Low-Intensity Chemotherapy and Blinatumomab in Patients With Philadelphia Chromosome Negative Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Study Drug Administration:

This study has 3 parts:

- Induction--the part of the study in which the study drugs are designed to create a
response from the disease. Induction will take place during Cycle 1 of the study. An
Induction cycle is about 42 days (6 weeks).

- Consolidation--the part of the study in which the drugs are designed to continue to
cause the disease to respond. Consolidation will take place during Cycles 2-4. Each
consolidation cycle is about 42 days (6 weeks).

- Maintenance--the part of the study in which chemotherapy is given to help keep the
disease under control. Maintenance will take place after Consolidation and will last for
up to 2 years. Each maintenance cycle is 4 weeks.

If you are found to be eligible to take part in this study, you will receive a central venous
catheter (CVC) if you do not already have one. 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.

Negative days are the days before the start of a cycle. While on this study, you will need to
be hospitalized on Days -3 to 6 of each cycle. In addition, you will need to stay in the
hospital on Day 21 of Cycle 1 and Days 1 and 2 of Cycle 2.

You will receive blinatumomab by vein continuously (nonstop) on Days 1-28 of Cycles 1-4. You
will not take blinatumomab on Days 29-42. Blinatumomab will be delivered by a small pump,
which you will carry with you for the whole time you receive the drug. This allows you to
receive the drug constantly over a long period of time. You will be given a shoulder or belt
bag to hold the pump and infusion bag. You will be able to wear regular clothes, walk around,
and perform daily living activities. You will be given instructions for taking a shower and
other activities. However, because the line must be kept free of infection and connected to
the pump at all times, some activities (like swimming) are not allowed during the study. The
study staff will give you more information on activities you should not do while receiving
the drug.

For blinatumomab doses where you are not hospitalized, you will need to return to the clinic
at certain times (about every 48 hours) to have the infusion bag changed. The study staff
will tell you how often the infusion bag must be changed. If the infusion is stopped for more
than 4 hours, you may need to return to the clinic to have the infusion started again.

You will receive dexamethasone by mouth or by vein about 1 hour before the start of the
blinatumomab dose on Day 1 of Cycles 1-4, within 1 hour after any time your dose is raised
(such as Day 5 of Cycle 1), Maintenance Therapy Cycles 6 and 12, and if your infusion has to
be stopped for more than 4 hours. You will also take dexamethasone on the schedule listed
below. Dexamethasone is given to prevent side effects associated with blinatumomab treatment.
If side effects do occur, you will receive additional dexamethasone by mouth or by vein. When
you are hospitalized, you will receive dexamethasone by vein over about 30 minutes. When you
are at home, you will take it by mouth.

You may be given other drugs to help prevent side effects. The study staff will tell you
about these drugs, how they will be given, and the possible risks.

Cycles 1-4 will take place in 2 parts: Part A and Part B. Part A will take place from Days 1-
21 of each cycle. Part B will take place from Days 22-42 of each cycle. All participants will
receive this treatment.

- During Part A, you will receive mini-hyper-CVD chemotherapy. This is a combination of
the drugs G-CSF or pegfilgrastim, cyclophosphamide, mesna, dexamethasone, methotrexate,
cytarabine, and vincristine.

- During Part B, you will receive MTX-ARA-C chemotherapy. This is a combination of the
drugs methotrexate and cytarabine. If needed, you will also receive leucovorin and
rituximab.

Part A Dose Administration:

During Cycle 1:

- Depending on what your insurance allows, you will either receive G-CSF each day as an
injection under the skin until your blood counts recover or on Day 1 you will receive
pegfilgrastim as an injection under the skin 1 time each cycle.

- On Days -3 to -1, you will receive cyclophosphamide 2 times each day (about 12 hours
apart) by vein over about 3 hours.

- On Days -3 to -1, you will receive mesna by vein continuously (nonstop) for about 36
hours to help prevent side effects related to cyclophosphamide.

- On Day 2, you will receive methotrexate intrathecally (by spinal tap).

- On Day 7, you will receive cytarabine intrathecally.

- On Days 0 and Day 7, you will receive vincristine by vein over 15 minutes.

- On Days -3 to 0 and Days 7-10, you will receive dexamethasone by mouth or by vein.

- If the doctor thinks it is needed, on Days -3 and 0, you will receive rituximab by vein
over 4-6 hours.

During Cycles 2-4:

- On Days 1-3, you will receive cyclophosphamide 2 times each day (about 12 hours apart)
by vein over about 3 hours.

- On Days 1-3, you will receive mesna by vein continuously (nonstop) for about 72 hours to
help prevent side effects related to cyclophosphamide.

- On Day 4 and Day 11, you will receive vincristine by vein over 15 minutes.

- On Day 5, you will receive G-CSF as an injection under the skin or, you will receive
pegfilgrastim as an injection under the skin until your blood counts recover.

- On Days 2, you will receive methotrexate intrathecally.

- On Days 7, you will receive cytarabine intrathecally.

- On Days 1-4 and Days 11-14, you will receive dexamethasone by mouth or by vein.

- If the study doctor thinks it is needed, on Day 1 and Day 8 of Cycle 2, you may receive
rituximab by vein over 4-6 hours.

Part B Dose Administration:

During Cycles 1-4:

- Depending on what your insurance allows, you will either receive G-CSF each day as an
injection under the skin until your blood counts recover or you will receive
pegfilgrastim as an injection under the skin on Day 25.

