Trial Information

Phase II Study of Hyper-CVAD Plus Imatinib Mesylate (Gleevec, STI571) for Philadelphia-Positive Acute Lymphocytic Leukemia

Before treatment starts, patients will have a complete exam, including medical history and
documentation of disease, blood, and marrow tests. A chest x-ray will be taken. CT scans
may be taken if needed. A bone marrow sample will be taken through a large needle. An EKG
and MUGA (heart function tests) will be performed.

During treatment, patients will give blood samples (about 1 tablespoon each) at least twice
a week. A bone marrow sample will be repeated 2 and 3 weeks from the beginning of treatment
to check on response. After two courses of chemotherapy, the tests done before treatment
will be repeated to check for response.

All patients will receive 2 kinds of chemotherapy courses for a total of 8 courses.
Chemotherapy courses will be given through a large vein by a central venous catheter (a
plastic tube usually placed under the collarbone). Imatinib mesylate will be given as a
pill with the chemotherapy.

Course 1 will start with cyclophosphamide given by vein over 2-3 hours every 12 hours for 6
doses over 3 days (Days 1,2,3). Mesna will be given by vein continuously for 4 days with
the cyclophosphamide to protect the bladder. Doxorubicin will be given by vein over 24
hours on Day 4. Vincristine will be given by short infusion on Days 4 and 11.
Dexamethasone (a steroid) will be given by mouth or by vein on Days 1-4 and 11-14. The
imatinib mesylate will be given by mouth with breakfast and a large glass of water daily on
Days 1-14. Medicines will be given to prevent nausea and to protect the kidneys from
increased amounts of uric acid, which may be released when leukemia cells die.

G-CSF (growth stimulating colony factor) will be given after completion of the chemotherapy.
It is given to allow for rapid recovery of the normal marrow. G-CSF will be injected under
the skin until the counts recover. Treatment to the brain will be given inside the spinal
fluid with methotrexate around Day 2 and cytarabine about day 7. This is done to prevent
the leukemia from developing there.

For patients aged 60 years or older, this Course 1 will be given in a protective isolation
room to decrease the risk of infection(s).

During Course 2, patients will be given methotrexate by infusion over 24 hours on the first
day and cytarabine at a high dose over 2 hours every 12 hours for 4 doses (Days 2 and 3).
Citrovorum factor (leucovorin), an antidote for side effects of methotrexate, will be given
by vein or by mouth for 2-3 days (Day 2 and on). Solumedrol (a steroid) will be given by
vein every 12 hours for 6 doses. Imatinib mesylate will be given by mouth with breakfast
and a large glass of water on Days 1-14 or daily, depending on tolerance with Course 1.
G-CSF will be given as in Course 1. The treatment to the brain inside the spinal fluid will
be given as in Course 1 around Days 2 and 7.

The chemotherapy will alternate between hyper-CVAD plus imatinib mesylate (Courses 1, 3, 5,
and 7) and methotrexate/cytarabine plus imatinib mesylate (Courses 2, 4, 6, and 8) to
complete a total of 8 courses. G-CSF will be given as in Course 1. Anti-nausea medicine
will be given with each course of chemotherapy. The urine will be alkalized to protect the
kidneys. Antibiotics will be given by mouth to prevent infection.

After the 8 courses, monthly maintenance chemotherapy plus imatinib mesylate will be given.
This includes daily imatinib mesylate, monthly vincristine by vein, and prednisone by mouth
for 5 days every month. Maintenance chemotherapy will be given for a total of 24 months,
and will be interrupted by 2 periods of intensive chemotherapy courses with hyper-CVAD and
imatinib mesylate at 6 and 13 months from the start of maintenance. Imatinib mesylate will
be continued daily as tolerated indefinitely.

After two courses of the intensive chemotherapy, the response to the treatment will be
evaluated. If the leukemia is responding, the therapy will be continued. Patients will be
taken off study if the leukemia starts to get worse.

During and after completion of treatment, patients will have a complete exam, including
blood tests. If needed, a chest X-ray or CT scan will be done. A bone marrow sample will
be taken through a large needle. Patients will then return every 2 to 3 months for a
checkup, including blood and bone marrow. X-rays and heart studies (MUGA or ECG) may be
repeated if needed.

An Ommaya reservoir may also be placed surgically as a route to treat leukemia in the brain
or to prevent leukemia in patients who have difficulty with the spinal treatments. An
Ommaya reservoir is an access port inserted under the skin of the scalp that enters into the
spinal fluid cavity of the brain.

Treatment will be given on an inpatient basis (3 to 5 days) for the 8 intensive courses of
chemotherapy, or as indicated by the clinical condition. The maintenance treatments will be
given as an outpatient, except for the courses of hyper-CVAD and imatinib mesylate.

This is an investigational study. The FDA has approved imatinib mesylate for use in chronic
myelogenous leukemia and other clinical research studies. About 55 patients will take
part in this study. All will be from MD Anderson.