Trial Information

A Phase 1/2 Trial Evaluating Treatment of Emergent Graft Versus Host Disease (GvHD) With AP1903 After Planned Donor Infusions (DLIs) of T-cells Genetically Modified With the iCasp9 Suicide Gene in Patients With Hematologic Malignancies

Gene Transfer:

Gene transfer involves drawing blood from a transplant donor, and then separating out the
T-cells using a machine. Researchers then perform a gene transfer to change the T-cells'
DNA, and then inject the changed T-cells into the body of the patient receiving the
transplant.

Study Drug Administration:

Patient will receive fludarabine, melphalan, and alemtuzumab to kill cancer cells and help
prevent patient's body from rejecting the stem cells. The day patient receives the stem
cells is called Day 0. The days before patient receives their stem cells are called minus
days. The days after patient receives the stem cells are called plus days.

On Day -7, patient will be admitted to the hospital and given fluids by vein to hydrate
them.

On Days -6 through -3, patient will receive fludarabine by vein over 1 hour each day.

On Day -2, patient will receive melphalan by vein over 30 minutes.

On Day -1, patient will receive alemtuzumab by vein over 2 hours.

On Day 0, patient will receive the stem cell transplant as a cell infusion by vein.

After the transplant, patient will receive tacrolimus and methotrexate. At first, patient
will receive tacrolimus as a continuous (nonstop) infusion until they are able to take it by
mouth. Patient will then take tacrolimus by mouth 2 times a day for about 3 weeks and then
patient's doctor will tell them how to taper it off (gradually stop taking it). On Days
+1, +3, and +6, patient will receive methotrexate by vein over 30 minutes.

Patient will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
after the transplant, until their blood cell levels return to normal. Filgrastim is
designed to help with the growth of white blood cells.

Between Day +42 and +56, if patient is in stable medical condition and has not developed
GvHD, they will receive a donor lymphocyte infusion containing genetically modified T-cells
by vein over 10-30 minutes. Patient will receive Benadryl (diphenhydramine) by vein over 15
minutes and Tylenol by mouth before the infusion to lower the risk of an allergic reaction.

If patient develops symptoms of GvHD after the T-cell infusion, they must return to the
clinic within 72 hours. If patient has GvHD, they will receive AP1903 and steroids by vein.
Patient will then come to the clinic every day for the next 3 days and for an additional 3
days after a second dose of AP1903, if given. In addition, patient will come to the clinic
on Days +7, +14, +28 and +56 after receiving AP1903. If patient's symptoms do not improve
after receiving AP1903, they will given standard drugs for GvHD.

Study Tests:

Between Days +28 and +56, patient will have the following tests and procedures to find out
if they will be eligible for the T-cell infusion:

- Patient will have a physical exam.

- Patient will be checked for possible reactions to treatment, including GvHD.

- Blood (about 4 tablespoons) will be drawn for routine tests, to check patient's liver
and kidney function, for chimerism studies (determination of donor or recipient cells),
and to check for cytomegalovirus (CMV).

- Patient will complete a quality of life questionnaire that will take 10-15 minutes.

- If patient's doctor thinks it is needed, they will have a bone marrow aspiration and
biopsy performed to check the status of the disease. To collect a bone marrow
aspiration/biopsy, an area of the hip is numbed with anesthetic, and a small amount of
bone marrow and bone is withdrawn through a large needle.

About twice a week until about 2 months after the T-cell infusion, and then 6 and 12 months
after the stem cell transplant:

- Patient will have a physical exam, including measurement of their height, weight and
vital signs.

- Patient's medical history will be recorded.

- Patient will have be checked for possible reactions to your treatment, including GvHD.

- Blood (about 4 tablespoons) will be drawn for routine tests, to check patient's liver
and kidney function, and to check for CMV and other infections. Part of the blood may
be used for chimerism studies, if patient's doctor thinks it is needed.

- Mouse protein antibodies are used in the gene transfer process. If patient's body
becomes immune to these proteins, they may develop antibodies against the mouse
antibodies (called "human anti-mouse antibodies" [HAMA]).

- Patient will complete the quality of life questionnaire.

- If patient's doctor thinks it is needed, they may have a bone marrow aspiration and
biopsy performed to check the status of the disease and for chimerism studies.

If patient's doctor thinks it is needed, some tests and procedures may be repeated more
frequently or at different time points during the study.

Immune System and T-cell Level Tests:

If possible, blood will be drawn to check the status of the disease and patient's immune
system function:

- 4 hours after the T-cell infusion,

- once a week for 1 month after the T-cell infusion,

- and then at 3, 6, and 12 months after the stem cell transplant

The amount of blood drawn will depend on patient's weight. Part of the blood drawn will be
tested to check the level and function of the infused T-cells.

Length of Treatment:

Patient will be off study after their 1-year follow-up visit. Patient will be taken off
study early if:

- not enough donor cells could be collected

- patient was not eligible to receive the T-cell infusion

- patient has graft failure (the donor cells did not "take")

- the disease comes back and needs another treatment

- patient is unable to keep appointments

- patient did not return to the clinic within 72 hours of having symptoms of GvHD

- patient's study doctor thinks it is in their best interest

If patient is taken off study, they will receive standard of care treatment.

Long-Term Follow-Up:

For safety reasons, the U.S. Food and Drug Administration (FDA) requires that patients who
receive infusions of stem cells treated with a gene transfer procedure must have long-term
follow-up yearly for at least 15 years after receiving the gene transfer.

Patient will be asked to sign a separate consent form for a long-term follow-up study,
Protocol 2006-0676. If for any reason patient is unable to receive the genetically modified
cells, they will not be enrolled on the long-term follow-up study.

This is an investigational study. The gene transfer or infusion with genetically-changed
T-cells and the drug, AP1903, are not FDA approved or commercially available for use in this
type of disease. They are currently being used for research purposes only. Fludarabine,
melphalan, and alemtuzumab are commercially available and FDA approved.

Up to 35 patients will take part in this study. All will be enrolled at MD Anderson.