Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To confirm tolerability of the combination regimen with the addition of inotuzumab
ozogamicin to the pediatric-inspired regimen of cancer and leukemia group B (CALGB) 10403.

II. To determine whether the addition of inotuzumab ozogamicin significantly improves the
event-free survival (EFS) in patients who achieve an induction response achieved with the
pediatric-inspired regimen of CALGB 10403, without censoring for transplant. (Phase III)

SECONDARY OBJECTIVES:

I. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall
survival (OS) in patients who achieve an induction response.

II. To determine whether the addition of inotuzumab ozogamicin significantly improves the
event-free survival (EFS) in patients who achieve an induction response achieved with the
pediatric-inspired regimen of CALGB 10403, with censoring for transplant.

III. To determine the impact of inotuzumab ozogamicin on minimal residual disease (MRD) and
correlate this with the EFS, DFS and OS.

IV. To determine the prognosis based on patients' low-density array (LDA) gene signature in
terms of EFS, DFS, and OS after treatment with or without inotuzumab ozogamicin when added to
the C10403 backbone regimen.

V. To evaluate the toxicity and tolerability of the addition of inotuzumab ozogamicin to the
pediatric-inspired regimen of CALGB 10403.

TERTIARY OBJECTIVES:

I. To assess both the correlation of MRD post-induction and at sequential timepoints with LDA
signature.

II. To evaluate the influence of MRD status (detectable vs. not and as a continuous measure)
in relation to EFS both in the univariate setting as well as adjusting for other clinical
features including initial white blood cell (WBC), ethnicity, gender and age at diagnosis.

III. To evaluate the impact of inotuzumab ozogamicin (inotuzumab) on the kinetics of MRD
during treatment with inotuzumab in patients randomized to the experimental treatment arm.

IV. To perform genomic analyses to identify and evaluate the incidence and clinical
significance of recurring novel fusion genes including those associated with the
BCR-ABL1-like signature and to correlate with MRD status, CR rate, EFS and OS.

V. To assess whether rs4958351 is correlated with L-asp allergic reaction in the adolescent
and young adult (AYA) population.

VI. To assess the incidence of inherited genetic variants in the GR1A1, CEP72, CPA2, TPMT,
NUDT15, GRIN3A, GRIK1, and other genes (which can be found using a whole genome association
study [GWAS]), are correlated with increased rates of target toxicities including peripheral
neuropathy, hepatotoxicity, pancreatitis, myelosuppression, neurotoxicity, thrombosis, and
osteonecrosis, and correlate with treatment discontinuation and other clinical response
parameters including complete response (CR) rate, EFS, and OS.

VII. To evaluate asparaginase pharmacokinetics in adolescents and young adults, and
investigate its correlation with toxicities and treatment outcomes.

VIII. To investigate the effect of anti-polyethylene glycol (PEG) and anti-agouti signaling
protein (ASP) antibodies (PEG-ASP) on ASP enzyme activity.

IX. To measure adherence to oral 6 mercaptopurine (MP) and methotrexate in AYAs with acute
lymphoblastic leukemia (ALL) and to examine sociodemographic and behavioral determinants of
adherence.

X. To determine the impact of adherence on risk of relapse among AYAs with ALL.

OUTLINE:

COURSE I (REMISSION INDUCTION THERAPY): All patients receive allopurinol orally (PO) once
daily until peripheral blasts and extramedullary disease are reduced and cytarabine
intrathecally (IT) over 1 minute on day 1. Patients also receive daunorubicin hydrochloride
intravenously (IV) and vincristine sulfate IV on days 1, 8, 15 and 22, dexamethasone PO or IV
twice daily (BID) on days 1-7 and 15-21, pegylated recombinant L-asparaginase erwinia
chrysanthemi IV on day 4, 5, or 6, and methotrexate IT over 1 minute on days 8 and 29.
Patients with central nervous system (CNS) 3 disease receive methotrexate IT over 1 minute
also on days 15 and 22. All patients then undergo bone marrow aspirate and biopsy on day 29.

Patients with response to remission induction therapy are randomized to 1 of 2 arms. Patients
with no response are omitted from the study.

ARM I:

COURSE II (REMISSION CONSOLIDATION CHEMOTHERAPY): Patients receive cyclophosphamide IV on
days 1 and 29, cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on
days 1-14 and 29-42, and vincristine sulfate IV on days 15, 22, 43, and 50. Patients also
receive pegylated recombinant L- asparaginase erwinia chrysanthemi IV on days 15 and 43, and
methotrexate IT on days 1, 8, 15, and 22. Patients with CNS3 receive methotrexate IT only on
days 1 and 8. CD20 positive (+) patients receive rituximab IV on days 1, 8, 29, and 36.
Patients then undergo bone marrow aspirate and biopsy on day 56.