- On Day 22, you will receive methotrexate by vein over about 24 hours.

- On Days 23 and 24, you will receive cytarabine by vein 2 times each day (about 12 hours
apart) over about 3 hours for a total of 4 doses.

- If the doctor thinks it is needed, you may receive leucovorin by vein over about 15
minutes or by mouth 4 times a day for up to 8 doses, beginning 12 hours after the
methotrexate dose ends to help reduce the risk of side effects. The study staff will
tell you which way you will receive leucovorin.

- If the study doctor thinks it is needed, On Days 22 and 29 of Cycles 1 and 2, you may
receive rituximab by vein over about 4 to 6 hours.

Maintenance Therapy (Cycles 1-24):

Each maintenance cycle will last about 28 days, except Cycles 6 and 12. Cycles 6 and 12 will
be about 42 days. The exact length will depend on how your body responds to the chemotherapy.

After your last consolidation cycle (Cycle 4), if the disease has not gotten worse, you will
start Maintenance Therapy. During Maintenance Therapy, you will receive the following drugs
for about 2 years:

- On Days 1-5 of Cycles 1-5, 7-11, and 13-24 you will take prednisone by mouth.

- On Day 1 of Cycles 1-5, 7-11, and 13-24 you will receive vincristine by vein 1 time over
about 15 minutes.

- On Days 1-28 of Cycles 1-5 and 7-11, you will receive 6-MP twice a day

- You will receive methotrexate by mouth 1 time each week of Cycles 1-5 and 7-11.

- On Days 1-28 of Cycles 6 and 12, you will receive blinatumomab by vein continuously.
°You will need to return to the hospital for days 1-6 of Cycle 6.

- For blinatumomab doses where you are not hospitalized, you will need to return to the
clinic at certain times (about every 48 hours) to have the infusion bag changed.

Length of Treatment:

You may receive up to 4 cycles of mini-hyper-CVD, MTX-ARA-C, and blinatumomab followed by 24
cycles of chemotherapy-based maintenance treatment. 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 in this study will be over after follow-up (described below).

Study Visits:

If it is more convenient for you, you may have some of the following tests/procedures
performed at your local doctor's office or clinic. Your local doctor will tell the study
doctor at MD Anderson the results of the testing. The study doctor and/or study staff will
discuss this option with you.

At least 1 time each week during Cycles 1-4, then every 4-6 weeks during Maintenance, blood
(about 2-3 tablespoons) will be drawn for routine tests.

On Days 1 and 14 of Cycles 1-4, Day 28 of Cycle 4, and Days 1 and 14 of Cycles 6 and 12 of
Maintenance therapy, blood (about 1-2 teaspoons) will be drawn to check the status of the
disease and for immune system testing.

On Day 21 of Cycles 1-4, you will have a chest x-ray.

On Days 21 and 42 of Cycle 1, Day 42 of Cycle 2 depending on the status of the disease, and
Day 42 of Cycle 4, and at any point during Maintenance that your doctor thinks it is needed,
you will have a bone marrow biopsy and/or aspiration to check the status of the disease, for
cytogenetic and immune system testing.

On Day 42 of Cycle 2, you will have an ECHO or a MUGA scan to check your heart function.

Every 3-6 months during Maintenance Cycles, blood (about 1-2 teaspoons) will be drawn to
check the status of the disease and for immune system testing.

Long-Term Follow-Up:

About 30 days after your last dose of study drugs and then about every 3 months for 1 year
and then about every 6 months after that from then on, you will be called by a member of the
study staff and asked how you are doing and if you have started any new medications. Each
call should last about 10 minutes.

Inclusion Criteria:

1. Patients >/= 18 years of age with first or second relapsed/refractory B-cell ALL.

2. Performance status
3. Adequate liver function as defined by the following criteria: Total serum bilirubin
the underlying leukemia approved by the PI; Alanine aminotransferase (ALT) ULN, unless due to the underlying leukemia approved by the PI; Aspartate
aminotransferase (AST) the PI or Aspartate aminotransferase (AST) leukemia approved by the PI

4. Signed informed consent

5. Women of childbearing potential (WOCBP) or male subjects with a partner who is WOCBP
must agree to use contraception during the study, if sexually active.

Exclusion Criteria:

1. Patients with Ph-positive ALL or Burkitt leukemia

2. Active, uncontrolled central nervous system (CNS) leukemia involvement

3. Active serious infection not controlled by oral or intravenous antibiotics.

4. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
squamous cell carcinoma) that in the investigator's opinion will shorten survival to
less than 1 year.

5. Known hepatitis B or C infection, or known seropositivity for HIV

6. Active Grade III-V cardiac failure as defined by the New York Heart Association
Criteria.

7. Patients with a cardiac ejection fraction (as measured by either MUGA or
echocardiogram) <40%

8. Prior history of treatment with blinatumomab

9. Treatment with any investigational antileukemic agents or chemotherapy agents in the
last two weeks, unless full recovery from side effects has occurred or patient has
rapidly progressive disease judged to be life-threatening by the investigator.

10. Pregnant and lactating women will not be eligible; women of childbearing potential
should have a negative pregnancy test prior to entering on the study and be willing to
practice methods of contraception. Women do not have childbearing potential if they
have had a hysterectomy or are postmenopausal without menses for 12 months. In
addition, men enrolled on this study should understand the risks to any sexual partner
of childbearing potential and should practice an effective method of birth control.