Cellular Immunotherapy in Treating Patients With High-Risk Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES: I. To examine the activity and safety of adoptive therapy using ex vivo
expanded memory T cells that are enriched and genetically-modified to express a cluster of
differentiation (CD)19-specific, hinge optimized, CD28-costimulatory chimeric antigen
receptor (CAR) as well as a truncated human epithelial growth factor receptor (EGFR) (Arm 1:
CD19R(EQ)28zeta/truncated human EGFR [EGFRt]+ central memory T cells [Tcm]; Arm 2:
CD19R(EQ)28zeta/EGFRt+ naive and memory T cells [Tn/mem]) shortly following a lymphodepleting
preparative regimen for adults with poor prognosis CD19+ acute lymphoblastic leukemia (ALL).

II. To determine the Phase II recommended dose (RP2D).

SECONDARY OBJECTIVES: I. To study additional antitumor activity endpoints of
CD19R(EQ)28zeta/EGFRt+ Tcm and CD19R(EQ)28zeta/EGFRt+ Tn/mem. II. To explore the efficacy of
infusional cetuximab to eliminate transferred CD19R(EQ)CD28zeta/EGFRt+ Tcm and
CD19R(EQ)28zeta/EGFRt+ Tn/mem.

OUTLINE: This is a dose-escalation study.

ARM I: Patients receive lymphodepleting regimen per treating physician's discretion 3-14 days
before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing
Tcm-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease,
whose tumor(s) continue to express the appropriate antigen target may receive an optional
second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells after 28 days.

ARM II: Patients receive lymphodepleting regimen per treating physician's discretion 3-14
days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing
Tn/mem-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease,
whose tumor(s) continue to express the appropriate antigen target may receive an optional
second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T cells after 28
days.

After completion of study treatment, patients are followed up at 24 hours, weekly for 1
month, monthly for 1 year, and then yearly for at least 15 years.

Inclusion Criteria:

- City of Hope (COH) pathology review confirms that research participant's diagnostic
material is consistent with history of ALL with history of
recurrence/progression/minimal residual disease (MRD) following prior therapy;
additionally, CD19 positivity must be documented in a pathology report; however, it is
not a requirement that the CD19 testing be performed by a COH pathologist; patients in
second complete remission (CR2) or higher with history of CD19+ ALL on previous bone
marrow biopsy are also eligible for the study

- Research participants with confirmed 1st or higher relapse of disease by morphology,
cytogenetics or molecular, or research participants with refractory or residual
disease

* MRD will be defined in this protocol by presence of malignant cells at 0.01% or more
by flow cytometry or polymerase chain reaction (PCR) analysis at the completion of
initial remission induction therapy

- Karnofsky performance status (KPS) of >= 70%

- Life expectancy >= 16 weeks at time of enrollment

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for six months following duration of study participation; should a woman become
pregnant or suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately

- All research participants must have the ability to understand and the willingness to
sign a written informed consent

- Note: For research participants who do not speak English, a short form consent
may be used with a COH certified interpreter/translator to proceed with screening
and leukapheresis, while the request for a translated full consent in processed;
however, the research participant is allowed to proceed with lymphodepletion and
T cell infusion only after the translated full consent form is signed

PROTOCOL-SPECIFIC CRITERIA:

- COH pathology review confirms that research participant's diagnostic material is
consistent with ALL; additionally, CD19 positivity must be documented in a pathology
report; however it is not a requirement that the CD19 testing be performed by a COH
pathologist

- Negative serum pregnancy test for women of childbearing potential

- If a research participant has undergone prior allogeneic stem cell transplant
(alloSCT), and has documented =< grade 2 graft versus host disease (GVHD) but the
donor is undergoing leukapheresis, the research participant may be considered eligible
for enrollment (at the discretion of the study PI) provided that immunosuppressants
can be tapered off completely prior to lymphodepletion

- If the research participant is to undergo leukapheresis, he/she must have a
pretreatment calculated creatinine clearance (absolute value) of >= 50 mL/minute

- If the research participant is to undergo leukapheresis, research participant must
have a serum bilirubin =< 2.0 mg/dl; Note: in the event a participant has elevated
levels of liver enzymes possibly related to underlying disease, the participant will
still be considered eligible

- If the research participant is to undergo leukapheresis, he/she must have alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the
institutional upper limits of normal; Note: in the event a patient has elevated levels
of liver enzymes possibly related to underlying disease, the patient will still be
considered eligible

- If the research participant is to undergo leukapheresis, he/she must have ejection
fraction measured by echocardiogram or multigated acquisition scan (MUGA) > 45%
(within 6 weeks of time of screening)

ELIGIBILITY TO PROCEED WITH PBMC COLLECTION:

- If the research participant is undergoing leukapheresis, he/she must have appropriate
venous access

- If the research participant is undergoing leukapheresis, he/she must be at least 2
weeks from having received the last dose of immunosuppressant medications

* Exceptions:

- Steroids and tyrosine kinase inhibitors are allowed up to 7 days prior to
leukapheresis

- Research participant cannot be on more than 5 mg prednisone or equivalent doses
of other corticosteroids at the time of leukapheresis

- If the research participant is undergoing leukapheresis and if the research
participant has undergone prior alloSCT two months must have elapsed since allogeneic
stem cell transplant to undergo PBMC collection for T cell manufacturing

- If the research participant is undergoing leukapheresis, the last dose of prior
chemotherapy, immunotherapy or radiation must be at least 2 weeks before the
leukapheresis procedure * Exception rule: The wash out period for Hydrea is 48 hours.

