Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine the morphologic response rate (complete response [CR] + complete response
with incomplete hematologic recovery [CRi]) following one cycle of treatment with inotuzumab
ozogamicin (InO) in children with relapsed or refractory CD22+ B acute lymphoblastic leukemia
(B-ALL).

SECONDARY OBJECTIVES:

I. To determine the CR/CRi rate following 2 cycles of InO therapy. II. To determine the
safety of single agent InO administered at the adult recommended phase 2 dose (RP2D) to
pediatric patients with relapsed or refractory CD22+ B-ALL.

III. To determine the level of minimal residual disease (MRD) by flow cytometry in responding
patients.

IV. To determine the incidence, severity, and outcomes of sinusoidal obstruction syndrome
(SOS) of the liver in patients during InO therapy and following subsequent treatment,
including myeloablative hematopoietic stem cell transplantation (HSCT).

V. To estimate the 3-year event-free survival (EFS), 3-year overall survival (OS), and among
responders duration of CR/CRi for pediatric patients with relapsed or refractory B-ALL
treated with InO.

VI. To describe InO pharmacokinetics and immunogenicity in pediatric patients in the presence
of overt leukemia and in remission.

EXPLORATORY OBJECTIVES:

I. To describe the levels of leukemic blast CD22 surface expression and site density, and to
explore the correlation with cytogenetics and clinical outcomes after treatment with InO.

II. To explore potential mechanisms of resistance to InO therapy including CD22 splice
variants and intracellular signaling pathways.

III. To explore the impact of InO on humoral immune function and peripheral B cell
populations.

IV. To describe the level of MRD by next-generation high-throughput sequencing (HTS)
techniques which may detect low level leukemic blast populations that have altered CD22
expression.

V. To prospectively explore candidate SOS biomarkers including the endothelial marker of
inflammation Angiopoietin 2 (Ang2) and the hepatic specific complement marker L-ficolin.

VI. To explore the use of prophylactic ursodeoxycholic acid (UDCA) to prevent hepatic damage
and SOS during InO therapy and subsequent HSCT.

OUTLINE:

Patients receive inotuzumab ozogamicin intravenously (IV) over 60 minutes on days 1, 8, and
15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for
1 year, and then yearly for 4 years.

Inclusion Criteria:

- Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL),
with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease

- NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL)
are eligible if they have an M2 or M3 marrow at the time of enrollment on this
study

- Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing
showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH)
testing or other molecular method

- Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by
local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of
CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended)

- In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate
is unable to be performed due to patient clinical status, flow cytometry of
peripheral blood specimen may be substituted if the patient has at least 1000/uL
circulating blasts; alternatively, CD22 expression may be documented by
immunohistochemistry of a bone marrow biopsy specimen

- Patients with and without Down syndrome are eligible and must have one of the
following:

- Second or greater relapse;

- Primary refractory disease with at least 2 prior induction attempts;

- First relapse refractory to at least one prior re-induction attempt

- Any relapse after HSCT

Patients with Down syndrome are also eligible with:

- First relapse with no prior re-induction attempt

- Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy
attempts including two different tyrosine kinase inhibitors (TKIs)

- Patients must have fully recovered from the acute non-hematologic toxic effects
of all prior anti-cancer therapy, defined as resolution of all such toxicities to
=< grade 2 or lower per the inclusion/exclusion criteria prior to entering this
study

- Myelosuppressive chemotherapy:

- No waiting period will be required for patients receiving standard
"maintenance-like" chemotherapy including oral mercaptopurine, weekly low-dose
oral methotrexate, and intermittent vincristine; otherwise, at least 14 days must
have elapsed since the completion of cytotoxic therapy, with the exceptions of
hydroxyurea or corticosteroids used for cytoreduction

- Intrathecal cytotoxic therapy: No waiting period is required for patients having
received intrathecal cytarabine, methotrexate, and/or hydrocortisone; intrathecal
chemotherapy given at the time of diagnostic lumbar puncture (LP) to evaluate for
relapse prior to study enrollment is allowed

- At least 7 days must have elapsed since the completion of therapy with a growth
factor; at least 14 days must have elapsed after receiving pegfilgrastim

