Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

STUDY OBJECTIVES

Primary Objective

- To determine the safety and tolerability of autologous iC9-CAR19 T cells administered to
adult and pediatric subjects with relapsed or refractory CD19+ Acute Lymphoblastic
Leukemia (ALL).

Secondary Objectives

- To identity a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and
pediatric subjects with relapsed or refractory CD19+ ALL.

- To measure the survival of iC9-CAR19 T cells in vivo.

- To determine the anti-leukemia overall response rate (ORR) mediated by autologous
iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or
refractory CD19+ ALL.

- To determine overall survival (OS) in adult and pediatric subjects with relapsed or
refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

- To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or
refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

- To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed
or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

- To measure patient-reported symptom, physical function, and health-related quality of
life at baseline and over time in adult subjects treated with iC9-CAR19 T cells.

ENDPOINTS

Primary Endpoint

Toxicity will be classified and graded according to the National Cancer Institute's Common
Terminology Criteria for Adverse Events (CTCAE, version 5), CAR-T-cell-related encephalopathy
(CRES) symptoms will be graded according to CRES Grading and CRS symptoms will be graded
according to CRS Grading.

(Note: The safety evaluation period for dose limiting toxicity assessment will encompass
toxicities related to the cell therapy that are experienced starting on the day of iC9-CAR19
T cell infusion up through 4 weeks post infusion. General safety monitoring will begin at the
time of procurement).

Secondary Endpoints

- The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose
finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria,
CRES grading criteria and CRS grading criteria

- Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase
chain reaction (PCR) and flow cytometry in samples of peripheral blood.

- Overall response rate (Complete Response (CR)/Complete Response with incomplete recovery
of counts (CRi)) to iC9-CAR19 T cell therapy will be determined using National
Comprehensive Cancer Network Response Criteria (NCCN) for ALL. Assessment of minimal
residual disease (MRD) will be included as criterion of response (ie, the percentage of
subjects who achieve CRm defined as MRD negative CR by either flow cytometry or PCR
analysis will be determined).

- Overall survival will be measured from the date of administration of iC9-CAR19 T cells
to the date of death.

- EFS applies to all subjects and will be measured from the date of administration of
iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from
CR or CRi, or death from any cause; subjects not known to have any of these events are
censored on the date they were last examined.

- RFS will apply only to subjects achieving CR or CRi and measured from the date of
achievement of a remission until the date of relapse or death from any cause; subjects
not known to have relapsed or died at last follow-up are censored on the date they were
last examined.

- Patient reported symptoms will be measured using selected symptoms from the NCI
PRO-CTCAE. Patient-reported physical function will be measured using the PROMIS Physical
Function Score derived from the PROMIS Physical Function Short Form 20a v1.0.
Patient-reported health-related quality of life will be measured using the PROMIS Global
Health Score derived from the PROMIS Global Health Short Form v1.0-1.1.

OUTLINE

Cell Procurement

Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects
for cell procurement. In subjects with low (CD3 count as assayed by flow cytometry less than
200/μl) T-cell count in the peripheral blood, a leukopheresis may be performed to isolate
sufficient T cells. The parameters for pheresis will be 2 blood volumes.

iC9-CAR19 Cells Administration

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy
regimen. The starting dose of 5 x 10^5 transduced cells/kg (dose level 1) will enroll at
least 3 adult subjects in the initial cohort. If there are no dose limiting toxicities within
4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x 10^6
transduced cells/kg in adults. If there is toxicity in 1/3 subjects in the initial cohort,
the cohort will be expanded to enroll 3 more subjects. If dose level 1 is determined to be
above a tolerable dose, de-escalation would occur to dose level -1 where subjects would
receive 1 x 10^5 transduced cells/kg. The first subject enrolled on each dose level will be
evaluated for a 4 week safety follow-up period prior to enrolling additional subjects on that
dose level.

Duration of Therapy

Therapy in this study involves 1 infusion of iC9-CAR19 cells.

Duration of Follow-up

Subjects will be followed for up to 15 years for replication-competent retrovirus evaluation
or until death, whichever occurs first. Subjects removed from study for unacceptable adverse
events will be followed until resolution or stabilization of the adverse event.

Inclusion Criteria - Cell Procurement:

- Written informed consent for procurement signed by subject or legal guardian of a
pediatric subject and HIPAA authorization for release of personal health information.

