Trial Information

Study to Infuse Haploidentical Natural Killer Cells in Patients With Relapsed or Refractory Neuroblastoma

Experimental Therapy:

NK cells are part of the immune system (the cells in the body that naturally fight disease
and infection). NK cells can sometimes destroy tumor cells, and they may be better at
destroying tumor cells when the NK cells are "mismatched" for certain proteins called human
leukocyte antigens (HLA). This can be determined by looking at the donor's and the
recipient's HLA types and by checking for other specialized proteins on the donor's NK cells
(called killer immunoglobulin receptors [KIR]).

The NK cells will be collected from the donor's blood and then processed using an
experimental device called a CliniMACS device. This device is designed to separate out the
NK cells from the rest of the donor's collected white blood cells, using a special magnet.
Before being infused into the recipient (you, if you choose to take part), the collected NK
cells will be treated with a study drug called interleukin-2 (IL-2) in order to try to
activate the NK cells' killing ability. You will also receive IL-2 injections to try to
help the NK cells survive after infusion and possibly increase in number.

Screening Tests:

Within 28 days before you can start treatment on this study, you will have "screening tests"
to help the study doctor decide if you are eligible to take part in this study. The
following tests will be performed:

- To check the status of the disease, you will have bone marrow aspirations and biopsies
performed. To collect a bone marrow biopsy and aspirate, up to 2 areas of the hip bone
are numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn
through a needle.

- For another check of the status of the disease, you will most likely need to have
computed tomography (CT) scans of the neck, sinuses, chest, stomach area (abdomen), and
hip area (pelvis), and the brain.

- If the doctor thinks it is necessary, the status of the disease will also be checked
with standard/routine tests such as positron emission tomography (PET) scans,
iodine-131-meta- iodobenzylguanidine (MIBG -- a test that uses injected radioactive
material and a special scanner to locate a tumor), and/or a bone scan.

- To measure your heart rate and level of oxygen in the blood, you will have a pulse
oximetry test. This test uses a clothespin-shaped device that goes on the finger for
about a minute.

- You will have a physical exam, including measurement of vital signs (blood pressure,
heart rate, temperature, and breathing rate).

- Your medical history will be recorded.

- Blood (about 4 tablespoons) will be drawn for routine tests and to check for diseases
(infections such as the human immunodeficiency virus [HIV]). You will be told the
results of this test for any diseases. If you have one of these infections, you will
probably not be able to participate in this study.

- Urine or an additional 4 teaspoons of blood may also be drawn for other routine tests
to check the disease status.

- Blood (up to 6 tablespoons) will be drawn and used to test for HLA and KIR typing, and
you and the donor will be told the results of this test.

- Females who are able to have children must have a negative serum pregnancy test (as
part of the blood sample described above, or possibly an additional 1 teaspoon).

These screening tests would also need to be repeated before an additional NK cell infusion
for this study, in order to see if you continue to be eligible to receive one. This will be
described further below.

Identifying an Eligible Donor:

Your relative, who must share half of your HLA genes to be eligible for the study, will be
tested to see if his or her KIR molecule has the "mismatch" that researchers believe should
help the donor's NK cells to target the tumor cells in your body.

The donor's blood will also be tested to guard against the possibility of transmitting an
infection to you during the NK cell infusion.

Samples of the donor's blood will be used to help researchers develop future tests that will
be used to track how long the infused NK cells survive and function in recipients' bodies.
In order to help track the cells after infusion, researchers prefer (but do not require)
that if you are a female recipient, your donor should be male and if you are a male
recipient, your donor should be female.

Conditioning Phase:

If you are found to be eligible to take part in this study, you will start the
"conditioning" phase of this study within 4 weeks after the screening tests. Over the
course of 6 days, you will receive chemotherapy with cyclophosphamide and fludarabine to
weaken your immune system in order to help the survival of the infused NK cells, and then
mesna to protect your bladder from side effects that cyclophosphamide may cause.

Cyclophosphamide, fludarabine, and mesna will preferably be infused through an indwelling
catheter (a tube that remains in a vein, such as tunneled in the arm or through the chest).
If you already have an indwelling catheter in place, you will not need to have a new one
placed. If a new catheter is needed, however, you will be asked to sign a separate informed
consent form for its placement.

