Trial Information

Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) for Patients With Relapsed or Refractory Acute Lymphocytic Leukemia (ALL)

The Study Drugs:

Everolimus is designed to stop cancer cells from multiplying. It may also stop the growth
of new blood vessels that help tumor growth, which may cause the tumor cells to die.

You will receive everolimus with 2 different chemotherapy combinations during alternating
cycles. This means that you will receive 1 combination on Cycles 1, 3, 5, and 7 and the
other combination during Cycles 2, 4, 6, and 8.

The first chemotherapy regimen is called hyper-CVAD. Hyper-CVAD includes cyclophosphamide,
vincristine, Adriamycin (doxorubicin), and dexamethasone. This combination is designed to
kill leukemia cells.

The other chemotherapy regimen includes the drugs methotrexate and ara-C (cytarabine). This
combination is also designed to kill leukemia cells.

Study Groups and Everolimus Dose Levels:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you joined this study. Up to 3 groups of 3-6 participants will be
enrolled in the Phase I portion of the study, and up to 30 participants will be enrolled in
Phase II.

If you are enrolled in the Phase I portion, the dose of everolimus you receive will depend
on when you joined this study. The first group of participants will receive the lowest dose
level of everolimus. Each new group will receive a higher dose of everolimus than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of everolimus is found.

If you are enrolled in Phase II, you will receive everolimus at the highest dose that was
tolerated in the Phase I portion.

In this study, everolimus is the only study drug where different dose levels are being
tested and compared. All other drugs will be given at the same dose level.

Central Venous Catheter (CVC):

If you do not already have a CVC, you will have a CVC placed. A CVC is a plastic tube
usually placed under the collarbone. You will sign a separate consent for this procedure.
Some of the study drugs will be given through the CVC.

Everolimus Administration:

During all cycles, you will take everolimus once a day followed by a big glass of water. The
tablets must not be chewed, broken or crushed. You may either take everolimus on an empty
stomach or after a low fat meal. Taking everolimus after large, fatty meals is not advised
because it will lower the amount of everolimus your body absorbs. Some examples of a low fat
meal include: cereal with fat free milk, muffin/bagel with fat free spread, fruit salad, and
so on. Always follow the instructions for use of everolimus given to you by your study
doctor. Your first dose of everolimus will occur 1 day before you begin receiving
chemotherapy.

Do not miss any tablets/capsules. You should take everolimus about the same time each day
preferably in the morning.

If your study doctor thinks it is needed or if you experience severe side effects,
everolimus may be stopped and then started again with a lower dose or may be stopped
completely.

Chemotherapy Administration:

Each cycle will last about 21 days. The timing of each new cycle will depend on when your
blood counts recover.

Cycles 1, 3, 5, and 7:

During Cycles 1, 3, 5, and 7, you will receive hyper-CVAD. The drugs will be given at the
following times:

- On Days 1-3, you will receive cyclophosphamide by vein over 2-3 hours every 12 hours.

- On Days 1-4 and 11-14, you will receive dexamethasone by mouth or by vein. If by vein,
the infusion will take a few seconds.

- On Day 4, you will receive doxorubicin over 24 hours through a CVC.

- On Days 4 and 11, you will receive vincristine by vein over 2-3 hours.

Cycles 2, 4, 6, and 8:

During Cycles 2, 4, 6, and 8, you will receive the methotrexate and cytarabine by vein as
follows:

- On Day 1, you will receive methotrexate by vein over 24 hours.

- On Day 1, you may receive leucovorin (citrovorum) by vein (over 15 minutes) for 2-3
days. Leucovorin is given to help prevent methotrexate side effects.

- On Days 2-3, you will receive cytarabine by vein over 2 hours every 12 hours.

- On Days 1-3, you will receive methylprednisone over 2 hours every 12 hours for 6 doses.

Cycles 1-8:

You will also receive either Neupogen (filgrastim) or pegfilgrastim to help your bone marrow
recover from chemotherapy. Filgrastim or pegfilgrastim will be injected under the skin
within 72 hours after each cycle of chemotherapy. If you receive filgrastim, it will be
given daily until your counts recover. If you receive pegfilgrastim, it will be given 1
time.

You will also receive small doses of methotrexate and Ara-C, one after the other, by a
spinal tap to help prevent the disease from coming back in the fluid surrounding your brain
during each cycle. During a spinal tap, a doctor or technician inserts a needle through the
skin and the soft tissues of the lower back to reach a pocket of fluid that is part of the
fluid space that surrounds the brain and the spinal cord. Once the fluid space is reached,
chemotherapy drugs can be administered. The procedure is done under local anesthesia. An
Ommaya reservoir (which holds the drugs being given) may also be implanted surgically if you
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. You will be
asked to sign a separate consent form for this procedure. The number of doses you receive
will depend on how many doses the study doctor thinks are needed. 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. Sometimes, a sample of the spinal fluid collected from
the spinal taps may be tested to look for leukemia cells.

Maintenance Chemotherapy:

After you have completed 8 cycles, you will begin monthly (about every 28 days, depending on
your blood cell count recovery) maintenance chemotherapy for about the next 24 months. You
will take the following drugs:

- You will take 6-mercaptopurine by mouth with water every day.

- You will receive methotrexate by vein (over 2 hours) or mouth every week.

- You will receive vincristine by vein over 30 minutes every 28 days.

- You will take prednisone by mouth for 5 days every month.

Study Visits:

During Cycle 1, blood (about 1 tablespoon) will be drawn for routine tests 1-3 times every
week. During Cycles 2-8, blood (about 1 tablespoon) will be drawn for routine tests every
1-4 weeks.

During Cycles 1 and 2, you will have physical exam every week. After Cycle 2, you will have
a physical exam every 3-4 weeks.

At Weeks 2 and 3 of Cycle 1, you will have a bone marrow aspirate to check for response.
Depending on the results of the sample, this will be repeated every 1-2 weeks.

At Week 4-6 of Cycle 1, you will have a chest x-ray.

After Cycle 2 is over, the following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 8 teaspoons) and urine will be collected for routine tests.

- You will have a bone marrow aspirate.

- You will have a chest X-ray or computed tomography (CT) scan if needed.

If you had a positive hepatitis B test at screening, every month, blood (about 1
tablespoon) will be drawn to test the level of hepatitis B virus in your blood.

If your have risk factors and/or a positive Hepatitis C test results at screening, every
month, blood (about 1 tablespoon) will be drawn to test the level of Hepatitis C virus in
your blood.

Length of Study:

You may receive up to 32 cycles of study drugs. You will be taken off study early if the
disease gets worse, your doctor decides it is in your best interest to stop, or you have
intolerable side effects.

End-of-Study Visit:

After your last dose of study drugs, you will have an end-of-study visit. At this visit,
the following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 8 teaspoons) will be drawn for routine tests.

- You will have a bone marrow aspirate.

- If your doctor thinks it is needed, you will have a chest x-ray or CT scan.

Follow-up Visits:

You will have follow-up visits every 3 to 6 months. At these visits, the following tests
and procedures will be performed:

- You will have a physical exam.

- You will have a bone marrow aspirate.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- If your doctor thinks it is needed, you will have a chest x-ray.

This is an investigational study. All the chemotherapy drugs used on this study are FDA
approved and commercially available for treating ALL. Everolimus is FDA approved and
commercially available for the treatment of certain types of breast cancer. At this time,
the combination is only being used in research.

Up to 42 patients will take part in this study. All will be enrolled at MD Anderson.