Inotuzumab Ozogamicin and Blinatumomab in Treating Patients With Newly Diagnosed, Recurrent, or Refractory CD22-Positive B-Lineage Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To confirm tolerability of the combination regimen of inotuzumab ozogamicin followed by
blinatumomab.

II. To estimate the 1-year event-free survival of older, transplant-ineligible patients with
newly diagnosed, Philadelphia (Ph)-negative, CD22-positive, B-cell acute lymphoblastic
leukemia (ALL) treated with inotuzumab ozogamicin induction followed by blinatumomab
consolidation. (Cohort 1) III. To estimate the 1-year event-free survival of patients with
relapsed or refractory Ph-negative, CD22-positive, B-cell ALL treated with inotuzumab
ozogamicin induction followed by blinatumomab consolidation. (Cohort 2)

SECONDARY OBJECTIVES:

I. To estimate the median, 1-year, and 3-year overall survival (OS) in all eligible patients.
(Cohort 1) II. To estimate the median, 1-year, and 3-year relapse-free survival (RFS) in all
eligible patients. (Cohort 1) III. To estimate the median and 3-year event-free survival
(EFS) in all eligible patients. (Cohort 1) IV. To estimate the complete response (CR) rate
and overall response rate (ORR, defined as complete response [CR] + complete response with
incomplete count recovery [CRi]) to inotuzumab ozogamicin followed by blinatumomab (regimen
CR rate and ORR). (Cohort 1) V. To estimate the CR rate and ORR (CR + CRi) to inotuzumab
ozogamicin induction alone (induction CR and ORR). (Cohort 1) VI. To estimate the minimal
residual disease (MRD) negativity rate in subjects achieving a CR or CRi. (Cohort 1) VII. To
estimate the treatment-related mortality with this regimen. (Cohort 1) VIII. To describe the
safety and tolerability of this regimen. (Cohort 1) IX. To estimate the median, 1-year, and
3-year OS in all eligible patients. (Cohort 2) X. To estimate the median, 1-year, and 3-year
RFS in all eligible patients. (Cohort 2) XI. To estimate the median and 3-year EFS in all
eligible patients. (Cohort 2) XII. To estimate ORR (CR/CRi and CR/complete response with
partial hematologic recovery [CRh]) to blinatumomab in patients with ALL refractory to
inotuzumab ozogamicin. (Cohort 2) XIII. To estimate the CR, CRi, and CRh rates at defined
time points and cumulatively for the entire regimen. (Cohort 2) XIV. To determine the MRD
negativity (< 10^-4) rate at defined time points including prior to allogeneic HCT and
cumulatively in patients achieving a CR, CRh, or CRi. (Cohort 2) XV. To determine the
allogeneic hematopoietic cell transplantation (HCT) rate in eligible subjects. (Cohort 2)
XVI. To estimate the treatment-related mortality with this regimen. (Cohort 2) XVII. To
describe the safety and tolerability of this regimen. (Cohort 2)

OTHER OBJECTIVES:

I. Results of the primary analysis will be examined for consistency, while accounting for the
stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

CORRELATIVE SCIENCE OBJECTIVES:

I. To correlate specific karyotype groups (normal or various primary and secondary
chromosomal abnormalities) with clinical and laboratory parameters.

II. To correlate specific karyotype groups with response rates, response duration, survival,
and cure in patients treated with inotuzumab ozogamicin followed by blinatumomab.

III. To correlate specific karyotype groups with MRD. IV. To determine karyotype changes at
relapse and the influence of the type of change (or no change) in karyotype at relapse.

V. To assess the correlation of quantitative MRD post-induction with inotuzumab ozogamicin
and at sequential consolidation time points with blinatumomab with RFS, EFS, and OS.

VI. To correlate the influence of MRD status (detectable versus [vs.] not and as a continuous
measure) in relation to EFS, RFS, and OS with other clinical and biological factors (e.g.
previously untreated vs. relapsed disease cohorts; age, initial white blood cell [WBC] count,
cytogenetics).

VII. To identify genetic variants and predictors of ex vivo resistance. VIII. To identify
genetic variants and predictors of MRD. IX. To identify genetic variants and predictors of
relapse. X. To determine inter-patient variability in drug sensitivity of adult ALL. XI. To
examine the associations of drug sensitivity with host and leukemia molecular features.

