A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma

Design

- Patients will undergo apheresis at the enrolling institution. PBMC will be shipped to a
central manufacturer for gene transduction, activation and expansion, then cryopreserved
and shipped back to the enrolling institution.

- The trial seeks to enroll up to 65 patients, that is, up to 20 patients in Cohort 1 and
up to 15 patients in Cohorts 2-4. Depending on the cohort patients are enrolled in,
patients will undergo lymphodepletion with cyclophosphamide with or without fludarabine.

- Cohort 1: Complete

- Cohort 2: Up to 15 patients may be enrolled to achieve at least 10 evaluable
patients treated with NY-ESO-1ᶜ²⁵⁹T. Patients will undergo lymphodepletion with
cyclophosphamide plus fludarabine on Days -3 and -2, and without fludarabine on
Days -5 and -4.

- Cohort 3: Up to 15 patients may be enrolled to achieve at least 10 evaluable
patients treated with NY-ESO-1ᶜ²⁵⁹T. Patients will undergo lymphodepletion with
cyclophosphamide only on Days -3 and -2. (Cohort Complete)

- Cohort 4: Up to 15 patients may be enrolled to achieve at least 5 evaluable
patients treated with NY-ESO-1ᶜ²⁵⁹T. Patients will undergo lymphodepletion with
cyclophosphamide plus fludarabine on Days -7 to -5.

On Day 0, patients ≥40 kg will receive the minimum cell dose of at least 1x10⁹ transduced
NY-ESO-1ᶜ²⁵⁹T cells with a maximum of 6x10⁹ transduced cells. The target dose for this
protocol is 5x10⁹ transduced NY-ESO-1ᶜ²⁵⁹T cells. Patients <40 kg will be dosed per body
weight with a minimum 0.025x10⁹ transduced cells/kg, with a target dose of 0.125 x10⁹
transduced cells/kg.

- Patients will be monitored for toxicity, antitumor effects and immune endpoints.

- Patients who have a confirmed response, or have stable disease for >3 months then
progress may receive a 2nd T cell infusion, provided eligibility criteria are met. The
2nd treatment cell infusion will be administered in the same manner as the first.
Patients who meet the eligibility criteria may receive a 2nd infusion of NY-ESO-1ᶜ²⁵⁹T
no sooner than 60 days and no later than 2 years following completion of the first
treatment.

Inclusion Criteria:

- Synovial sarcoma that has been treated with standard chemotherapy containing
ifosfamide and/or doxorubicin and remains: unresectable or metastatic or
progressive/persistent or recurrent disease

- Measurable disease

- Patients must have proven positive tumor sample for NY-ESO-1 as follows:

- Cohort 1 -Positive expression is defined as 2+ and/or 3+ by immunohistochemistry
in ≥ 50% of cells.

- Cohort 2 -Positive expression is defined as ≥1+ by immunohistochemistry in ≥1%
cells, but not to exceed 2+ and/or 3+ in ≥ 50% of cells.

- Cohort 3 -Positive expression is defined as 2+ and/or 3+ by immunohistochemistry
in ≥ 50% of cells.

- Cohort 4 -Positive expression is defined as 2+ and/or 3+ by immunohistochemistry
in ≥ 50% of cells.

- HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 by high resolution testing at a local or
central laboratory

- Weigh more than 18 kg

- All previous cytotoxic chemotherapy, monoclonal antibody therapy, or immune therapy
must be washed out 3 weeks before apheresis and must be completed at least 3 weeks
prior to pre-infusion lymphodepletive chemotherapy.

- Systemic corticosteroid or other immunosuppressive therapy should be washed out 2
weeks before apheresis and must be completed at least 2 weeks prior to pre-infusion
lymphodepletive chemotherapy.

- Biologic or other approved molecular targeted small molecule inhibitors should be
washed out 1 week or 5 half-lives (whichever is longer) before apheresis and must be
completed at least 1 week or 5 half-lives (whichever is longer) prior to pre-infusion
lymphodepletive chemotherapy.

- Any grade 3 or 4 hematologic toxicity of any previous therapy must have resolved to
grade 2 or less prior to apheresis and any grade 3 or 4 toxicity must have resolved to
grade 2 or less prior to pre-infusion lymphodepletive chemotherapy.

- ECOG 0-1, or for children ≤10 years of age, Lansky > 60

- Life expectancy > 3 months

- Left ventricular ejection fraction ≥ 40% or fractional shortening ≥ 28%

- T. bilirubin < 2 mg/dl (Patients with Gilbert Syndrome total bilirubin <3xULN and
direct bilirubin ≤ 35%)

- AST, ALT ≤ 2.5 x upper limit of normal

- ANC ≥ 1.0 x 10⁹/L

- Platelets ≥ 75 x 10⁹/L

- Age-adjusted normal serum creatinine or a creatinine clearance ≥ 40 ml/min

- Ability to give informed consent for patients greater than 18 years of age. For
patients less than 18 years of age the legal guardian must give informed consent.

- Male patients must be willing to practice birth control (including abstinence) during
and for 4 months after treatment. Female patients must be willing to practice birth
control (including abstinence) during treatment and for 4 months after gene modified
cells are no longer detected in body.

Exclusion Criteria:

- Active HIV, HBV, HCV or HTLV 1/2 infection (due to increased risk of complications
during lymphodepleting regimen and confounding effects on the immune system). Active
hepatitis B or C infection is defined by seropositive for hepatitis B surface antigen
(HbSAg) or hepatitis C antibody.