Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the 3-year survival rate in elderly patients with newly diagnosed Philadelphia
(Ph)-negative acute lymphoblastic leukemia (ALL) treated with blinatumomab followed by POMP
(prednisone, vincristine sulfate, methotrexate, and mercaptopurine) maintenance.

II. To evaluate in a preliminary manner (feasibility study) the safety of dasatinib-steroid
based induction followed by blinatumomab treatment in combination with dasatinib followed by
dasatinib-based maintenance in patients with newly diagnosed Ph-positive ALL,
relapsed/refractory Ph-positive ALL, and Ph-like dasatinib-sensitive mutations or kinase
fusions (DSMKF) ALL (newly-diagnosed relapsed or refractory).

SECONDARY OBJECTIVES:

I. To evaluate toxicities in these patient populations treated with these regimens.

II. To estimate the rates of complete response (CR), complete remission with incomplete count
recovery (CRi) and disease-free survival in Ph-negative patients.

III. To estimate disease-free and overall survival in Ph-positive ALL and Ph-like DSMKF ALL.

IV. To estimate in each cohort the rate of minimal residual disease (MRD) negativity, and the
time to achieve MRD negativity (exploratory analysis).

V. To determine whether anti-idiotype antibodies directed against blinatumomab develop with
blinatumomab treatment in this study.

OUTLINE: Patients are assigned to 1 of 2 treatment cohorts according to Philadelphia
chromosome status.

COHORT I (PHILADELPHIA CHROMOSOME NEGATIVE PATIENTS):

INDUCTION: Patients receive blinatumomab intravenously (IV) continuously over 24 hours on
days 1-28 in the absence of disease progression or unacceptable toxicity.

RE-INDUCTION: Patients not achieving CR or CRi after Induction, receive blinatumomab IV
continuously over 24 hours on days 1-28 in the absence of disease progression or unacceptable
toxicity.

POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 3 cycles in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Patients receive prednisone orally (PO) on days 1-5, vincristine sulfate IV on
day 1, mercaptopurine PO on days 1-28, and methotrexate PO on days 1, 8, 15, and 22.
Treatment repeats every 28 days for 18 cycles in the absence of disease progression or
unacceptable toxicity.

COHORT II (PHILADELPHIA CHROMOSOME POSITIVE PATIENTS):

INDUCTION: Patients receive dasatinib PO twice daily (BID) on days 1-84 and prednisone PO on
days 1-24 with tapering on days 25-32 in the absence of disease progression or unacceptable
toxicity.

RE-INDUCTION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28.
Treatment repeats every 42 days for 2 cycles in the absence of disease progression or
unacceptable toxicity.

POST-REMISSION: Patients receive blinatumomab IV continuously over 24 hours on days 1-28 and
dasatinib PO once daily (QD) on days 1-42. Treatment repeats every 42 days for 3 cycles in
the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive dasatinib PO BID on days 1-28 and prednisone PO on days 1-5.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 2 years, and then annually until 10 years from initial registration.

Inclusion Criteria:

- Registration Step 1 - Induction/Re-Induction:

- Patients must have a new morphologic diagnosis of precursor B cell acute lymphoblastic
leukemia (ALL) (non T cell) based on World Health Organization (WHO) criteria;
patients with Burkitt's (L3) are excluded; patients with Ph-positive or Ph-like ALL
with dasatinib-sensitive mutations or kinase fusions may have relapsed or refractory
diagnoses

- NOTE: Relapsed/refractory Ph-positive patients or Ph-like patients with
dasatinib-sensitive mutations or kinase fusions who have previous exposure to
either dasatinib or another 2nd or 3rd generation tyrosine kinase inhibitor (TKI)
will begin protocol therapy with Cohort 2: re-induction cycle 1

