Trial Information

Adoptive Transfer of Haploidentical NK Cells in Combination With Epratuzumab for the Treatment of Relapsed Acute Lymphoblastic Leukemia

Study Drugs:

Epratuzumab is designed to attach to certain proteins on the surface of ALL cells. This may
cause the cancer cells to die.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may
slow or stop their growth. This may cause the cancer cells to die.

Fludarabine is designed to make cancer cells less able to repair damaged DNA (the genetic
material of cells). This may increase the likelihood of the cells dying.

IL-2 is designed to help NK cells live longer and work better.

Experimental Therapy:

NK cells are the cells in the body that fight disease and infection. NK cells may destroy
tumor cells, particularly when the NK cells are "mismatched" for certain proteins, called
human leukocyte antigens (HLA). Researchers think that this ability to destroy tumor cells
can be predicted by learning the donor's and the recipient's HLA types to see if they are a
mismatch, and by checking for other specialized proteins found on the surface of the donor's
NK cells. These proteins are called killer immunoglobulin receptors (KIR).

The NK cells will be collected from the donor's blood and then processed in a lab at M. D.
Anderson, where researchers will use a machine, called a CliniMACS device, to separate out
the NK cells from the rest of the donor's collected white blood cells and treat them
overnight with a drug called IL-2. This is done to make the NK cells stronger before they
are given to the recipient. You will also receive IL-2 injections under your skin to try to
help the NK cells survive longer and to possibly increase the number of NK cells in your
body after the infusion.

Screening Tests:

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

- You will have a bone marrow biopsy and/or aspiration to check the status of the
disease. To collect a bone marrow biopsy and/or aspirate, an area of the hip is numbed
with an anesthetic, and a small amount of bone marrow and bone is withdrawn through a
needle.

- You will have a spinal tap to check the status of the disease. A spinal tap (also
called a lumbar puncture) is when a special needle is inserted into the lower back
through the space between the bones to draw a sample of the fluid that surrounds the
spinal cord.

- You will have a pulse oximetry test to measure your heart rate and the level of oxygen
in the blood. To perform this test, a clothespin-shaped device will be placed on your
finger for about 1 minute.

- Your medical history will be recorded.

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

- Blood (about 4 tablespoons) will be drawn for routine tests. This blood will also be
checked for infections such as the human immunodeficiency virus (HIV). You will be
told the results of this test. If you have an infection, you may not be able to take
part in this study.

- Blood (about 2 tablespoons) will be drawn to test for HLA and KIR. You and the donor
will be told the results of this test.

- Females who are able to have children must have a negative blood pregnancy test. This
test will be performed with the blood drawn for routine tests as described above. If
there is not enough blood leftover for this test, additional blood (about 1 teaspoon)
will be drawn.

These screening tests, except for the HLA and KIR-typing, would also need to be repeated
before an additional leukapheresis procedure can be done as a part of this study, in order
to see if you continue to be eligible to have another one performed.

Identifying an Eligible Donor:

Your relative will be tested to see if his or her KIR has a type of "mismatch" that
researchers think will help the donor's NK cells target the cancer cells in your body. They
must also share half of your HLA genes to be eligible to take part in this study.

The donor's blood will also be checked for infections, such as HIV, to protect against the
possibility of transmitting an infection to you during the NK cell infusion.

To help track the NK cells after infusion, researchers prefer (but do not require) that if
you are a female recipient, your donor is male and if you are a male recipient, your donor
is female.

Epratuzumab Administration:

If you and the donor are found to be eligible to take part in this study, on Day -4 (4 days
before the NK cell infusion) and Day -1 (1 day before the NK cell infusion), you will have
an epratuzumab infusion. The length of time this infusion will take will be different for
each patient. This will be done using an indwelling catheter (a tube that remains in a
vein, such as tunneled in the arm or through the chest to continuously inject or drain a
part of your body). If you already have an indwelling catheter in place, you will not need
to have a new one placed. However, if a new catheter is needed, you will be asked to sign a
separate informed consent form for its placement.

On Day -1 (1 day before the NK cell infusion) and on Days 3, 6, 10, 13, and 17, you will
receive an epratuzumab infusion. This will take several hours.

Conditioning Phase:

This phase will start within 28 days after the screening tests. During this phase, you will
receive chemotherapy with cyclophosphamide and fludarabine to weaken your immune system in
order to help the infused NK cells survive. You will stay in the hospital from Day -6 until
after the NK cell infusion or longer if the doctor thinks it is necessary.

On Day -6 through Day -2, you will receive fludarabine 1 time each day by vein, over about
30 minutes each time.

On Days -5 and -4, you will receive cyclophosphamide 1 time each day by vein, over about 2
hours each time.

On Days -5 and -4, you will receive mesna 5 times per day by vein, over about 15 minutes
each time. Mesna is given to protect your bladder from side effects that may be caused by
cyclophosphamide.

Cyclophosphamide, fludarabine, and mesna will all be infused through the same indwelling
catheter.

Infusion of NK cells:

On Day 0, you will receive the NK cells by vein, preferably through an indwelling catheter.
If you do not have an indwelling catheter, you may receive the infusion intravenously (IV --
by vein). The doctor will decide the amount of NK cells to be infused, which will affect
how long the infusion lasts. Usually the infusion should last less than 1 hour.

To help prevent an allergic reaction to the infused NK 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. If the study doctor thinks it is necessary, you may also receive a steroid
to help prevent side effects.

If the doctor thinks that 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.

This study allows eligible recipients under the age of 2 years of age to participate. You
and/or a caregiver will be trained how to give the IL-2 injections to yourself. This drug
will be injected under the skin for 9 doses. You will take 3 doses per week over a 3-week
period after receiving the NK cells.

Measuring NK Cell Survival Through Blood Test:

On Day 0 (before the NK cell infusion and again 2 hours later), and 1 time on each of the
following days: Days 2, 7, 14, 21, and 28, blood (about 4 teaspoons each time) will be drawn
and tested to see how long the NK cells survive in your body.

If the disease gets worse or the infused NK cells can no longer be seen, this blood draw
schedule may be stopped early.

Follow-Up Visits:

You will have follow-up visits at least 3 times per week during the first 3 weeks, and then
1 time about 28 days after your NK cell infusion. Then, you will have additional follow-up
visits at about Months 2 and 3. At these visits, the following tests and procedures will be
performed:

- You will have any changes in your medical history recorded.

- You will have a physical exam, including a measurement of your vital signs.

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

On Days 14 and 28, and during Months 2 and 3, you will have a bone marrow biopsy and/or
aspiration.

Length of Study:

You will remain on active study for up to 3 months following your NK cell infusion that you
agree to have performed.

This is an investigational study. Cyclophosphamide, fludarabine, mesna, and IL-2 are FDA
approved and commercially available. Cyclophosphamide and fludarabine are approved for
treating leukemia in adults. IL-2 is FDA-approved, but not for the treatment of leukemia.

Epratuzumab is not FDA approved or commercially available. It is only being used in
research.

The use of the CliniMACS machine and infusing NK cells combined with epratuzumab in patients
with ALL are only being done in research.

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