- Age 3 to 17 years of age for pediatric subjects (weight must be ≥ 10 kg), ≥ 18 to 70
years of age for adults at the time of consent.

- Karnofsky score > 60% if > 16 years old or Lansky performance score of greater than
60% if <16 years old.

- Relapsed or refractory precursor B cell ALL:

- Second or greater bone marrow relapse OR

- Any bone marrow relapse >100 days after allogeneic stem cell transplant OR

- Primary refractory ALL defined as no complete response after 2 cycles of a standard of
care chemotherapy regimen OR

- For adult subjects: first bone marrow relapse with duration of first CR <1 year OR
first CR duration >/=1 year and refractory to >/= 1 cycle of therapy for treatment of
relapse.

- Subjects with isolated non-CNS extramedullary disease will be eligible as long as the
time-of-remission criteria above for bone marrow relapses or primary refractory ALL
are met and the biopsy for extramedullary disease confirms CD19 expression

- For pediatric subjects: first bone marrow or isolated non-CNS extramedullary relapse
refractory to 1 cycle of standard therapy for relapsed ALL.

- While active CNS3 leukemia will be excluded, subjects with concurrent CNS3 disease and
bone marrow relapse who have responded to CNS-directed therapy prior to enrollment
will be allowed to participate. Intrathecal chemotherapy will be allowed to continue
between lymphodepleting chemotherapy and cell infusion.

- Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible.
Intrathecal chemotherapy will be allowed to continue between lymphodepleting
chemotherapy and cell infusion.

- Subjects with Ph+ ALL will be eligible if they have failed ≥ 2 ABL tyrosine kinase
inhibitors. Subjects with the T315I ABL kinase point mutation will be eligible if they
have failed ponatinib-containing therapy, regardless of the number of prior ABL
tyrosine kinase inhibitors.

- CD19 positivity of lymphoblasts confirmed by flow cytometry or immunohistochemistry
per institutional standards.

- Life expectancy ≥ 12 weeks.

- Demonstrate adequate renal and hepatic function as defined in the table below; all
screening labs to be obtained within 72 hrs prior to procurement.

- Serum Creatinine: ≤ 1.5 x ULN

- Bilirubin: ≤ 1.5 x upper limit of normal (ULN), unless attributed to Gilbert's
Syndrome

- Aspartate Aminotransferase (AST): ≤ 3.0 × ULN

- Alanine aminotransferase (ALT): ≤ 3.0 × ULN

- For pediatric patients, adequate renal function is defined below:

Age Maximum Serum Creatinine (mg/dL) Male Female 3 to <6 years ≤0.8 ≤0.8 6 to <10 years ≤1
≤1 10 to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4 16 to <18 years ≤1.7 ≤1.4

- Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to procurement.

- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 3 months after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method. Female participants will inform their male partners that they
must use the methods of birth control required by the protocol.

- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 3 months after the last
dose of study therapy.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures.

- Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the
need for intrathecal prophylaxis prior to procurement is left to the discretion of the
investigator. Maintenance doses of chemotherapy are defined as methotrexate ≤30
mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days.
Corticosteroid-containing maintenance therapy is permitted only if corticosteroids are
administered >14 days prior to procurement.

Exclusion Criteria - Cell Procurement:

- Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing who cannot
safely delay definitive treatment for their ALL by at least 4 weeks in the opinion of
the investigator.

- Lumbar puncture must be performed prior to procurement and subjects with evidence of
CNS3 disease will be excluded from study entry. Subjects with concurrent CNS3 disease
and bone marrow relapse who have responded to CNS-directed therapy prior to
enrollment/lymphodepletion will be allowed to participate. Subjects with CNS2 disease
and concurrent bone marrow relapse will be eligible. Intrathecal chemotherapy will be
allowed to continue between lymphodepleting chemotherapy and cell infusion.

- Pregnant or breastfeeding.

- Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been
disease-free for at least five years.

- Subjects must not have tumor in a location where enlargement could cause airway
obstruction.

- Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on
room air.

- Subjects must not have left ventricular ejection fraction of <40% (shortening fraction
<27% for pediatric subjects) as measured by echocardiogram or MUGA.

