Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

This study is a phase I dose finding trial to determine if chimeric antigen receptor T
(CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch
can be safely administered to adult subjects with relapsed or refractory B-cell Lymphoma. The
safety of iC9-CAR19 cells will be investigated using the 3+3 design. The starting dose of 1 x
106 transduced cells/kg (dose level 1) will enroll at least 3 subjects in the initial cohort.
If there are no dose limiting toxicities (DLTs) within 4 weeks of the cell infusion in these
3 subjects, then the next cohort will evaluate 2 x 106 transduced cells/kg. If there is
toxicity in 1/3 subjects in the initial cohort, the cohort will be expanded to enroll up to 6
subjects. During iC9-CAR19 T cell dose exploration, AP1903 (0.4 mg/kg), a dimerizing agent
that is designed to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T
cell death by apoptosis will be given to subjects who develop grade 4 cytokine release
syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions, and to
subjects who develop grade ≥3 CAR-T-cell-related encephalopathy syndrome (CRES) or grade 2
CRES that does not improve to grade ≤1 within 72 hours with standard of care interventions.

Cell Procurement

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

Lymphodepleting Regimen

Subjects will receive a "pre-conditioning" cytoreductive regimen of bendamustine 70 mg/m2/day
administered IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3
consecutive days. These agents will be administered per institutional guidelines. Prophylaxis
(e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
chemotherapy will be provided per institutional guideline

Administration of iC9-CAR19 T cells

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
receive iC9-CAR19 T cells within 2 - 14 days after completing the lymphodepleting
chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels
specified in the table in section 4.1. A recently published trial in refractory DLBCL
established that a dose of 2 x 106 CAR19+ T cells/kg was safe and associated with significant
in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.

Duration of Therapy

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

Duration of Follow-up

Subjects who receive a cell infusion will be followed for up to 15 years for
replication-competent retrovirus evaluation or until death, whichever occurs first. Subjects
who are removed from study and do not receive the cellular therapy product due to
unacceptable adverse events will be followed until resolution or stabilization of the adverse
event.

Inclusion Criteria for the Study:

Unless otherwise noted, subjects must meet all of the following criteria to participate in
all stages of this study:

- Written informed consent and HIPAA authorization for release of personal health
information.

- Adults ≥18 years of age.

- Histologically confirmed B-cell NHL, including the following types defined by WHO
2016:

Aggressive Lymphomas:

- DLBCL not otherwise specified (NOS)

- T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type;
EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Lymphomatoid
granulomatosis; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large
B-cell lymphoma; ALK-positive large B-cell lymphoma

- Primary mediastinal (thymic) large B-cell lymphoma

- High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade
B-cell lymphoma, NOS

- B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
classical Hodgkin lymphoma

- Transformation of indolent lymphoma or CLL to DLBCL will also be included

Indolent Lymphomas:

- Follicular lymphoma

- Splenic marginal zone lymphoma

- Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

- Nodal marginal zone lymphoma

- Mantle cell lymphoma

- Subjects with CNS disease will not be excluded as long it has been stable for 3 months

--For aggressive lymphomas, relapsed or refractory disease, defined as one of the
following:

- Residual disease after primary therapy and not eligible for autologous stem cell
transplant (ASCT)

- Relapsed or persistent disease after prior ASCT

- Beyond 1st complete remission with relapsed or persistent disease and not eligible or
appropriate for conventional allogeneic or ASCT

- For indolent lymphomas, subjects must have received at least 2 prior lines of
therapy for their lymphoma

- Subjects relapsed after allogeneic stem cell transplant will be eligible if they
meet other inclusion criteria and have no active graft vs host disease (GVHD)

- Measurable or assessable disease by Lugano criteria

- Karnofsky score of > 60%

- Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
course of the study, and for 6 months after the study is concluded. WOCBP are
those who have not been surgically sterilized or have not been free from menses
for > 1 year. The two birth control methods can be composed of: two barrier
methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP
subjects will also be instructed to tell their male partners to use a condom.

Exclusion Criteria for the Study:

Subjects meeting any of the following exclusion criteria will not be able to participate in
this study (procurement, lymphodepletion and cell infusion):

- Subject is pregnant or lactating.

