Hyper-CVAD in Combination With Inotuzumab Ozogamicin as Frontline Therapy for Adults With Acute Lymphocytic Leukemia

Study Drug Administration Each cycle is 21 days (+/- 7 days).

Intensive Chemotherapy (Cycles 1 and 3):

If you are found to be eligible to take part in this study, you will receive hyper-CVAD
during Cycles 1 and 3 as follows:

- On Days 1-3, you will receive cyclophosphamide by vein over 3 hours every 12 hours, for
a total of 6 doses per cycle.

- On Days 1-3, you will receive mesna as a non-stop infusion starting about 1 hour before
the cyclophosphamide infusion and ending about 12 hours after the last dose of
cyclophosphamide.

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

- The doctor will decide if you will receive ofatumumab or rituximab. If you receive
ofatumumab, you will receive it by vein over about 2 hours (or longer if the doctor
thinks it is needed) on Days 1, 2, and 11 of Cycle 1 and Days 1 and 11 of Cycle 3. If
you receive rituximab, you will receive it by vein over about 2 hours (or longer if the
doctor thinks it is needed) on Days 1 and 11 of Cycles 1 and 3.

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

- On Day 4, you will receive doxorubicin by vein over 24 hours through a central venous
catheter. 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 4 and 11, you will receive vincristine by vein over 1 hour.

- On Day 7, you will receive cytarabine intrathecally.

- After you complete chemotherapy, you will either receive pegfilgrastim as a one-time
dose or filgrastim (G-CSF) as an injection under the skin every day until your white
blood cell counts recover.

You will receive methotrexate and cytarabine during Cycles 2 and 4 as follows:

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

- On Days 2 and 3, you will receive cytarabine over 2 hours by vein every 12 hours, for a
total of 4 doses per cycle.

- Starting on Day 2, you will receive leucovorin by vein 4 times a day for 8 doses per
cycle.

- On Days 1 and 8, you will receive ofatumumab by vein over about 2 hours (or longer if
the doctor thinks it is needed) or rituximab by vein over about 2 hours (or longer if
the doctor thinks it is needed).

- On Day 5, you will receive cytarabine intrathecally.

- On Day 8, you will receive methotrexate intrathecally.

- After you complete chemotherapy, you will either receive pegfilgrastim as a one-time
dose or filgrastim as an injection under the skin every day until your white blood cell
counts recover.

During Cycles 5-8: you will receive inotuzumab ozogamicin by vein over about 1 hour on Days 1
and Day 8 of each cycle.

Maintenance Therapy:

Each cycle is 28 days.

For Cycles 9-20 (12 cycles), you will receive the following drugs:

- Three (3) times a day, you will take mercaptopurine tablets by mouth.

- One (1) time a week, you will take methotrexate tablets by mouth.

- On Day 1 of each cycle, you will receive vincristine by vein over about 1 hour.

- On Days 1-5 of each cycle, you will take prednisone tablets by mouth.

Other Drugs:

If your doctor thinks it is needed, you may also receive drugs through a spinal tap to help
lower the risk of the disease coming back in the fluid surrounding your brain.

You may also be given other drugs to help lower the risk of other side effects (for example,
you may receive allopurinol, ursodiol, or rasburicase). Your doctor will tell you about these
drugs, how they will be given, and the possible risks.

Length of Treatment:

You may receive up to 20 cycles of study drugs. You will no longer be able to receive the
study drugs if the disease gets worse, if intolerable side effects occur, if you are unable
to follow study directions, or if you receive stem cell transplant therapy.

Your participation on the study will be over after the follow-up bone marrow
aspirations/biopsies or after the end of the Maintenance Therapy.

Study Visits:

Prior to each cycle, you will have a physical exam.

Once a week during Cycles 1-4, blood (about 2-3 tablespoons) will be drawn for routine tests.

If the doctor thinks it is needed, you will have a bone marrow aspiration and biopsy on the
following schedule:

- Day 14 of Cycle 1, then 1 time a week for as long as the doctor thinks is needed based
on the disease status

- 3 chemotherapy cycles after a complete response in the disease and/or before you start
inotuzumab ozogamicin

- Day 21 of Cycle 5, then after every cycle (exact schedule will depend on the disease
status at the start of inotuzumab ozogamicin), then every 4 months after that. The study
staff will let you know when the every 4 month follow-up procedures will stop, and it
will be based on the disease status.

Every 4 weeks during Cycles 9-20, blood (about 2-3 tablespoons) will be drawn for routine
tests.

At any time, if your doctor thinks it is needed, you will have a CT scan, a PET scan, and/or
a chest x-ray to check the status of the disease.

Follow-up:

Thirty (30) days after you have received your last dose of the inotuzumab ozogamicin, you
will be called by a member of the study team and asked how you are feeling and about any
other drugs or treatments you are receiving. The phone call should last about 10 minutes.

Long-term Follow-up:

After you have received your last dose of study drugs, you will be called by a member of the
study team every 6 months. You will be asked how you are feeling and about any other drugs or
treatments you are receiving. The phone call should last about 10 minutes.

Inclusion Criteria:

1. Patients at least 16 years of age with newly diagnosed, previously untreated B-lineage
ALL, or having achieved CR with one course of induction chemotherapy.

2. Patients with extramedullary disease only are eligible

3. Failure to one induction course of chemotherapy (these patients will be analyzed
separately).

4. Performance status of 0-3.

5. Adequate organ function with creatinine less than or equal to 2.0 mg/dL (unless
considered tumor related), bilirubin less than or equal to 2.0 mg/dL (unless
considered tumor related).

6. Adequate cardiac function as assessed by history and physical examination.

7. No active or co-existing malignancy with life expectancy less than 12 months.

8. 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. Pregnant or nursing women

2. Known to be HIV-positive

3. Ph-positive ALL

4. Active and uncontrolled disease/infection as judged by the treating physician

5. Unable or unwilling to sign the consent form

6. Subjects who have current active hepatic or biliary disease (with exception of
patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement or stable
chronic liver disease per investigator assessment)

7. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or
antiviral treatment such as, but not limited to, chronic renal infection, chronic
chest infection with bronchiectasis, tuberculosis and active Hepatitis C.