A Phase 2 Study of Inotuzumab Ozogamicin in Children and Young Adults with Relapsed or Refractory CD22+ B-Acute Lymphoblastic Leukemia (B-ALL).

Inclusion Criteria

- Patients must be >= 1 year and < 22 years of age at the time of enrollment

- 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 1,000/uL

circulating blasts; alternatively, CD22 expression may be documented by

immunohistochemistry of a bone marrow biopsy specimen

- Patients with 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 (Cohort 1 ONLY)

Patients with Down syndrome are eligible ONLY for Cohort 1 with:

- Any of above disease status, OR

- First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or

prior HSCT are NOT eligible for Cohort 2 combination therapy

- 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 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. Apply

to Cohort 2:

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. For

agents not listed, the duration of this interval must be discussed with the study

chair and the study-assigned Research Coordinator prior to enrollment.

- A waiting period prior to enrollment is not required for patients receiving

standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine,

6MP, and/or methotrexate).

- A waiting period is not required for patients receiving a single dose of

intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior

to enrollment

- >= 14 days must have elapsed after the completion of other cytotoxic therapy,

with the exception of hydroxyurea, for patients not receiving standard

maintenance therapy. For patients who previously received calaspargase pegol, >=

21 days must have elapsed after the last dose. Additionally, patients must have

fully recovered from all acute toxic effects of prior therapy.

- Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior

to the start of protocol therapy.

- Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced

platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of

agent. For agents not listed, the duration of this interval must be discussed with the

study chair and the study-assigned research coordinator prior to enrollment.

- Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of

last dose of antibody, and toxicity related to prior antibody therapy must be

recovered to grade =< 1. There is an exception for blinatumomab infusions, for which

patients must have been off 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.

- Corticosteroids: If used to modify immune adverse events related to prior therapy, >=

14 days must have elapsed since last dose of corticosteroid. A waiting period prior to

enrollment is not required for patients receiving corticosteroid for leukemia

therapy/cytoreduction.

- Radiotherapy: >= 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.

- Stem cell transplant or rescue without TBI: For Cohort 1, 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 vs. host disease (GVHD). For Cohort 2, no prior HSCT is

allowed.

- Chimeric antigen receptor (CAR) T cell therapy: At least 30 days must have elapsed

from the last 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 any other

extramedullary site of relapse

- Patients who have been previously treated with inotuzumab ozogamicin

- Patients who have previously received HSCT (Cohort 2 only)

- Patients with Down syndrome (Cohort 2 only)

- History of allergic reaction attributed to compounds of similar or biologic

composition to inotuzumab ozogamicin or other agents in the study

- Note: Patients with history of allergy to pegaspargase/calaspargase pegol are

eligible for enrollment on Cohort 2 if Erwinia formulation of asparaginase can be

obtained

- 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 or anti-rejection medications

- 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, (Cohort 1 only) for all patients,

corticosteroids may be administered as a premedication for inotuzumab ozogamicin

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, Schwachman

(Schwachman-Diamond-Blackfan) syndrome or any other known bone marrow failure syndrome

- There have been no human studies of inotuzumab ozogamicin in pregnant women and no

reports of exposure in utero; based on nonclinical safety studies, inotuzumab

ozogamicin has the potential to impair human male and female fertility and to

adversely affect human embryo fetal development; women of childbearing potential

should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin;

there is no information regarding the presence of inotuzumab ozogamicin in human milk,

the effects on the breast-fed infant, or the effects on milk production; because of

the potential for adverse reactions in breast-fed infants, women should not

breast-feed during treatment with inotuzumab ozogamicin 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 prior to enrollment

- 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

inotuzumab ozogamicin

- Men with female partners of childbearing potential should use effective

contraception during treatment with inotuzumab ozogamicin and for at least 5

months after the last dose of inotuzumab ozogamicin

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

infants