Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma

This study is the first time iC9.GD2.CAR.IL-15 cells have been given to humans and the first
use of iC9.GD2.CAR.IL-15 T cells in combination with AP1903. AP1903 (also known as rimiducid)
is a drug that can be used to turn on (induce) the safety switch on the iC9.GD2.CAR.IL-15 T
cells if you have any bad effects, such as pain, that does not respond to normal treatment.
The FDA has not yet approved giving iC9.GD2.CAR.IL-15 T cells alone or in combination with
AP1903. Also, giving iC9.GD2.CAR.IL-15 T cells with or without lymphodepleting chemotherapy
has not yet been approved by the FDA. Additionally, AP1903 is also not a FDA-approved drug
alone or in combination with iC9.GD2.CAR.IL-15 T cells. During iC9.GD2.CAR.IL-15 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.GD2.CAR.IL-15 T cell death by apoptosis will be
given to subjects who develop grade 3 pain symptoms that do not respond to standard of care
interventions over a period of more than 3 weeks and to subjects who develop grade ≥3
neurotoxicity that does not respond to standard of care interventions.

Cell Procurement

Peripheral blood, up to 3 mL/kg (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 or patients who are unable to donate adequate
amounts of 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 cyclophosphamide 500
mg/m2/day administered IV on days 1-2 followed by an IV dose of fludarabine 30 mg/m2/day
administered on days 1-4. These agents will be administered per institutional guidelines.
Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and
cyclophosphamide chemotherapy will be provided per institutional guideline

Administration of iC9.GD2.CAR.IL-15 T cells

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
receive iC9.GD2.CAR.IL-15 T cells within 2 - 14 days after completing the lymphodepleting
chemotherapy regimen. We will administer iC9.GD2.CAR.IL-15 post lymphodepletion at dose
levels specified in the table in section 4.2. After dose exploration is completed, an
additional 8 patients will be enrolled at the maximum tolerated dose (MTD) that was
identified during dose exploration. The safety and efficacy of the MTD will be further
assessed in these 8 patients.

Duration of Therapy

Therapy in this study involves 1 infusion of iC9.GD2.CAR.IL-15 T 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:

1. Age greater than 18 months and less than 18 years at the time of consent.

2. Adequate performance status as defined by Lansky or Karnofsky performance status of ≥
60 (Lansky for <16 years of age).

3. Life expectancy >12 weeks.

4. Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial
diagnosis. Bone marrow samples are acceptable as confirmation of neuroblastoma.

5. High risk neuroblastoma with persistent or relapsed disease, defined as:

- First or greater relapse of neuroblastoma following completion of aggressive
multi-drug frontline therapy.

- First episode of progressive neuroblastoma during aggressive multi-drug frontline
therapy.

- Persistent/refractory neuroblastoma as defined by less than a complete response
(by the revised INRC) at the conclusion of at least 4 cycles of aggressive
multidrug induction chemotherapy on or according to a high-risk neuroblastoma
protocol (such as A3973 or ANBL0532).

- Patients must be diagnosed with high risk neuroblastoma at initial diagnosis or
if non-high risk at time of initial diagnosis must have had evidence of
metastatic progression when >18 months of age. (See Section 12.9 for COG and INRG
definitions if needed)

6. Subjects must have measurable or evaluable disease per Revised International
Neuroblastoma Response Criteria (See Section 12.6)

7. Adequate central nervous system function as defined by:

- No known CNS disease

- No seizure disorder requiring antiepileptic drug therapy

8. Adequate cardiac function as defined by:

• Shortening fraction of ≥27% by echocardiogram

9. Adequate pulmonary function as defined by:

• No chronic oxygen requirement and room air pulse oximetry >94%.

10. Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to cell procurement. NOTE: Premenarchal females do not require pregnancy
testing.

11. Females 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 or an intrauterine device that meets <1% failure rate for protection from
pregnancy in the product label.

12. 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.

