Trial Information

Phase II Study of Combination of Hyper-CVAD and Dasatinib in Patients With Philadelphia (Ph) Chromosome Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

The intensive chemotherapy used in this study includes a combination of 7 chemotherapy
drugs. These drugs include cyclophosphamide, vincristine, Adriamycin (doxorubicin),
dexamethasone, methotrexate, cytarabine (Ara-C), and dasatinib and possibly rituximab.

The maintenance therapy used in this study includes a combination of 3 chemotherapy drugs.
These drugs include vincristine, prednisone, and dasatinib.

Ara-C is designed to insert itself into DNA (the genetic material of cells) and stop the DNA
from repairing itself.

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

Dasatinib is designed to block a protein that cancer may need to grow, survive, or spread.

Dexamethasone, doxorubicin, methotrexate, and prednisone are each designed to stop or slow
the growth of cancer cells, which may cause the cells to die.

Vincristine is designed to interfere with the multiplication of cancer cells, which may slow
or stop their growth and spread throughout the body. This may cause the cancer cells to
die.

Rituximab is designed to attach to lymphoma cells, which may cause them to die.

If you are found to be eligible to take part in this study, you will receive intensive
chemotherapy therapy and dasatinib followed by maintenance therapy. You will receive 2 kinds
of intensive chemotherapy regimens (hyper-CVAD therapy and methotrexate plus cytarabine)
that will alternate about every 3 weeks for a total of 8 cycles (4 courses of each regimen).

You will have further routine blood draws (about 1 tablespoon each time) at different time
points throughout this study. You will have blood drawn during Course 1 (about twice
weekly); for the remainder 7 courses (about once a week); and during the maintenance phase
(about once every 4-6 weeks).

You will have further bone marrow biopsies performed at different time points throughout
this study. You will have a bone marrow biopsy to see if the treatment is controlling the
disease, during Course 1 on Days 14 and 21, as well as whenever the study doctor thinks it
is necessary to see if the Ph chromosome and/or BCR-ABL is still present.

Intensive Chemotherapy:

You may receive up to 8 cycles of intensive chemotherapy in the hospital (about 4 or 5
days). For participants 60 years and older, you will receive the entire first course in the
hospital (about 21 days), in a protected environment, until you have healthy recovery of
your blood counts.

Hyper-CVAD therapy will be given during the odd-numbered courses (1, 3, 5, and 7). You will
receive cyclophosphamide by vein on Days 1-3, which will be given every 12 hours for a total
of 6 doses. While you are receiving cyclophosphamide, you will also receive MESNA by a
central venous catheter (CVC), which will be given over 24 hours until about 12 hours after
your last dose of cyclophosphamide. This drug is used to help protect your bladder from the
side effects (such as irritation and bleeding in the bladder) of cyclophosphamide. A CVC is
a sterile flexible tube that will be placed into a large vein while you are under local
anesthesia. Your doctor will explain this procedure to you in more detail, and you will be
required to sign a separate consent form for this procedure. You will receive vincristine by
vein on Days 4 and 11, which will be given over 30 minutes during each cycle of hyper-CVAD
therapy. You will receive doxorubicin on Day 4 through a large vein by a CVC over 24-48
hours after your last dose of cyclophosphamide. This will depend on your heart function
because the drug is being given over such a long period of time. You will receive
dexamethasone on Days 1-4 and Days 11-14 by mouth or by vein over 30 minutes during each
cycle of hyper-CVAD therapy.

Methotrexate plus Ara-C will be given during the even-numbered courses (2, 4, 6, and 8). You
will receive methotrexate on Day 1 by vein over 24 hours. You will receive Ara-Con Days 2
and 3 of each cycle, which will be given by vein over 2 hours every 12 hours for a total of
4 doses each time. Your dose of Ara-C may be decreased depending on your age, kidney
function, or certain side effects you may experience. You will receive citrovorum or
leucovorin after the completion of methotrexate, which will help decrease the side effects
(such as mouth sores and kidney damage) of methotrexate. You will also receive a growth
factor (G-CSF) after the completion of all cycles of Hyper-CVAD and methotrexate plus
cytarabine. You will receive G-CSF as in injection just under your skin every day until you
have healthy recovery of your white blood cells, which will be determined by the study
doctor.

If the doctor thinks it is needed, on Days 1 and 11 of Cycles 1-4, you will also receive
rituximab by vein over several hours.

You will also receive small doses of methotrexate and Ara-C by a spinal tap to help prevent
relapse of the disease in the fluid surrounding your brain. A spinal tap requires the
insertion of a needle through the skin and the soft tissues of the lower back to reach a
pocket of fluid that is a part of the fluid space that surrounds the brain and the spinal
cord. Once the fluid space is reached, a sample of the fluid will be collected. The
procedure is done under local anesthesia. It can also be used to give chemotherapy. You may
be given treatment with methotrexate and Ara-C, alternately, to the brain by spinal tap
during each cycle for a total 6-8 doses. The number of doses you receive will depend on how
many doses the study doctor thinks is necessary. If you start with leukemia in the brain, it
will be given 2 times a week until there is no leukemia present and then 1 time a week for 4
weeks. Occasionally, a sample of the fluid obtained from the spinal taps may be examined by
sensitive tests for presence of leukemia. A sample will also be sent to determine the amount
of dasatinib to see if it reaches the fluid around the brain.

Dasatinib will be given by mouth on Days 1-14 of Cycle 1 and every day of Cycles 2-8 .

If the disease is responding to therapy and you have not experienced any intolerable side
effects, you will continue on intensive chemotherapy for up to 8 courses, and you will then
proceed to the maintenance therapy phase. You will be taken off this study if the disease
gets worse or you experience any intolerable side effects.

Maintenance Therapy:

Maintenance therapy, which will last for up to 2 years, will be given after you complete all
8 courses of intensive chemotherapy. You will receive vincristine on Day 1 by vein about
every 28 days. You will receive prednisone on Days 1-5 by mouth about every 28 days. You
will receive dasatinib every day by mouth 2 times a day. During Months 6 and 13, you may
receive another course of hyper-CVAD, depending on how you are feeling and if you have
presence of disease. You will also receive rituximab during these months if your doctor
thinks it is needed.

Your doses of all chemotherapy that is given in this study may be increased or decreased
depending on your organ function and side effects. Throughout intensive chemotherapy and
maintenance therapy, you will also receive other drugs, fluids, or blood products (such as
antibiotics, antiemetics, antacids, saline, platelets, and plasma), including allopurinol
(by mouth) or rasburicase (by vein), to help protect your body against tumor lysis syndrome.
This is a condition brought on by the death of large tumors, which causes damage to kidneys.

This is an investigational study. All of the drugs used in this study are FDA approved and
commercially available. Their use together in this study is investigational. Up to 115
patients will take part in this study. All will be enrolled at MD Anderson.