Trial Information

A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined With Intervenous Busulfan Followed by Allogeneic Hemopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

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
transplantation.

Clofarabine is designed to interfere with the growth and development of cancer cells.

Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the
cancer cells to die.

Study Groups:

You will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups.

- Group 1 will receive busulfan, fludarabine, and clofarabine.

- Group 2 will receive busulfan and fludarabine.

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.

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.

Study Drug Administration and Procedures:

Both groups will receive a "test" dose of busulfan by vein over about 45 minutes to 1 hour.
This low-level test dose of busulfan is to check how fast busulfan is processed by your body
and cleared from your blood. This information will determine the amount of busulfan you
will receive. You may receive the busulfan test dose as an outpatient during the week
before you are admitted to the hospital or as an inpatient 8 days before your stem cell
transplant.

About 11 samples of blood (about 1 teaspoon each time) will be drawn for pharmacokinetic
(PK) testing. PK testing measures the amount of study drug in the body at different time
points and will also help determine your dose of busulfan. These blood samples will be
drawn at various times before you receive busulfan and over the next 11 hours. These blood
draws will be repeated again on the first day of high-dose busulfan treatment (Day -6, which
is 6 days before the transplant).

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 for technical or
scheduling reasons, you will receive the standard fixed dose of busulfan.

On Days -6 through -3, you will receive fludarabine by vein over 1 hour, then clofarabine
(if you are in Group 1) by vein over 1 hour, then busulfan by vein over 3 hours.

After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive
(lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host
disease (GvHD), a reaction of the donor's immune cells against the recipient's body.

If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor,
you will also receive antithymocyte globulin (ATG) by vein over 4 hours on the 3 days before
the transplant. This drug is designed to further weaken your immune system to reduce the
risk of rejecting of the transplant.

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.

While you are in the hospital, you will be checked for any side effects as part of your
standard of care. Blood (about 2 teaspoons) will be drawn every day to check for side
effects, for routine tests, to check your blood counts, kidney and liver function, and to
check for infections.

As part of standard care, you will remain in the hospital for about 3-4 weeks after
transplant. After you are released from the hospital, you must remain in the Houston area
to be monitored for infections and other transplant side effects until about 3 months after
transplant. During this time, you will return to the clinic at least 1 time each week. The
following tests and procedures will be performed:

- 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 for routine tests.

Around 14-30 days after the transplant (when the transplant "engrafts", or "takes"), you
will have a bone marrow aspirate to check the status of the disease.

Around Day 30, and about 3, 6, and 12 months after the transplant, the following tests and
procedures will be performed:

- 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 to check the status of the disease. To collect
a bone marrow aspiration, an area of the hip or other site is numbed with anesthetic,
and a small amount of bone marrow is withdrawn through a large needle.

Length of Study:

You will be taken off study 5 years after the end of treatment. You may be taken off study
early if the disease gets worse, if you have any intolerable side effects, of if you are
unable to follow study directions.

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.

It may be life-threatening to leave the study after you have begun to receive the study
drugs but before you receive the stem cells.

This is an investigational study. Busulfan and fludarabine are both FDA approved and
commercially available for the treatment of AML and MDS. Clofarabine is FDA approved for
treating other types of cancer, but is being used in AML and MDS for research only. The use
of these study drugs together at the dose level used in this study is investigational.

Up to 250 patients will take part in this study. All will be enrolled at MD Anderson.