COURSE III (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV on
days 1, 11, 21, 31, and 41, methotrexate IV and IT on days 1, 11, 21, 31, and 41, and
pegylated recombinant L- asparaginase erwinia chrysanthemi IV on days 2 and 22. CD20+
patients receive rituximab IV on days 1 and 11.

COURSE IV (DELAYED INTENSIFICATION): Patients receive vincristine sulfate IV on days 1, 8,
15, 43, and 50, dexamethasone PO or IV BID on days 1-7 and 15-21, doxorubicin IV on days 1,
8, and 15, and pegylated recombinant L- asparaginase erwinia chrysanthemi IV on day 4, 5, or
6 and day 43. Patients also receive cyclophosphamide IV on day 29, cytarabine IV or SC on
days 29-32 and 36-39, thioguanine PO on days 29-42 and methotrexate IT on days 1, 29, and 36.
CD20+ patients receive rituximab IV on days 1 and 8. Patients then undergo bone marrow
aspirate and biopsy on day 50.

COURSE V (MAINTENANCE THERAPY): Patients receive vincristine sulfate IV on days 1, 29, and
57, dexamethasone PO or IV BID on days 1-5, 29-33, and 57-61, and mercaptopurine PO on days
1-84. Patients also receive methotrexate IT or PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64,
71, and 78. Treatment repeats every 12 weeks for up to 3 years in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone
marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 courses in
the absence of disease progression or unacceptable toxicity. Patients also receive remission
consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and
maintenance therapy as in Arm I.

After completion of study treatment, patients are followed up every month for the first year,
every 2 months for the second year, every 3 months for the third year, and every 6 months for
the fourth through tenth year.

Inclusion Criteria:

REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

- Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO
criteria) are eligible. Patients with Burkitt type ALL are NOT eligible

- Patients who have BCR-ABL fusion transcript determined by fluorescence in situ
hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) or
t(9;22)(q34;q11) by cytogenetics are not eligible and should be considered for
enrollment on studies that incorporate imatinib during induction; please note: flow
cytometry is to be performed at the local reference lab and must include assessment of
CD20 and CD22 positivity, as well as CD29 and CD22 anti-positivity

- No prior therapy except for limited treatment (< 7 days) with corticosteroids or
hydroxyurea and a single dose of intrathecal cytarabine

- No prior therapy for acute leukemia except emergency therapy (corticosteroids or
hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due
to leukemic infiltration of the kidneys; when indicated, leukapheresis or exchange
transfusion is recommended to reduce the WBC

- Single-dose intrathecal cytarabine is allowed prior to registration or prior to
initiation of systematic therapy for patient convenience; systemic chemotherapy must
begin within 72 hours of this intrathecal therapy

- Patients receiving prior steroid therapy are eligible for study; the dose and duration
of previous steroid therapy should be carefully documented on case report forms

- Not pregnant and not nursing; for women of childbearing potential only, a negative
urine or serum pregnancy test done =< 7 days prior to registration is required

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

- Patients with down syndrome are excluded from this study

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of
normal (ULN), unless suspected leukemic involvement of the liver

- Direct bilirubin =< 3 x upper limit of normal (ULN), unless suspected leukemic
involvement of the liver

- Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault

RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2)

- Completion of remission induction therapy

- Patients with M2 marrow or better are eligible; patients with M3 or M4 marrow (greater
than 25% lymphoblasts) will not be eligible to be randomized

- Rating: M0, M1; Blast Cells (%): 0-5.0

- Rating: M2; Blast Cells (%): 5.1-25.0

- Rating: M3; Blast Cells (%): > 25-50

- Rating: M4; Blast Cells (%): > 50.0

- The term "blast cell" includes any cell that cannot be classified as a more
mature normal element, and includes "leukemic cells," pathologic lymphocytes, and
stem cells

- No ascites, effusions or significant edema

- Absolute neutrophil count (ANC) >= 1,000/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with known
Gilbert's syndrome

- Aspartate aminotransferase (AST) =< 8 x upper limit of normal (ULN)

- Completion of first 12 weeks (12+ weeks) of maintenance therapy (Course V)

- Patient has at least 24 weeks (24+ weeks) remaining before end of maintenance therapy
(Course V)

- Patient is in complete continuous first remission at entry into A041501-HO1

- Patient is receiving oral anti-metabolite chemotherapy during the maintenance phase of
therapy; treatment plan must call for the following doses of antimetabolites: 6MP 75
mg/m2/day orally; methotrexate (MTX) 20 mg/m2/week orally (modification of 6 MP or MTX
dosing based on laboratory or clinical parameters is acceptable)

- Patient is able and willing to use the Medication Event Monitoring System (MEMS)
TrackCap (e.g. not using a pillbox)