- Patients with the following systemic viral infections will be excluded: active HIV,
HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those
samples confirming lack of active infection will be used to generate transduced cells)
Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV
viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2,
negative for Hepatitis B surface antigen, or negative for HCV antibody or HCV viral
load.

- Patients who are on treatment for other active uncontrolled infections (not referenced
above) with resolution of signs/symptoms are not excluded. Non-influenza, non-RSV,
isolated upper respiratory infections are not excluded. Other active uncontrolled
infections will be excluded.

- Prior to procurement current use of systemic corticosteroids at doses ≥10mg/day
prednisone or its equivalent; those receiving <10mg/day may be enrolled at discretion
of investigator. Physiologic replacement with hydrocortisone is allowed at doses 6-12
mg/m2/day, or equivalent.

- Received anti-CD19 antibody-based therapy OR cytotoxic chemotherapy not described as
maintenance therapy in the procurement inclusion criteria within 2 weeks of
procurement.

Inclusion Criteria - Lymphodepletion

- Written informed consent for the main study signed by subject or legal guardian of a
pediatric subject.

- Karnofsky score > 60% if ≥16 years old or Lansky performance score of greater than 60%
if <16 years old

- Life expectancy ≥ 12 weeks.

- Subjects who have received prior therapy with murine antibodies must have
documentation of absence of human anti-mouse antibodies (HAMA) prior to
lymphodepletion on this study.

- Demonstrate adequate renal and hepatic function as defined in the table below; all
screening labs to be obtained within 72 hrs prior to lymphodepletion.

- Serum Creatinine: ≤ 1.5 x ULN

- Bilirubin: ≤ 1.5 x upper limit of normal (ULN), unless attributed to Gilbert's
Syndrome

- Aspartate Aminotransferase (AST): ≤ 3.0 × ULN

- Alanine aminotransferase (ALT): ≤ 3.0 × ULN

- For pediatric patients, adequate renal function is defined below:

Age Maximum Serum Creatinine (mg/dL) Male Female 3 to <6 years ≤0.8 ≤0.8 6 to <10 years ≤1
≤1 10 to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4 16 to <18 years ≤1.7 ≤1.4

- Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to 72 hours prior to lymphodepletion.

- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 3 months after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method. Female participants will inform their male partners that they
must use the methods of birth control required by the protocol.

- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 3 months after the last
dose of study therapy.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures.

- Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the
need for intrathecal prophylaxis prior to lymphodepletion is left to the discretion of
the investigator. Maintenance chemotherapy is defined as methotrexate ≤30 mg/m2/week,
mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. For subjects who receive
chemotherapy, including intrathecal chemotherapy, that does not fit this definition of
maintenance chemotherapy, a two week washout between the last dose of standard of care
chemotherapy and the beginning of lymphodepletion will be required.

- Subjects must have autologous transduced activated T-cells that meet the Certificate
of Analysis (CofA) acceptance criteria.

Exclusion Criteria- Lymphodepletion

- Pregnant or breastfeeding.

- Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been
disease-free for at least five years.

- Subjects must not have tumor in a location where enlargement could cause airway
obstruction.

- Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on
room air.

- Treatment with any investigational drug within 14 days (ie, two weeks) prior to
lymphodepletionn or has received any tumor vaccines within the previous five weeks
prior to lymphodepletion.

- Patients with the following systemic viral infections will be excluded: active HIV,
HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV
antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for
HTLV1 and 2, negative for Hepatitis B surface antigen, or negative for HCV antibody or
HCV viral load.

- Patients who are on treatment for other active uncontrolled infections (not referenced
above) with resolution of signs/symptoms are not excluded. Non-influenza, non-RSV,
isolated upper respiratory infections are not excluded. Other active uncontrolled
infections will be excluded.

- Use of systemic corticosteroids at doses ≥10mg/day prednisone or its equivalent; those
receiving <10mg/day may be enrolled at discretion of investigator. Physiologic
replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.

Inclusion Criteria- iC9-CAR19 Cell Infusion

- Females and males of childbearing potential must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 3 months after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method. Female participants will inform their male partners that they
must use the methods of birth control required by the protocol.

- Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 3 months after the last
dose of study therapy.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures.

Exclusion Criteria- iC9-CAR19 Cell Infusion

- Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically
necessary e.g., to treat CRS).

- Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion
may prompt exclusion from cell infusion at the discretion of the investigator.