EXPLORATORY OBJECTIVES:

I. To estimate the median, 1-year, and 3-year RFS, EFS, and OS in patients achieving a CR/CRi
to inotuzumab ozogamicin. (Cohort 1) II. To compare the median, 1-year, and 3-year RFS, EFS,
and OS among patients achieving MRD-negative vs. MRD-positive CR/CRi to inotuzumab
ozogamicin. (Cohort 1) III. To compare the median, 1-year, and 3-year RFS, EFS, and OS among
patients achieving MRD-negative vs. MRD-positive CR/CRi at any time. (Cohort 1) IV. To
describe the rate, severity, and timing of sinusoidal obstruction syndrome/veno-occlusive
disease (SOS/VOD) of the liver after limited inotuzumab ozogamicin exposure and identify risk
factors for SOS/VOD. (Cohort 1) V. To estimate the rate of cytokine release syndrome in this
population. (Cohort 1) VI. To estimate the median, 1-year, and 3-year RFS from time of CR/CRi
to inotuzumab ozogamicin in patients receiving inotuzumab ozogamicin followed by blinatumomab
and not undergoing allogeneic hematopoietic cell transplantation (HCT). (Cohort 2) VII. To
estimate median, 1-year, and 3-year OS after CR/CRi to inotuzumab ozogamicin in patients not
undergoing allogeneic HCT. (Cohort 2) VIII. To compare in a non-randomized fashion median,
1-year, and 3-year OS, median, 1-year, and 3-year RFS, cumulative incidence of relapse (CIR),
and non-relapse mortality (NRM) between patients achieving CR/CRi and receiving consolidation
with or without allogeneic HCT. (Cohort 2) IX. To describe the rate, severity, and timing of
sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) of the liver after limited
inotuzumab ozogamicin exposure and identify risk factors for SOS/VOD. (Cohort 2) X. To
estimate the rate of cytokine release syndrome in this population. (Cohort 2)

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT 1: Patients receive inotuzumab ozogamicin intravenously (IV) over 1 hour on day 1, 8,
and 15 (Course IA). By the end of Course IA (day 21), patients with adequate ALL
cytoreduction continue to Course IB/IC, and patients who fail to achieve ALL cytoreduction
continue to Course II. By the end of Course II, patients with CR-CRi to Course IB/IC and
Course II continue to Course IIIA, patients without adequate ALL cytoreduction to Course IA
or refractory to Course IB/IC but CR/CRi to Course II continue to Course IIIB.

COHORT 2: Patients receive inotuzumab ozogamicin IV over 1 hour on day 1, 8, and 15 (Course
IA). By the end of Course IA (day 21), patients with adequate ALL cytoreduction continue to
Course IB/IC, and patients who fail to achieve ALL cytoreduction continue to Course II.
Patients with CR/CRi at the end of Course II continue to Course IIIB.

COURSE IB/IC: Patients receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15.
Treatment continues for 1 course (28 days) in the absence of disease progression or
unacceptable toxicity.

COURSE II: Patients receive blinatumomab IV continuously on days 1-28 and 43-70. Treatment
continues for 1 course (84 days) in the absence of disease progression or unacceptable
toxicity.

COURSE IIIA: Patients receive blinatumomab IV continuously on days 1-28 and 43-70. Treatment
continues for 1 course (84 days) in the absence of disease progression or unacceptable
toxicity.

COURSE IIIB: Patients receive blinatumomab IV continuously on days 1-28, 43-70, and 85-112.
Treatment continues for 1 course (126 days) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years, and
then every 6 months for up to 10 years.

Inclusion Criteria:

- Pre-registration Eligibility Criteria (Step 0)

- Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory
prior to registration; the bone marrow sample should be from the first aspiration
(i.e. first pull). Aspirate needle should be redirected if needed to get first pull
bone marrow aspirate. It should be initiated as soon as possible after
pre-registration. The specimens should be sent to the HEME Biobank.

- Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate:

- Patients may receive the day 1 of course IA dose of intrathecal (IT)
methotrexate during the prior-to-registration lumbar puncture (or the venous
line placement) to avoid a second lumbar puncture. If the dose is
administered prior to registration, then systemic chemotherapy must begin
within 7 days of this IT chemotherapy.

- Registration Eligibility Criteria (Step 1)

- Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on
World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are
not eligible.

- CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local
hematopathology evaluation.

- Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ
hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive
for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible.

- No active central nervous system (CNS) leukemia (i.e. only CNS-1 disease allowed).
Active CNS leukemia is defined as morphologic evidence of lymphoblasts in the
cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease
within 28 days prior to registration, symptomatic CNS leukemia (i.e. cranial nerve
palsies or other significant neurological dysfunction) within the 28 days prior to
registration, and/or known asymptomatic parenchymal CNS mass lesions; see below for
additional guidance. Prophylactic intrathecal medication alone is not an exclusion.

- Categories of CNS Involvement for CNS Evaluation Prior to Registration:

- CNS 1: CSF has < 5 WBC/uL with cytospin negative for blasts; or >= 10 red
blood cell (RBC)/uL with cytospin negative for blasts.

- CNS 2: CSF has < 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL
with cytospin positive for blasts; or >= 10 RBC/uL, WBC/uL >= 5 but less
than Steinherz/Bleyer algorithm with cytospin positive for blasts (see
below).