- Tumor in a location where enlargement could cause airway obstruction.

- Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its
equivalent; those receiving <10mg daily may be enrolled at discretion of investigator.

- Active infection with HIV, HTLV, HBV, HCV (can be pending at the time of cell
procurement; only those samples confirming lack of active infection will be used to
generate transduced cells) defined as not being well controlled on therapy. Subjects
are required to have negative HIV antibody or negative HIV viral load, negative HTLV1
and HTLV2 antibodies, negative Hepatitis B surface antigen, and negative HCV antibody
or viral load. In addition, subjects with positive Hepatitis B core antibody, will
have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load
will also be excluded.

- Subject must either have core antibody negative HBV (results can be pending at the
time of cell procurement) OR if a subject is hepatitis B core antibody positive they
must have their hepatitis B viral load checked. These subjects will be excluded if
their viral load is positive at baseline. Subjects who are core antibody positive and
viral load negative at baseline will be considered eligible.

- 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.

Eligibility criteria to be met prior to procurement:

- Subjects must sign a consent to undergo cell procurement.

- Life expectancy ≥ 12 weeks.

- Evidence of adequate organ function as defined by:

The following is required within 7 days prior to procurement:

- Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome
may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated
bilirubin is <1.5× ULN)

- AST ≤ 3 times ULN

- Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault (See Section 12.3)

- Pulse oximetry of >90% on room air

- Left ventricular ejection fraction (LVEF) ≥35% as measured by ECHO, with no
additional evidence of decompensated heart failure.

- Imaging results from within 90 days prior to procurement to assess presence of
active disease.

- Negative serum pregnancy test within 72 hours prior to procurement or
documentation that the subject is post-menopausal. Post-menopausal status must be
confirmed with documentation of absence of menses for >1 year, or documentation
of surgical menopause involving bilateral oophorectomy.

Eligibility criteria to be met prior to lymphodepletion:

- Written informed consent to enroll in the CAR T-cell therapy trial must be obtained
prior to lymphodepletion.

- Imaging results from within 7 days prior to lymphodepletion. Imaging must occur at
least 3 weeks after most recent therapy (used as baseline measure for documentation of
progression before the lymphodepletion) to document measurable or assessable disease.
Imaging does not need to be repeated if it is within 7 days prior to lymphodepletion.

- Evidence of adequate organ function as defined by:

The following are required within 72 hours prior to lymphodepletion:

- Adequate bone marrow function (ANC ≥1.0 x 109/L and platelets ≥75 x 109/L). Subjects
cannot have received platelet transfusion within 7 days of lymphodepletion.

- Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome
may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated
bilirubin is <1.5× ULN)

- AST ≤ 3 times ULN

- Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault

- Pulse oximetry of > 90% on room air

- Negative serum pregnancy test within 72 hours prior to lymphodepletion or
documentation that the subject is post-menopausal. Post-menopausal status must be
confirmed with documentation of absence of menses for > 1 year, or documentation
of surgical menopause involving bilateral oophorectomy.

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

- Available autologous transduced activated T cells product meets the certificate
of analysis.

- Has not received any investigational agents or received any tumor vaccines within
the previous six weeks prior to lymphodepletion.

- Subject is not taking a prohibited or contraindicated medication prior to
lymphodepletion. Contraindicated medications should be discontinued at least two
weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the
contraindicated medication, whichever is shorter.

- Subject is not taking strong inhibitors of CYP1A2 (e.g., fluvoxamine,
ciprofloxacin) as these may increase plasma concentrations of bendamustine, and
decrease plasma concentrations of its metabolites. See
http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong
inhibitors of CYP1A2. (This applies to subjects who receive bendamustine for
lymphodepletion (required) up through 72 hours after the last dose of
bendamustine).

- Subject has not received chemotherapy within the previous 3 weeks prior to
lymphodepletion.

Eligibility criteria to be met prior to cell infusion after lymphodepletion:

- No evidence of uncontrolled infection or sepsis.

- Negative serum pregnancy within 7 days of cell infusion (does not need to be repeated
if pre-lymphodepletion pregnancy test is within window).