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

The purpose of this early (pilot) clinical trial is to test the effects (both good and bad) of chemotherapy and adoptive immunotherapy with T cells engineered to recognize NY-ESO-1 peptide in patients with unresectable, metastatic or recurrent synovial sarcoma.

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.

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.

Lead Organization
Adaptimmune Limited