- At least 7 days must have elapsed since completion of therapy with a biologic agent
(including tyrosine kinase inhibitors); for agents that have known adverse events
occurring beyond 7 days after administration, this period prior to enrollment must be
extended beyond the time during which adverse events are known to occur

- At least 3 half-lives must have elapsed since prior therapy that included a monoclonal
antibody with the exception of blinatumomab; patients must have been off blinatumomab
infusion for at least 3 days and all drug related toxicity must have resolved to grade
2 or lower as outlined in the inclusion/exclusion criteria

- >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small
port); >= 3 months must have elapsed if prior cranial or craniospinal XRT was
received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI)
was received; >= 6 weeks must have elapsed if other substantial bone marrow
irradiation was given

- At least 90 days must have elapsed since stem cell transplant and at least 30 days
from donor lymphocyte infusion; patient must have had no more than one previous HSCT
and currently have no evidence of active graft versus (vs.) host disease (GVHD)

- At least 30 days must have elapsed from the last chimeric antigen receptor (CAR)-T
cell infusion

- Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years
of age and Lansky for patients =< 16 years of age; patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or

- A serum creatinine based on age/gender as follows:

- 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)

- 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)

- 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)

- 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)

- 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)

- Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5
x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L

Exclusion Criteria:

- Patients with any prior history of SOS irrespective of severity

- Patients with isolated central nervous system (CNS), testicular, or other
extramedullary site of relapse

- Patients who have been previously treated with inotuzumab ozogamicin

- History of allergic reaction attributed to compounds of similar or biologic
composition to inotuzumab ozogamicin or other agents in the study

- Patients with active optic nerve and/or retinal involvement are not eligible; patients
who are presenting with visual disturbances should have an ophthalmologic exam and, if
indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal
involvement

- Patients who are currently receiving another investigational drug

- Patients who are currently receiving or plan to receive other anti-cancer agents
(except hydroxyurea, which may be continued until 24 hours prior to start of protocol
therapy and intrathecal chemotherapy)

- Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are
receiving cyclosporine, tacrolimus, or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection
post-transplant are not eligible for this trial; at least 3 half-lives must have
elapsed after the last dose of GVHD medications (meds)

- Patients who are currently receiving or plan to receive corticosteroids except as
described below

- Systemic corticosteroids may be administered for cytoreduction up to 24 hours
prior to the start of protocol therapy, as a premedication for InO and as
treatment for allergic reactions or for physiologic replacement/stress dosing of
hydrocortisone for documented adrenal insufficiency; corticosteroids are not
allowed for other indications

- Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections;
testing to prove negative status is not required for enrollment unless it is deemed
necessary for usual medical care of the patient

- Patients who have an active uncontrolled infection defined as:

- Positive bacterial blood culture within 48 hours of study enrollment;

- Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with
clinical signs of infection; fever that is determined to be due to tumor burden
is allowed if patients have documented negative blood cultures for at least 48
hours prior to enrollment and no concurrent signs or symptoms of active infection
or hemodynamic instability

- A positive fungal culture within 30 days of study enrollment or active therapy
for presumed invasive fungal infection

- Patients may be receiving IV or oral antibiotics to complete a course of therapy
for a prior documented infection as long as cultures have been negative for at
least 48 hours and signs or symptoms of active infection have resolved; for
patients with clostridium (c.) difficile diarrhea, at least 72 hours of
antibacterial therapy must have elapsed and stools must have normalized to
baseline

- Active viral or protozoal infection requiring IV treatment

- Patients known to have one of the following concomitant genetic syndromes: Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman
syndrome, or any other known bone marrow failure syndrome

- Women of childbearing potential should be advised to avoid becoming pregnant while
receiving InO; women should not breast-feed during treatment with InO and for at least
2 months after the final dose

- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained within 7 days of starting protocol
therapy

- Female patients who are sexually active and of reproductive potential are not
eligible unless they agree to use an effective contraceptive method for the
duration of their study participation and for 8 months after the last dose of InO

- Men with female partners of childbearing potential should use effective
contraception during treatment with InO and for at least 5 months after the last
dose of InO

- Lactating females are not eligible unless they agree not to breastfeed their
infants