Trial Information

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

Study Drugs:

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 ponatinib. This is called hyper-CVAD.
You may also receive rituximab. These chemotherapy drugs are 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.

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

Cytarabine 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.

Ponatinib 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 leukemia cells, which may cause them to die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive intensive
chemotherapy therapy and ponatinib 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).
Each study cycle is about 3-4 weeks.

Intensive Chemotherapy:

You may receive up to 8 cycles of intensive chemotherapy in the hospital (about 4 or 5 days
as inpatient). 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: Cycles 1, 3, 5, and 7:

On Days 1-3 of Cycles 1, 3, 5, and 7, you will receive cyclophosphamide by vein over about 3
hours 2 times a day about every 12 hours. While you are receiving cyclophosphamide, you will
receive mesna as a continuous infusion by a central venous catheter (CVC) starting about 1
hour before you receive cyclophosphamide and ending about 12 hours after the last dose of
cyclophosphamide. Mesna is given to lower the risk of side effects. 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.

On Days 1 and 11 of Cycles 1, 3, 5, and 7 (+/- 2 days), you will receive vincristine by vein
over about 30 minutes.

On Day 4 of Cycles 1, 3, 5, and 7, you will receive doxorubicin by a CVC over 24-48 hours.

On Days 1-4 and 11-14 of Cycles 1, 3, 5, and 7 (+/- 2 days), you will take dexamethasone by
mouth 1 time a day or by vein over 30 minutes.

On Days 1-14 of Cycle 1 and every day during Cycles 2-8, you will take ponatinib by mouth 1
time a day.

If the doctor thinks it is needed, on Days 1 and 11 of Cycles 1 and 3 and on Days 1 and 8
for Cycles 2 and 4, you will also receive rituximab by vein over several hours.

You will also receive methotrexate alternating with cytarabine by a spinal tap
(intrathecally) to help lower the risk of the disease coming back in the fluid surrounding
your brain. A spinal tap (also called a lumbar puncture) is when fluid surrounding the
spinal cord is removed by inserting a needle into the lower back. The affected area is
numbed with local anesthetic during the procedure. It can also be used to give
chemotherapy. The number of doses you receive will depend on how many doses the study
doctor thinks is 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. Occasionally, a
sample of the fluid obtained from the spinal taps may be tested for leukemia. A sample will
also be tested to see if it reaches the fluid around the brain.

On Day 2 of Cycles 1, 2, 3, and 4 (+/- 2 days), you will receive intrathecal methotrexate.

On Day 7 of Cycles 1, 2, 3, and 4 (+/- 2 days), you will receive intrathecal cytarabine.

Methotrexate alternating with cytarabine by vein: Cycles 2, 4, 6, and 8 On Day 1 of Cycles
2, 4, 6 and 8, you will receive methotrexate by vein over about 24 hours (+/- 3 hours).

On Days 1-3 of Cycles 2, 4, 6, and 8, you will receive solumedrol by vein over less than 30
minutes about every 12 hours.

On Days 2 and 3 of Cycles 2, 4, 6, and 8, you will receive cytarabine by vein 2 times a day
over about 3 hours each time.

On Days 2-5 of Cycles 2, 4, 6, and 8, you will receive leucovorin by vein over about 1 hour
or by mouth every 6 hours beginning about 12 hours (+/- 2 hours) after you finish receiving
methotrexate. Leucovorin is given to lower the risk of side effects such as mouth sores and
kidney damage.

You will also receive filgrastim or pegfilgrastim after all cycles of Hyper-CVAD and
methotrexate plus cytarabine. You will receive it either as injection just under your skin
every day, or only once after chemotherapy, until you have healthy recovery of your white
blood cells, which will be determined by the study doctor.

If the disease is responding to therapy and you have not had any intolerable side effects,
you will continue on intensive chemotherapy for up to 8 courses, and you will then go to the
maintenance therapy phase. You will be taken off this study if the disease gets worse or you
have 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. Each maintenance cycle will be about 28 days.

On Day 1, you will receive vincristine by vein over about 30 minutes.

On Days 1-5, you will take prednisone by mouth.

You will take ponatinib as a single dose every day by mouth. You may continue to take
ponatinib every day for as long as you are receiving benefit and you are not having
intolerable side effects.

Post-Remission Therapy:

During Months 6 and 13, you may receive another course of hyper-CVAD, depending on how you
are feeling and the status of the disease.

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.

Study Visits:

At each study visit, you will be asked how you are feeling and about any drugs you may be
taking.

Before Day 1 of Cycle 2, you will have an ECG (+/- 2 days).

On Day 1 of Cycles 2-8, you will have a chest x-ray.

Blood (about 1 tablespoon) will be drawn for routine tests 1-2 times each week during Cycle
1, every 1-3 weeks during Cycles 2-8, and every 4-6 weeks during maintenance cycles.

You will have a bone marrow aspiration and/or biopsy (about 1 teaspoon) to check the status
of the disease on Days 14 and 21 (+/- 5 days) of Cycle 1, and every 2-3 cycles during
consolidation, then every 3-6 months during maintenance.

The blood draws for routine tests, bone marrow aspirations/biopsies, and ECGs may be
repeated more often anytime the doctor thinks it is needed.

Length of Treatment:

You may receive the intensive chemotherapy for up to 8 cycles (about 8 months) and then
maintenance therapy for up to 2 years. You may continue to take ponatinib as long as you
are receiving benefit. You will no longer be able to take the study drugs if the disease
gets worse, if intolerable side effects occur, or if you are unable to follow study
directions.

Your participation on the study will be over once you have completed the follow-up.

Follow-up:

You will have a follow-up visit 30 days after your last dose of the study drugs. At this
visit, you will be asked about any side effects you may be having. If you cannot make it to
the clinic for this visit, it can be done over the phone with a member of the study staff.
The phone call should last about 10 minutes.

This is an investigational study. Ponatinib is FDA approved to treat patients with certain
types of leukemia. Its use in this study is investigational.

All other drugs used in this study are FDA approved and commercially available. Their use
together in this study is investigational.

Up to 60 patients will take part in this study. All will be enrolled at MD Anderson.