Trial Information

Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated T-ALL and Lymphoblastic Lymphoma

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

The maintenance therapy used in this study includes a combination of 5 chemotherapy drugs.
These drugs include L-asparaginase, methotrexate, prednisone, 6-mercaptopurine, and
vincristine.

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.

Dexamethasone, doxorubicin, methotrexate, prednisone, and 6-mercaptopurine are each designed
to stop or slow the growth of cancer cells, which may cause the cells to die.

Nelarabine is designed to inhibit ("turn off") the growth and division of cancer cells.

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.

If you are found to be eligible to take part in this study, you will receive 2 kinds of
intensive chemotherapy regimens (hyper-CVAD therapy and methotrexate plus Ara-C) that will
alternate for a total of 8 courses (4 courses each). One (1) course of therapy is between 21
and 28 days. All chemotherapy will be given through a large vein by a central venous
catheter. A central venous catheter 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.

Intensive Chemotherapy:

Hyper-CVAD therapy will be given during Courses 1, 3, 5, and 7. For this therapy, you will
receive cyclophosphamide by vein over 2-3 hours every 12 hours for a total of 6 doses. It
will be given over 3 days (Days 1, 2, and 3). You will receive doxorubicin by vein over 24
hours on Day 4. The doxorubicin infusion may be extended up to 48 hours, if you are
considered to have poor heart function (provided this is known) because you may tolerate
this drug better as a slow continuous infusion. You will receive vincristine by vein over
15-30 minutes on Days 4 and 11. You will receive dexamethasone 1 time a day by mouth or by
vein over a few minutes on Days 1-4 and Days 11-14. You will also receive G-CSF (Filgrastim)
by vein over a few minutes or just under the skin starting about 24-72 hours after the
completion of each course of chemotherapy and until your white blood cell count has
recovered (which will help with rapid recovery of normal bone marrow).

For participants 60 years or older, this first course of chemotherapy will be given in a
protective isolation room for monitoring by study staff to help watch for and decrease the
risk of infections.

Methotrexate will be given in combination with Ara-C during Courses 2, 4, 6, and 8. You will
receive methotrexate by vein over 24 hours on Day 1. You will receive Ara-C by vein on Days
2-3, over 2-3 hours every 12 hours for a total of 4 doses. Doses of Ara-C will be adjusted
according to the level of methotrexate you receive. Blood (about 1 teaspoon) will be drawn
to measure the study drug level. Leucovorin, used to help decrease the side effects of
methotrexate, will be given by vein (over 15 minutes) or by mouth (every 6 hours) for 2-3
days (or until the blood level of methotrexate is low enough to stop leucovorin). Filgrastim
will be given at the same dose and schedule as during Courses 1, 3, 5, and 7.

During treatment, you will have a physical exam, including measurement of your vital signs.
You will have blood drawn (about 1 tablespoon each) at least once a week and sometimes up to
3 times a week. After 1 or 2 courses of chemotherapy, the tests done during the screening
visit will be repeated to check for disease response to treatment. A bone marrow biopsy will
be repeated starting at 2 weeks into therapy. This biopsy will be repeated about every week
until the disease response to treatment is known.

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

To decrease the risk that leukemia will develop in the brain, you will be given treatment to
the brain by an injection into your spinal fluid with methotrexate around Day 2. Ara-C will
be given by an injection into your spinal fluid on about Day 7 of the course. The total
number of these treatments may be up to 8, which means that you will have 2 with each course
until the total number of these treatments is reached. During Courses 5 and 6 (when you
receive nelarabine), injections into your spinal fluid will be given later (around Days 15
and 22 of each course). An Ommaya reservoir may also be surgically placed as a route to
treat leukemia in the brain or to decrease the risk of leukemia in the brain. It would be
placed in participants who have difficulty with the spinal treatments. An Ommaya reservoir
is a tube inserted under the skin of the scalp that enters into the spinal fluid cavity of
the brain.

After the first 4 courses, you will receive 1 course of nelarabine. Nelarabine will be given
by vein over 2 hours once a day for 5 days. After about 21-35 days, you will continue with
Course 5 (Hyper-CVAD). After Course 5, you will receive a second course of nelarabine at the
same dose and schedule as before. Once this course is complete, you will continue with
Course 6 (methotrexate and cytarabine).

After completion of the treatment, you will have a complete physical exam, including
measurement of your vital signs. You will have blood drawn (about 8 teaspoons) for routine
tests. You will have a chest x-ray or CT scans performed, if needed. You may have a bone
marrow biopsy repeated. If you had enlarged lymph glands in the center of the chest, you may
receive radiation to the chest. If you do not need radiation, you will proceed with monthly
maintenance chemotherapy. If you did require radiation (based on what your doctor thinks is
best), you will start maintenance chemotherapy after finishing radiation.

Maintenance Therapy:

Maintenance chemotherapy will be given for a total of 30 months and will be interrupted by 2
periods of intensive chemotherapy courses. For maintenance therapy, you will receive
6-mercaptopurine by mouth up to 3 times a day, methotrexate by mouth once a week,
vincristine by vein once a month over a few minutes, and prednisone by mouth once a day for
5 days in a row every month. The first period of intensive chemotherapy courses will be
given at Courses 6 and 7 into the maintenance program. For the intensive chemotherapy at
this time, you will receive nelarabine by vein over 2 hours once a day for 5 days in a row
for about 21-35 days apart from each other. The second period of intensive chemotherapy
courses will be given at Courses 18 and 19. It will start first with methotrexate by vein on
Day 1 and L-asparaginase by vein on Day 2. These will be given once a week for 4 doses. The
following month, you will receive hyper-CVAD (like during Course 1 at the very beginning of
treatment). The hyper-CVAD may begin before the combination of methotrexate and
L-asparaginase.

Intensive chemotherapy will be given on an inpatient or outpatient basis (depending on what
the study doctor thinks is safe) for the 8 intensive cycles of chemotherapy. The maintenance
treatments may be given on an outpatient basis. However, under some circumstances (such as
intolerance to intensive chemotherapy), you may be moved from the intensive chemotherapy to
the maintenance phase before the completion of 8 cycles of intensive chemotherapy or without
having received nelarabine.

After completion of all therapy, you will return every 3-6 months for a checkup. You may
have x-rays repeated, if needed. If you have a complete remission, you will have bone marrow
biopsies repeated about every 4 months to evaluate the marrow for "minimal residual
disease," which is the presence or absence of very small amounts of leukemia that cannot be
usually detected by routine blood tests.

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 and for use in
research only. Up to 60 patients will take part in this study. All will be enrolled at M. D.
Anderson.