- Patients must have a diagnosis of Philadelphia chromosome negative ALL or Ph
chromosome positive ALL by cytogenetics, fluorescence in situ hybridization (FISH) or
polymerase chain reaction (PCR); patients will be registered to receive treatment in
either Cohort 1 (ph-) or Cohort 2 (Ph+ or Ph-like DSMKF) based on these results;
diagnostic specimens must be submitted to the site's local Clinical Laboratory
Improvement Amendments (CLIA)-approved cytogenetics laboratory and results of tests
(cytogenetics, FISH or PCR) must confirm Ph status prior to registration; if not
already known, breakpoint cluster region- abelson murine leukemia viral oncogene
homolog 1 (BCR-ABL) status (p190 or p210) must be evaluated in Ph-positive patients by
PCR

- For Cohort 2, Ph-like testing is not required specifically for this study;
however, to be registered to Cohort 2 under the Ph-like DSMKF criterion, the
patient must have a known or presumed activating Ph-like signature and
dasatinib-sensitive mutation or kinase fusion, such as: ABL1, ABL2, colony
stimulating factor 1 receptor (CSF1R), platelet derived growth factor receptor
beta (PDGFRB), platelet derived growth factor receptor alpha (PDGFRA), or
fibroblast growth factor receptor (FGFR)s that was otherwise identified as part
of normal standard of care; prior to registering any patients with a known or
presumed activating Ph-like signature and dasatinib-sensitive mutations or kinase
fusions (DSMKF) treating physicians must confirm eligibility with the study
chairs via email; the study chairs must respond via email with confirmation of
patient eligibility prior to patient registration

- All newly diagnosed patients must have evidence of ALL in their marrow or peripheral
blood with at least 20% lymphoblasts present in blood or bone marrow collected within
28 days prior to registration; all relapsed/refractory patients (Cohort 2) must have
at least 5% lymphoblasts present in blood or bone marrow collected within 28 days
prior to registration; for relapsed/refractory patients, pathology and cytogenetics
reports (both from time of original diagnosis) must be submitted at time of
registration; if a bone marrow aspirate cannot be obtained despite an attempt (dry
tap), appropriate immunohistochemistry (IHC) testing, including CD19, must be
performed on the bone marrow biopsy to determine lineage; for ALL in marrow or
peripheral blood, immunophenotyping of the blood or marrow lymphoblasts must be
performed to determine lineage (B cell, T cell or mixed B/T cell); appropriate marker
studies including cluster of differentiation (CD)19 (B cell), must be performed;
co-expression of myeloid antigens (CD13 and CD33) will not exclude patients; if
possible, the lineage specific markers (myeloid cells) should be determined; the
blood/bone marrow sample for these assays must be obtained within 28 days prior to
registration; patients with only extramedullary disease in the absence of bone marrow
or blood involvement are not eligible

- Patient must not have a history or presence of clinically relevant central nervous
system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe
brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain
syndrome, psychosis, active ALL in the CNS confirmed by cerebrospinal fluid (CSF)
analysis, or other significant CNS abnormalities

- Patients must have a lumbar puncture to determine CNS involvement of ALL within 14
days prior to registration; patients with CNS3 are excluded from the trial; patients
with CNS1 or CNS2 will be eligible, but will be monitored for CNS involvement; note
that intrathecal methotrexate administered during the pre-study lumbar puncture may
count as the first dose of intrathecal therapy required as part of the study

- Cohort I, Ph-negative Patients Only

- Patients must not have received any prior chemotherapy, radiation therapy, or other
therapy for the treatment of ALL (other than those noted below) and must not be
receiving any immunosuppressive therapy; patients may not have received any prior
investigational therapy within 28 days prior to registration; patients must not have
received any monoclonal antibody therapy within 42 days of registration; patients may
have received the following within any time prior to registration: low dose
chemotherapy-including: cyclophosphamide 1 g/m^2, oral 6-mercaptopurine, or oral
methotrexate (other low dose chemotherapy may be allowable, however any other options
not listed here should be confirmed with the study chairs), TKI therapy, steroids,
hydroxyurea, leukapheresis, intrathecal chemotherapy or vincristine (vincristine
sulfate)

- In the event that the patient's bone marrow blast count is >= 50% blasts, patients may
be registered but should receive steroids for 3-5 days in order to reduce tumor burden
prior to blinatumomab administration, as follows