The Conditioning schedule is the following:

-Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day
-2, you will receive fludarabine by vein, over about 30 minutes.

On Days -5 and -4, you will receive cyclophosphamide by vein, over about 2 hours each time.

-Five times per day on Days -5 and -4, you will receive mesna by vein, over about 15 minutes
each time.

Infusion of NK Cells:

On Day 0 you will receive the NK cells by vein, preferably through an indwelling catheter.
The doctor will decide what amount of NK cells will be infused, which will affect how long
the infusion lasts, but usually it lasts less than 1 hour.

To help prevent an allergic reaction to the infused cells (such as fever and chills), you
will receive Benadryl (diphenhydramine) by vein, over 15-30 minutes, and Tylenol
(acetaminophen) by mouth. You will also receive fluids by vein to help decrease the risk of
kidney damage.

You or a caregiver will be trained in how to perform the IL-2 injections yourself. This
drug will be injected under the skin for 9 doses over the course of 3 weeks.

If the doctor decides you are not eligible to receive the NK cell infusion on Day 0, you
will be taken off study without receiving the donor's NK cells. The collected NK cells will
be thrown away.

Blood Test for Measuring NK Cell Survival:

Blood (up to 4 teaspoons each time) will be drawn and tested to see how long the NK cells
survive in your body. This blood will be drawn on Day 0 (before the NK cell infusion and
again 2 hours later) and on Days 2, 7, 14, 21, and 28. (It is possible that this blood draw
schedule will stop earlier if the disease gets worse or the infused NK cells can no longer
be seen.)

Possible Additional NK Cell Infusion:

If the neuroblastoma responds and you did not suffer a new intolerable side effect from the
NK cells, then you may be eligible to receive 1 additional infusion of NK cells. If so, the
rest of the study procedures would be the same as before (the screening tests to determine
your eligibility, the requirement that the donor still be eligible, the Conditioning Phase
with chemotherapy, the IL-2 injections, and the blood tests). You must use the same donor
as before, if he or she is still eligible.

Hospitalization:

So that you can be monitored for side effects, you will need to stay in the hospital from
Day -6 until after the NK cell infusion (or longer if medically necessary).

Follow-Up Visits:

After your final NK cell infusion, you will return for follow-up visits at least 3 times a
week during the first 3 weeks. Then you will return for follow-up visits at around Day +28
and again 3 months after the last NK cell infusion. Following your 3 month visit, you will
be asked to return for follow-up visits every 3 months up until one year after the last NK
cell infusion. Below is a schedule of what will be done at each visit:

- Initial 3 weeks post infusion (3 times per week):

- Any changes in your medical history will be recorded, and a physical exam will be
performed.

- Blood (up to 2 tablespoons) will be drawn for routine tests.

Day 28, at 3, 6, 9, and 12 months after infusion visits:

- Any changes in your medical history will be recorded, and a physical exam will be
performed.

- Blood (up to 2 tablespoons) will be drawn for routine tests.

- Urine or an additional 4 teaspoons of blood may be drawn for other routine tests to
check the disease status.

- CT scans of the neck, sinus, chest, abdomen, and pelvis will be performed, and a CT of
the brain may also be performed if the study doctor feels it is needed.

MIBG scan may be performed if your tumor was positive on MIBG scan in the past or if your
doctor feels it is needed.

-Bone marrow biopsies/aspirations may be performed once in the first month, then may be done
at each visit if you had neuroblastoma in your bone marrow at the time you started on the
study or if your doctor feels it is necessary.

PET scan and/or bone scan may be performed sometime in Months 2 or 3, and again in months 6
-12 if your doctor feels it is needed.

This is an investigational study. Cyclophosphamide, fludarabine, mesna, and IL-2 are
commercially available but not FDA approved for use in neuroblastoma. Injecting IL-2 under
the skin is not FDA approved for use in increasing the production of NK cells. The
CliniMACS device is not commercially available or FDA approved. Infusing NK cells in
patients with neuroblastoma is also considered experimental. At this time and for this
purpose, NK cell infusions and the CliniMACS device are being used in research only.

Up to 10 recipients and 10 donors will take part in this study. All will be enrolled at M.
D. Anderson.