Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Older Patients With Previously Untreated Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of inotuzumab ozogamicin in combination with
low-intensity chemotherapy in elderly patients (age 60 or older) with acute lymphoblastic
leukemia (ALL). (Phase I) II. Evaluate the efficacy of inotuzumab ozogamicin in combination
with low-intensity chemotherapy in elderly patients with ALL. (Phase II) III. To evaluate the
side effects of the treatment. (Phase II) IV. Evaluate the regimen efficacy in
refractory-relapsed ALL. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of inotuzumab ozogamicin followed by a
phase II study.

COURSES 1, 3, 7, AND 9: Patients receive cyclophosphamide intravenously (IV) over
approximately 3 hours twice daily (BID) on days 1-3; vincristine sulfate IV over 30 minutes
on days 1 and 8; inotuzumab ozogamicin IV over approximately 1 hour on day 3 of course 1 and
day 2 or 3 of course 3; methotrexate intrathecally (IT) on day 2 of courses 1 and 3; and
cytarabine IT on day 8 of courses 1 and 3. Patients may also receive rituximab IV on days 1
and 8 of courses 1 and 3. Courses alternate every 3-4 weeks in the absence of disease
progression or unacceptable toxicity.

COURSES 2, 4, 8, AND 10: Patients receive methotrexate IV over approximately 2 hours and then
continuously over approximately 22 hours on day 1; cytarabine IV over approximately 3 hours
BID on days 2-3; inotuzumab ozogamicin IV over approximately 1 hour on day 2 or 3 of courses
2 and 4; cytarabine IT on day 5 of courses 2 and 4; and methotrexate IT on day 8 of courses 2
and 4. Patients may also receive rituximab IV on days 1 and 8 of courses 2 and 4. Courses
alternate every 3-4 weeks in the absence of disease progression or unacceptable toxicity.

COURSES 5, 6, 11, AND 12: Patients receive blinatumomab as a continuous intravenous infusion
(CIVI) on days 1-29. Treatment repeats every 42 days for 4 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive mercaptopurine orally (PO) BID and methotrexate PO once
weekly for 3 years. Patients also receive vincristine sulfate IV over 30 minutes once monthly
and prednisone PO daily five times a month for 1 year. Treatment continues in the absence of
disease progression or unacceptable toxicity. Patients who did not receive blinatumomab
during induction and consolidation can receive 4 consecutive courses of blinatumomab as in
courses 5, 6, 11, and 12, at any time during maintenance, after discussion with the principal
investigator and if in the best interest of the patient.

TREATMENT OF MINIMAL RESIDUAL DISEASE (MRD): Patients with MRD may receive additional courses
of inotuzumab ozogamicin IV every 3-4 weeks for up to 6 doses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days

Inclusion Criteria:

- Patients with previously untreated ALL of pre-B, Philadelphia chromosome (Ph-)
negative ALL; minimal prior therapy (less than 1 week of steroids, vincristine, and/or
1 dose of anthracycline or alkylating agents) are allowed

- Zubrod performance status 0-3

- Bilirubin =< 1.95 mg/dL

- Serum glutamate pyruvate transaminase (SGPT) or serum glutamic oxaloacetic
transaminase (SGOT) =< 3 x upper limit of normal (ULN) unless considered due to tumor

- Creatinine =< 2 mg/dL

- Even if organ function abnormalities are considered due to tumor, the upper limit for
bilirubin is =< 2.6 mg/dL and creatinine =< 3 mg/dL

- Provision of written informed consent

- Patients in first remission are eligible

- Patients with refractory-relapsed ALL of any age are eligible, provided they are not
eligible for regimens of higher priority

Exclusion Criteria:

- Ph-positive ALL, Burkitt's leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma

- Patient with active heart disease (New York Heart Association [NYHA] class >= 3 as
assessed by history and physical examination)

- Patients with a cardiac ejection fraction (as measured by either multigated
acquisition scan [MUGA] or echocardiogram) < 40% are excluded

- Patients with active hepatitis are excluded

- Pregnant or breast-feeding women are excluded