- Prephase treatment with dexamethasone (10-20 mg/m^2) for 3-5 days is required for
patients with bone marrow blasts >= 50%, peripheral blood blasts 15,000/uL or
higher, or elevated lactate dehydrogenase (LDH) suggesting rapidly progressive
disease per investigator opinion

- Pre-treatment should conclude at least 24 hours prior to the first dose of
blinatumomab (although additional dexamethasone is automatically given as a
pre-med prior to the first dose); at the time of first infusion of
blinatumomab, the absolute peripheral blast count should be < 25,000/uL

- Note: For the purposes of the study, day 1 of the cycle will be the first
day of blinatumomab administration

- It is preferred, but not required, that corticosteroids and hydroxyurea should start
only after all diagnostic samples have been obtained; however, if the patient was
previously on corticosteroids and/or hydroxyurea, this is allowable provided that the
patient still has measurable disease at time of the bone marrow aspirate

- Corticosteroids and/or hydroxyurea, as well as any of the other therapies
mentioned (with the exception of IV cyclophosphamide), may continue to be
administered, at physician discretion, until 1 day prior to blinatumomab
administration

- IV cyclophosphamide must be discontinued at least 7 days prior to
blinatumomab administration

- Patients must not be candidates for allogeneic hematopoietic stem cell transplant;
NOTE: Subjects up to age 70 years who are considered fit for allogeneic hematopoietic
stem cell transplant, should be considered for enrollment on E1910, in order to avoid
competing with that study; if a patient is considered unfit for intensive chemotherapy
at the time of initial diagnosis, but subsequently achieves a complete remission (CR),
then it will be left to the treating physician's discretion to consider hematopoietic
stem cell transplant (HSCT)

- Patients must have complete history and physical examination within 28 days prior to
registration

- Patients must have a Zubrod performance status of 0-2

- Patients must have serum creatinine =< 1.5 mg/dl within 14 days prior to registration

- Patients must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
=< 3.0 x institutional upper limit of normal (IULN) within 14 days prior to
registration

- Patients must have total bilirubin =< 2.0 x IULN within 14 days prior to registration

- Patients must have alkaline phosphatase =< 2.5 x IULN within 14 days prior to
registration

- Patients must not have systemic fungal, bacterial, viral or other infection that is
not controlled (defined as exhibiting ongoing signs/symptoms related to the infection
and without improvement, despite appropriate antibiotics or other treatment)

- Patients must not have Common Terminology Criteria for Adverse Events (CTCAE) >= grade
2 neuropathy (cranial, motor or sensory) within 14 days prior to registration

- Patients known to be positive for HIV (the human immunodeficiency virus) may be
eligible, providing they meet the following additional criteria within 28 days prior
to registration:

- No history of acquired immune deficiency syndrome (AIDS)-defining conditions

- CD4 cells > 350 cells/mm^3

- If on antiretroviral agents, must not include zidovudine or stavudine

- Viral load =< 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on
combination antiretroviral therapy (cART) or =< 25,000 copies HIV mRNA/mm^3 if
not on cART

- Highly active antiretroviral therapy (HAART) regimens are acceptable providing
they have only weak P450A4 interactions

- Patients must not have any known autoimmune disease

- Patients must not have testicular involvement; if clinical or ultrasound findings are
equivocal, biopsy must be performed; all tests for establishing testicular involvement
must be completed within 14 days prior to registration

- Patients with evidence of extramedullary disease at diagnosis will have computed
tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen and
pelvis to obtain baseline values within 28 days prior to registration

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
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 five years

- Patients must have the following tests within 28 days prior to registration to obtain
baseline measurements:

- Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized
ratio (INR)/fibrinogen (all patients)

- Neurologic assessment

- Patients must have specimens submitted for blinatumomab immunogenicity assessment;
collection of pretreatment specimens must be completed within 28 days prior to
registration to S1318; specimens must be submitted to LabConnect

