Inotuzumab Ozogamicin and Vincristine Sulfate Liposome in Treating Patients With Relapsed or Refractory CD22+ B-cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of vincristine sulfate liposome (liposomal
vincristine) and inotuzumab ozogamicin combination therapy in adult patients with relapsed
and/or refractory B lineage acute lymphoblastic leukemia (B-ALL).

II. To evaluate the overall response rate (ORR consisting of complete remission [CR],
morphologic CR with incomplete blood count recovery [CRi], partial remission [PR],
hematological improvement [HI]) of combination therapy with liposomal vincristine and
inotuzumab ozogamicin in adult patients with relapsed and/or refractory B lineage acute
lymphoblastic leukemia.

SECONDARY OBJECTIVES:

I. To evaluate the leukemia-free survival (LFS) and overall survival (OS) of patients treated
with this combination.

II. To evaluate the number of patients able to proceed onto subsequent hematopoietic stem
cell transplantation (HSCT) following combination therapy following combination therapy.

III. To evaluate the overall incidence of unique toxicities associated with these agents,
specifically peripheral neuropathy following vincristine sulfate liposome and veno-occlusive
disease of the liver (VOD) following inotuzumab ozogamicin therapy.

EXPLORATORY OBJECTIVES:

I. To explore minimal residual disease (MRD) as a potential correlative biomarker of response
to combination vincristine sulfate liposome and inotuzumab ozogamicin therapy.

II. To explore potential biomarkers of response to vincristine sulfate liposome and
inotuzumab ozogamicin therapy.

III. To perform an analysis of the estimated cost of outpatient administration of vincristine
sulfate liposome and inotuzumab ozogamicin.

IV. To evaluate quality of life (QOL) of patients with relapsed/refractory B-ALL treated with
vincristine sulfate liposome and inotuzumab ozogamicin.

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

INDUCTION/RE-INDUCTION: Patients receive vincristine sulfate liposome intravenously (IV) over
1 hour and inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Treatment repeats every
28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
Patients who achieve clinical benefit, defined as stable disease (SD), PR or CR, or CRi after
1-2 cycles, will continue on to maintenance therapy for up to 4-5 cycles. Patients who do not
achieve clinical benefit after cycle 1 but do not experience dose-limiting toxicities (DLTs)
receive a second cycle of vincristine sulfate liposome and inotuzumab ozogamicin.

MAINTENANCE: Patients receive vincristine sulfate liposome IV over 1 hour on days 1 and 15
and inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28
days for up to 4-5 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months for up to 12 months.

Inclusion Criteria:

- Eastern Cooperative Oncology Group performance status between 0-2

- Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine
clearance (Cockcroft and Gault) > 30 mL/min

- Alanine aminotransferase (ALT) =< 5 x ULN

- Direct bilirubin < 2.0 mg/dL

- Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO)
or multiple-gated acquisition (MUGA) scan performed within 28 days of enrollment

- Diagnosis of relapsed/refractory CD22+ B-cell ALL with disease in the bone marrow
and/or peripheral blood by morphology (>=5% blasts). CD22-positive B-ALL is defined as
expression by at least 20% of malignant lymphoblasts as determined by local flow
cytometry and/or immunohistochemistry from a peripheral blood and/or bone marrow
sample obtained within 2 weeks of screening

- Relapsed or refractory disease, defined as first or greater bone marrow relapse from
CR or overall response, specifically:

- Any bone marrow relapse after allogeneic HSCT: subjects must be at least 1 month
from HSCT at the time of screening and off immunosuppressive medication for at
least 2 weeks at time of initial treatment (with the exception of low-dose
steroids =< 20 mg prednisone equivalent) and have no active graft versus (vs.)
host disease (GVHD);

- Philadelphia chromosome (Ph) negative B-ALL which has not achieved CR or CRi
after at least 1 attempt at remission induction using standard intensive
chemotherapy regimen(s);

- Philadelphia chromosome (Ph) positive B-cell ALL intolerant to or ineligible for
BCR-ABL tyrosine kinase inhibitor (TKI) therapy or with disease which has
progressed after at least two lines of prior TKI therapy

- Participants of childbearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Receipt of chemotherapy, radiotherapy, or investigational drug therapy within 2 weeks
prior to treatment on study or those who have not recovered from adverse events due to
agents administered > 2 weeks earlier

- Active central nervous system involvement; patients who have a history of central
nervous system (CNS) disease which has been effectively treated (as defined by at
least one negative cerebrospinal sample prior to screening) are eligible

- Prior malignancy, unless treated with curative intent and with no evidence of active
disease present for > 5 years before screening, with the following exceptions:

- Subjects with stage I breast cancer that has been completely and successfully
treated, requiring no therapy or only anti-hormonal therapy

- Subjects with T1N0M0 or T2N0M0 colorectal cancer who have been completely and
successfully resected and who are disease-free for > 2 years prior to screening

- Subjects with indolent prostate cancer, defined as clinical stage T1 or T2a,
Gleason score =< 6, and prostate-specific antigen (PSA) < 10 ng/mL, requiring no
therapy or only anti-hormonal therapy

- Subjects with a history of basal cell or squamous cell carcinoma of the skin, or
carcinoma in situ of the cervix, fully resected, and with no evidence of active
disease

- Uncontrolled intercurrent medical illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that in the opinion of the investigator would limit
compliance with study requirements

- Uncontrolled systemic fungal, bacterial, viral, or other infection defined as
exhibiting ongoing signs and symptoms due to infection despite appropriate
anti-infective therapy at time of screening

- Pregnant or nursing female participants

- Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV)
infection at the time of screening

- Presence of grade II-IV acute or extensive chronic graft versus host disease (GVHD) at
time of screening

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug including, but not limited to, medical, psychological,
familial, social, or geographical considerations