A Phase 1/2 Open-label Study to Investigate the Safety, Efficacy, and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Adults with Relapsed or Refractory B cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)

Subjects are eligible to be included in the study only if all of the following
criteria apply:
• 101 Subject has provided informed consent prior to initiation of any study
specific activities/procedures and/or the subject*s legally acceptable
representative has provided informed consent prior to any study-specific
activities/procedures being initiated when the subject has any kind of
condition that, in the opinion of the Investigator, may compromise the ability
of the subject to give written informed consent.
• 102 Age >= 18 years at time of informed consent
Disease status: All subjects must fulfill at least 1 of inclusion criteria
#103, #104, or #105 for eligibility.
For Ph-IIM cohort (subjects with MRD+ ALL [phase 2]) only: Subjects will be
eligible for Ph-IIM if they have B ALL and meet the MRD criteria defined in
inclusion criterion #109 below. With the exception of disease status criteria
(ie, inclusion criteria #103, #104, #105, #106), Ph-IIM cohort subjects must
satisfy all other inclusion criteria to be eligible.
• 103 Subjects with B-precursor ALL with any of the following:
o Either refractory (to primary induction) therapy or refractory to at least
1 salvage therapy OR
o In untreated first, second, third or greater relapse or refractory relapse
* First Relapse is defined as achievement of first CR (CR1) during
upfront therapy then relapse during or after continuation therapy
* Primary Refractory disease is defined as the absence of CR after
standard induction therapy
* Refractory relapse is defined as lack of CR after salvage treatment
* Second relapse or later relapse is defined as relapse after achieving
a second CR (CR2) in first or later salvage
* Refractory to salvage is defined as no attainment of CR after salvage
• 104 Relapsed or Refractory at any time after first salvage therapy.
• 105 Relapse at any time after allogeneic hematopoietic stem cell transplant
(HSCT).
• 106 Greater than or equal to 5% blasts in the BM (Exception: Isolated Non-CNS
extramedullary disease [EMD]).
• 107 Eastern Cooperative Oncology Group (ECOG) Performance Status <= 2.
• 108 Subjects with relapse or refractory B Cell ALL Ph+ disease and that are
intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are
eligible.
• 109 For subjects in the MRD cohorts only (Ph-IIM cohort), BMB must be <5% and
>=0.1%. This will replace inclusion criterion #106 for subjects in this cohort
• 111 Subjects enrolled in SC1 and SC2 comparison cohort (Ph-IIC) must provide
consent to participate in the additional PK sample collection requirements.
• 112 Subjects with Isolated (< 5% BMB) Non-CNS Extra Medullary Disease (EMD)
are eligible in phase 2 cohorts Ph-IIR and Ph-IIM only.

Subjects are excluded from the study if any of the following criteria apply:
Disease Related
• Active ALL in the CNS. Presence of > 5 white blood cells (WBC) per cubic
millimeter in cerebrospinal fluid (CSF) with lymphoblasts present (confirmed by
CSF analysis) and/or clinical signs of CNS leukemia. If CSF leukemia is present
subjects will have to receive intrathecal therapy and have documented negative
CSF prior to enrolling.

Other Medical Conditions
• History or presence of clinically relevant CNS pathology or event such as
epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain
injuries, dementia, Parkinson*s disease, cerebellar disease, organic brain
syndrome, psychosis or severe (>= grade 3) CNS events including ICANS from prior
CD19 CART or other T-cell-engager therapies.

• Current autoimmune disease or history of autoimmune disease with potential
CNS involvement.
• Active acute or chronic graft versus host disease requiring systemic
treatment with immunosuppressive medication.
• Known hypersensitivity to blinatumomab or to any component of the product
formulation.
• Known infection with human immunodeficiency virus (HIV) or chronic infection
with hepatitis B virus or hepatitis C virus.
• Symptoms and/or clinical signs and/or radiological and/or sonographic signs
that indicate an acute or uncontrolled chronic infection, any other concurrent
disease or medical condition that could be exacerbated by the treatment or
would seriously complicate compliance with the protocol.

• History of malignancy other than ALL within 3 years prior to start of
protocol-specified therapy except for:
o Malignancy treated with curative intent and with no known active disease
present for 3 years before enrollment and felt to be at low risk for recurrence
by the treating physician.
o Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease.
o Adequately treated cervical carcinoma in situ without evidence of disease.
o Adequately treated breast ductal carcinoma in situ without evidence of
disease.
o Prostatic intraepithelial neoplasia without evidence of prostate cancer.


• Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
• Cancer chemotherapy within 2 weeks before the start of protocol-specified
therapy. With the exception of intrathecal chemotherapy and/or low dose
maintenance therapy for example vinca alkaloids, mercaptopurine, methotrexate,
or hydroxyurea (any low dose chemotherapy as stated above must be discontinued
before starting pre-phase) or pre-phase chemotherapy and/or dexamethasone as
outlined in Section 6.1.2.1 and Section 6.1.2.2, respectively.
• Immunotherapy (eg, rituximab, alemtuzumab) within 4 weeks before start of
protocol-specified therapy. Prior failed CD19 directed therapy such as prior
blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued
CD19+ expression), if treatment ended > 4 weeks prior to start of protocol
therapy and no prior CNS complications.

Prior/Concurrent Clinical Study Experience
• Currently receiving treatment in another investigational device or drug
study, or less than 30 days since ending treatment on another investigational
device or drug study. Other investigational studies are not permitted while
participating in this study.

Diagnostic Assessments
• Abnormal screening laboratory values as defined below:
o Total bilirubin >3.0 mg/dL prior to start of treatment (unless due to
Gilbert*s or Meulengracht disease)
o Estimated Creatinine clearance < 60 mL/min

Other Exclusions
• Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 96 hours after the last dose
of protocol-specified therapy.
• Female subjects of childbearing potential unwilling to use 1 highly effective
method of contraception during treatment and for an additional 96 hours after
the last dose of protocol-specified therapy. Refer to Section 11.5 for
additional contraceptive information.
• Female subjects of childbearing potential with a positive pregnancy test
assessed during Screening by a serum pregnancy test and/or urine pregnancy
test.