- Cohort 2, Ph-positive and Ph-like DSMKF Patients Only

- Patients must NOT have received a prior autologous or allogeneic hematopoietic stem
cell transplant at any time. Patients must NOT have received any chemotherapy,
investigational agents, or undergone major surgery within 14 days prior to
registration, with the following exceptions:

- Monoclonal antibodies must not have been received for 1 week prior to
registration

- Chimeric antigen receptor (CAR) T-cells must not have been received for 28 days
prior to registration

- Steroids, hydroxyurea, vincristine, 6-mercaptopurine, methotrexate, thioguanine
and intrathecal chemotherapy are permitted within any timeframe prior to
registration; Food and Drug Administration (FDA)-approved TKIs may also be
administered until 1 day prior to start of study therapy (C1, D1); IV
cyclophosphamide may be administered at doses of 1 g/m^2 or less until up to 7
days prior to registration

- For patients 65-69 years of age, patient must be deemed not suitable for standard
intensive induction chemotherapy at the discretion of the local investigator, or must
have refused standard intensive chemotherapy

- Patients must not have active pericardial effusion, ascites or pleural effusion of any
grade based on chest x-ray and echocardiogram within 28 days prior to registration;
exception: if the effusion is suspected to be related to the leukemia, the patient may
have pericardial effusion =< grade 2 or pleural effusion =< grade 1

- Patients must have ejection fraction >= 45% based on echocardiogram performed within
28 days prior to registration

- Patients must have QTcF (by Fridericia calculation) < 480/msec based on
electrocardiogram (EKG) performed within 28 days prior to registration

- Patients must not be receiving any proton pump inhibitors at the time of registration

- Patients must agree to have specimens submitted for blinatumomab immunogenicity
testing if subsequently moved to a blinatumomab containing treatment regimen on
protocol

- Pretreatment cytogenetics must be performed on all patients; collection of
pretreatment specimens must be completed within 28 days prior to registration to
S1318; specimens must be submitted to the site's preferred CLIA-approved cytogenetics
laboratory; BCR-ABL status must be verified in Ph-positive patients by FISH,
cytogenetics, and/or PCR prior to enrollment; if a patient is Ph-positive, PCR for
both p190 and p210 must be sent

- Patients must be offered participation in specimen submission for future research;
with patient's consent, specimens must be submitted as outlined

- ALL PATIENTS: Patients or their legally authorized representative must be informed of
the investigational nature of this study and must sign and give written informed
consent in accordance with institutional and federal guidelines

- ALL PATIENTS: As a part of the Oncology Patient Enrollment Network (OPEN) registration
process the treating institution's identity is provided in order to ensure that the
current (within 365 days) date of institutional review board approval for this study
has been entered in the system

- Registration Step 2 - Post-Remission Therapy:

- COHORT 1 PH-NEGATIVE PATIENTS ONLY: Patients must have achieved CR or CRi within 2
cycles of induction/re-induction with blinatumomab

- NOTE: day 1 of post-remission = day 43 of the preceding cycle (+/- 3 days)

- COHORT 2 PH-POSITIVE AND PH-LIKE DSMKF PATIENTS ONLY: Newly diagnosed Ph+,
newly-diagnosed Ph-like DSMKF, and relapsed/refractory Ph+ patients without prior
dasatinib or other 2nd or 3rd generation TKI therapy, must have achieved CR or CRi
within 1 cycle of induction with dasatinib/prednisone, or within 2 cycles of
re-induction with blinatumomab; relapsed/refractory Ph+ or Ph-like DSMKF patients with
prior dasatinib or other 2nd or 3rd generation TKI therapy must have achieved CR or
CRi within 2 cycles of re-induction therapy with blinatumomab

- NOTE: day 1 of post-remission = day 85 of the preceding induction cycle (+/- 3
days), or day 43 of the preceding re-induction cycle (+/- 3 days) as applicable

- Serum creatinine =< 1.5 mg/dl within 14 days prior to registration

- AST and ALT =< 3.0 x institutional upper limit of normal (IULN) within 14 days prior
to registration

- Total bilirubin =< 2.0 x IULN within 14 days prior to registration

- Absolute neutrophil count (ANC