ELIGIBILITY TO UNDERGO LYMPHODEPLETION:

- Research participant's absolute leukemic blast count does not exceed 10,000 cells/uL

- Confirmed absence of central nervous system (CNS) disease

- Research participant has a released cryopreserved T cell product for T cell infusions
on approximately day 0

- KPS >= 70%

- Non-hematological toxicity related to prior therapy must either have returned to =<
grade 3, baseline, or deemed irreversible

- Participants of reproductive potential must agree to use and utilize an adequate
method of contraception throughout treatment and for at least 8 weeks after T cell
infusion

- Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or
higher on room air

- Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary
syndrome, or uncontrolled hypertension

- Preservation of renal function, serum creatinine did NOT increase by more than 2 fold
above the normal reference range

- Total bilirubin =< 2.0 mg/dL

- * Note: in the event a participant has elevated levels of liver enzymes possibly
related to underlying disease/disease progression, the participant will still be
considered eligible

- ALT and AST =< 2.5 times the institutional upper limits of normal

- * Note: in the event a participant has elevated levels of liver enzymes possibly
related to underlying disease/disease progression, the participant will still be
considered eligible

- Research participants without clinically significant encephalopathy/new focal deficits

- No clinical evidence of uncontrolled active infectious process

ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED T CELLS:

- Research participant has undergone lymphodepletion

- Pulmonary: Not requiring supplemental oxygen or mechanical ventilation, oxygen
saturation 90% or higher on room air

- Cardiovascular: Not requiring pressor support, no symptomatic cardiac arrhythmias, no
acute coronary syndrome, or uncontrolled hypertension

- Renal function: Preservation of renal function, serum creatinine did NOT increase by
more than 2 fold above the normal reference range

- Liver function: Total bilirubin =< 2.0 mg/dL * Note: in the event a participant has
elevated levels of liver enzymes possibly related to underlying disease/disease
progression, the participant will still be considered eligible

- Liver function: ALT and AST =< 2.5 times the institutional upper limits of normal *
Note: in the event a participant has elevated levels of liver enzymes possibly related
to underlying disease/disease progression, the participant will still be considered
eligible

- Research participant without clinically significant encephalopathy/new focal deficits

- Infectious diseases: No clinical evidence of uncontrolled active infectious process

ELIGIBILITY CRITERIA TO UNDERGO OPTIONAL T CELL ABLATION:

- Research participant is scheduled for an alloSCT

- Research participant has >= 1% chimeric antigen receptor (CAR) modified T cells in the
peripheral blood

- Pulmonary criteria: Not requiring supplemental oxygen or mechanical ventilation,
oxygen saturation 90% or higher on room air

- Cardiovascular criteria: Not requiring pressor support, no symptomatic cardiac
arrhythmias, no acute coronary syndrome, or uncontrolled hypertension

- Renal function criteria: Preservation of renal function, serum creatinine did NOT
increase by more than 2 fold above the normal reference range

- Liver function criteria: Total bilirubin =< 2.0 mg/dL

* Note: in the event a participant has elevated levels of liver enzymes possibly
related to underlying disease/disease progression, the participant will still be
considered eligible

- Liver function criteria: AST and ALT =< 2.5 times the institutional upper limits of
normal

* Note: in the event a participant has elevated levels of liver enzymes possibly
related to underlying disease/disease progression, the participant will still be
considered eligible

- Neurological: Research participant without clinically significant encephalopathy/new
focal deficits

- Infectious diseases criteria: No clinical evidence of uncontrolled active infectious
process

Exclusion Criteria:

- Research participants with any uncontrolled illness including ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social
situations that would limit compliance with study requirements

- Research participants with known active hepatitis B or C infection; research
participants who are human immunodeficiency virus (HIV) positive based on testing
performed within 4 weeks of enrollment; research participants with any signs or
symptoms of active infection, positive blood cultures or radiological evidence of
infections

- Research participants receiving any other investigational agents, or concurrent
biological, chemotherapy, or radiation therapy

* Note: Please note that the above criterion is not applicable at the time of
enrollment if the research participant's donor is undergoing leukapheresis

- Research participants with presence of other active malignancy. However, research
participants with history of prior malignancy treated with curative intent and in
complete remission are eligible

- Pregnant and lactating women

- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I study

- Research participants with CNS involvement by leukemia, if deemed to be controlled and
treatable by study team, at the time of enrollment are eligible; however, the CNS
disease has to have been adequately treated with complete resolution of CNS leukemia
confirmed by cerebral spinal fluid (CSF) analysis and imaging studies (if applicable)
to be eligible to proceed with lymphodepletion

- History or presence of clinically relevant CNS pathology such as uncontrolled seizure
disorder, stroke, severe brain injuries, dementia, cerebellar disease or psychosis

- Any known contraindications to cyclophosphamide, fludarabine, etoposide, cetuximab or
tocilizumab

- Dependence on corticosteroids

- Defined as doses of corticosteroids of greater than 5 mg/day of prednisone or
equivalent doses of other corticosteroids

- Note: topical and inhaled corticosteroids in standard doses and physiologic
replacement for subjects with adrenal insufficiency are allowed

- Please note that this criterion is not applicable if the research participant's
donor is undergoing leukapheresis.

- Active autoimmune disease requiring systemic immunosuppressive therapy

- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study