13. As determined by the enrolling physician, subject is willing and able to comply with
study procedures.

Exclusion Criteria:

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

1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

2. Has a known additional malignancy that is active and/or progressive requiring
treatment.

3. History of hypersensitivity reactions to murine protein-containing products.

4. History of hypersensitivity to cyclophosphamide or fludarabine.

5. Systemic steroid use except as below:

- Physiologic replacement for adrenal insufficiency is allowed at doses of
hydrocortisone 6-12 mg/m2/day or equivalent.

- Inhaled steroids are allowed.

- Other than the above, systemic steroids must be stopped >14 days prior to
procurement, but may be resumed after procurement if needed as per treating
physician. Systemic steroids must be stopped 48 hours prior to lymphodepletion
and not used after infusion unless clinically required.

6. Uncontrolled infection requiring systemic therapy.

7. 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. 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.

A. Eligibility criteria to be met prior to procurement A.1 Written informed consent to
undergo cell procurement signed by legal guardian must be obtained prior to procurement.
Written assent required as applicable for age <15 years old.

A.2 Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to cell procurement. NOTE: Premenarchal females do not require pregnancy
testing.

B. Eligibility criteria to be met prior to lymphodepletion B.1 Written informed consent to
enroll in the iC9.GD2.CAR.IL-15 cell therapy trial signed by legal guardian must be
obtained prior to starting lymphodepletion. Written assent required as applicable for age
<15 years old.

B.2 Subjects who received bridging chemotherapy or radiation therapy must repeat imaging
within 14 days prior to lymphodepletion (used as baseline measure for documentation of
progression before the lymphodepletion). Required is anatomic imaging (MRI or CT) and
functional imaging with MIBG (or PET if mass is MIBG-nonavid). A mass which is neither
MIBG-avid nor PET-avid will require biopsy to confirm neuroblastoma or
ganglioneuroblastoma.

B.3 Treatment with any investigational drug within 21 days of lymphodepletion or any tumor
vaccines within the previous six weeks prior to lymphodepletion.

B.4 Adequate performance status as defined by Lansky or Karnofsky performance status of ≥
60 (Lansky for <16 years of age).

B.5 Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to lymphodepletion. NOTE: Premenarchal females do not require pregnancy
testing.

B.6 Available autologous transduced activated T cells product meets the certificate of
analysis.

B.7 Subject has not received aldesleukin (IL-2) within 28 days of starting lymphodepletion.

B.8 Subject has not received:

- filgrastim (G-CSF) (or biosimilar) within 7 days of starting lymphodepletion;

- sargramostim (GM-CSF) within 14 days of starting lymphodepletion;

- pegfilgrastim within 21 days of starting lymphodepletion.

B.9 Systemic steroid use is prohibited, except as below:

- Physiologic replacement for adrenal insufficiency is allowed at doses of
hydrocortisone 6-12 mg/m2/day or equivalent.

- Inhaled steroids are allowed.

- Other than the above, systemic steroids must be stopped 48 hours prior to
lymphodepletion and not used after infusion unless clinically required.

B.10 Prior autologous stem cell transplant is allowed as long as it occurred ≥4 weeks prior
to lymphodepletion.

B.11 Prior therapeutic 131I-MIBG is allowed as long as it is completed ≥4 weeks prior to
lymphodepletion.

B.12 Prior anti-GD2 therapy (such as dinutuximab) is allowed as long as it is completed ≥4
weeks prior to lymphodepletion.

B.13 Subject did not have major surgery within 14 days of starting lymphodepletion.

B.14 Subjects that have received bridging therapy with murine antibodies must have
documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion.

B.15 Subject is not taking a prohibited or contraindicated medication listed in Section
4.2.11 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.

B.16 Subject does not have disease progression that would, in the opinion of the treating
physician, place the subject at significant potential risk, such as location of lesion that
would have high risk with tumor swelling (examples include airway or spinal canal).

B.17 No evidence of uncontrolled infection or sepsis.

C. Eligibility criteria to be met prior to cell infusion after lymphodepletion C.1 No
evidence of uncontrolled infection or sepsis.