 32 mg/m2 within 2 weeks of the preparative regimen. Fludarabine 40 mg/m2 by vein on Day -13 to Day -10. Busulfan adjusted dose determined to achieve systemic exposure represented by an average daily AUC of 6000 µMol-min ± 5% for the entire 4-day treatment period on Day -13 to Day -10. Patients over age 60 and/or with performance status =2 receive and AUC of 4000 microM x min for each dose. Alloreactive NK infusion on Day -8. Alloreactive NK cell infusion given at one of 4 dose levels based on the number of NK cells (CD3-,CD 56+ cells)/kg recipient body weight. Dose levels are: 10^6, 10^7, 3 x 10^7, 10^8. Interleukin-2 0.5 million units subcutaneously on Day -8 to Day -4. Hematopoietic stem cell infusion on Day 0.|
1. Patients with age </= 65 years with one of the following:
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
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
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
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 </= 1.5 mg/dl (unless Gilbert's syndrome). b.
SGPT </= 200 IU/ml unless related to patient malignancy. c. Hepatitis B surface
antigen negative and hepatitis C antibody negative. d. No evidence of chronic active
hepatitis or cirrhosis. e. Patients with a history of hepatitis C, but have a negative
viral load, are eligible. f. The protocol chairman will determine the eligibility of
patients related to hepatic abnormalities.
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.
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.
|Maximum Eligible Age:||65 Years|
|Minimum Eligible Age:||7 Years|
Primary Outcome Measures
|Measure:||Maximum Tolerated Natural Killer (NK) Cell Dose|
|Time Frame:||42 days|
|Description:||Optimal NK cell dose determined in each of three distinct patient subgroups, A = KIR mismatched haplo donors, B = KIR mismatched cord blood donors, C = matched SIB donors. Same dose-finding design used within each subgroup. Four NK cell doses studied are: 106, 107, 3 x 107, and 108 NK cells. Cohorts of 2 patients used, starting at lowest NK cell dose level. Dose-limiting toxicity (DLT) defined as any of the events graft failure, severe (grade 3,4) infusional toxicity, severe grade 4 organ toxicity, or death by day 42.|
|Phase:||Phase 1/Phase 2|
|Lead Sponsor:||M.D. Anderson Cancer Center|
- Acute myeloid leukemia
- Myelodysplastic syndromes
- Blood And Marrow Transplantation
- Myeloproliferative Diseases
- High Risk Myeloid Malignancies
- Allogeneic stem cell transplant
- Natural Killer Cells
- Immune cells
- Stem cell transplant
- Antithymocyte globulin