- CNS 3: CSF has >= 5 WBC/uL with cytospin positive for blasts; or >= 10
RBC/uL, >= 5 WBC/uL and positive by Steinherz/Bleyer algorithm (see below);
or clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye
involvement or hypothalamic syndrome). Steinherz/Bleyer Method of Evaluating
Initial Traumatic Lumbar Punctures:

- If the patient has leukemia cells in the peripheral blood and the
lumbar puncture is traumatic and contains >= 5 WBC/uL with blasts, the
following algorithm should be used to define CNS disease: CSF WBC/CSF
RBC > 2 x (Blood WBC/Blood RBC count)

- Patients with known or suspected testicular involvement by leukemia are allowed
provided that the patient receives concomitant scrotal/testicular radiotherapy.

- Unilateral or bilateral testicular enlargement should be assessed by ultrasound
or other imaging technique. Biopsy is recommended if clinical findings are
equivocal or suggestive of hydrocele or a non-leukemic mass, but further
assessments are per treating physician discretion.

- Not pregnant and not nursing.

- This study involves agents that have known genotoxic, mutagenic, and teratogenic
effects. Therefore, for women of childbearing potential only, a negative
pregnancy test done =< 7 days prior to registration is required.

- Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

- No unstable cardiac disease such as myocardial infarction, angina pectoris,
uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of
registration.

- No impaired cardiac function, defined as left ventricular ejection fraction (LVEF) <
45% or New York Heart Association (NYHA) stage III or IV congestive heart failure
(CHF).

- Patients with known human immunodeficiency virus (HIV) infection are eligible if they
have been on effective antiretroviral therapy with an undetectable viral load tested
within 6 months of registration.

- Patients with hepatitis B virus (HBV) are eligible only if they meet all the
following:

- On HBV-suppressive therapy.

- No evidence of active virus.

- No evidence of HBV-related liver damage.

- Patients with hepatitis C virus (HCV) are eligible only if they meet all the
following:

- Successfully completed complete-eradication therapy with undetectable viral load.

- No evidence of HCV-related liver damage.

- No history of clinically relevant neurologic disorder such as epilepsy, seizure,
aphasia, stroke, severe brain injury, structural brain abnormality, benign brain
tumor, dementia, Parkinson's disease, movement disorder, cerebellar disease, or other
significant CNS abnormalities.

- No prior additional malignancy (i.e. in addition to ALL) except adequately treated
basal- or squamous-cell skin cancer, in situ cervical cancer, stage I or II cancer
from which the patient is currently in complete remission, or any other cancer from
which the patient has been disease-free for >= 2 years.

- No history of clinically significant ventricular arrhythmia, unexplained non-vasovagal
syncope, or chronic bradycardic states such as sinoatrial block or higher degree of
atrioventricular block unless a permanent pacemaker has been implanted.

- No history of chronic liver disease, including cirrhosis.

- No history of sinusoidal occlusion syndrome/veno-occlusive disease of the liver.

- No uncontrolled infection or recent history (within 4 months prior to registration) of
deep tissue infections such as fasciitis or osteomyelitis.

- Total bilirubin, serum =< 1.5 x upper limit of normal (ULN)*

- Except in the event of: 1) Gilbert disease, in which case total bilirubin must be
=< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to
leukemic infiltration, in which case total bilirubin must be =< 2 x ULN.

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

- Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min

- QT interval by Fridericia's correction formula (QTcF) =< 470 msec

- Cohort 1 Patients Only

- Age >= 60 years.

- No prior treatment for ALL except a single dose of intrathecal chemotherapy,
corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count
and prevent ALL complications. Allowed therapy may be administered for no more than 14
days and must be completed >= 24 hours prior to the initiation of protocol therapy.

- No plan for allogeneic or autologous hematopoietic cell transplantation (HCT).

- Cohort 2 Patients Only:

- Age >= 18 years.

- Relapsed or refractory disease in salvage 1 or 2.

- No isolated extramedullary relapse.

- Prior allogeneic HCT permitted.

- Patients with prior allogeneic HCT must have completed transplantation >= 4 months
prior to registration.

- Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease
and must have completed immunosuppressive therapy >= 30 days prior to registration.

- Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy,
or other CD19-directed therapy is not allowed.

- Prior treatment with rituximab must be completed >= 7 days prior to registration.

- Prior treatment with other monoclonal antibodies must be completed >= 6 weeks prior to
registration.

- Prior treatment for ALL must be completed >= 14 days prior to registration with the
following exceptions: intrathecal chemotherapy, hydroxyurea, corticosteroids,
6-mercaptopurine, methotrexate, vincristine, and/or leukapheresis to reduce
circulating absolute lymphoblast count to =< 10,000/uL or prevent complications
related to ALL are allowed but must be completed >= 24 hours prior to the initiation
of protocol therapy.

- Patients should have resolution of any acute non-hematologic toxicities of prior
therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) version (v)5.0 grade =< 1.

- Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment allowed as above
to reduce blast count to =< 10,000/uL)