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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: NY-ESO-1(c259)T Cells
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 treated with NY-ESO-1 T Cells<br>High NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy. | Drug: NY-ESO-1(c259)T Cells<br>* Lymphodepleting chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 0.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy.<br>|
| Experimental: Cohort 2 treated with NY-ESO-1 T Cells<br>Low NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy. | Drug: NY-ESO-1(c259)T Cells<br>* Lymphodepleting chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 0.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy.<br>|
| Experimental: Cohort 3 treated with NY-ESO-1 T Cells<br>High NYESO-1 expression and the use of cyclophosphamide only for lymphodepletion rather than fludarabine as the lymphodepleting chemotherapy. | Drug: NY-ESO-1(c259)T Cells<br>* Lymphodepleting chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 0.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy.<br>|
| Experimental: Cohort 4 treated with NY-ESO-1 T Cells<br>High NY-ESO-1 expression and the use of reduced dose cyclophosphamide plus fludarabine regimen as the lymphodepleting chemotherapy. | Drug: NY-ESO-1(c259)T Cells<br>* Lymphodepleting chemotherapy followed by infusion with NY-ESO-1(c259) transduced autologous T cells. Subjects will receive one infusion of NY-ESO-1 genetically engineered T cells on Day 0.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was calculated as the percentage of participants with a confirmed complete response (CR) or partial response (PR) relative to the total number of participants in the analysis population per response evaluation criteria in solid tumors (RECIST) version (v)1.1 as determined by the local investigators. | Up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Response | Duration of overall response (DOR) is defined as the time from first documented evidence of confirmed CR or confirmed PR until first documented date of disease progression or death due to any cause or surgical resection or start of prohibited medications. Duration of overall response was evaluated per RECIST v1.1. Median and full range of DOR are presented. | Up to 4.5 years | 
| Progression Free Survival | Progression free survival is defined as the interval between the date of first T cell infusion and the earliest documented evidence of disease progression or death due to any cause or surgical resection or start of prohibited medications. Progression free survival was evaluated per RECIST v1.1. Median and inter-quartile range (first quartile and third quartile) of progression free survival are presented. | Up to 4.5 years | 
| Best Overall Response | Best overall response is the best response recorded from the start of treatment (first T cell infusion) until disease progression/recurrence. Response categories from best to worst are confirmed CR, confirmed PR, stable disease (SD) and confirmed progressive disease (PD). Best overall response is a stable disease, if CR or PR are unconfirmed. Data for number of participants with CR, PR, SD and PD are presented. | Up to 4.5 years | 
| Overall Survival | Overall survival is defined as the interval between the date of the first T-cell infusion and date of death from any cause. Median and inter-quartile range (first quartile and third quartile) of overall survival are presented. | Up to 4.5 years | 
| Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. Number of participants who had non-SAEs and SAEs are presented. | Up to 5 years | 
| Number of Participants With Worst Post-Baseline Grade Results for Hematology Parameters | Blood samples were collected for the analysis of hematology parameters. No data collected separately for this outcome measure as any abnormal value would be recorded as an adverse event. | Up to 4.5 years | 
| Number of Participants With Worst Post-Baseline Grade Results for Clinical Chemistry Parameters | Blood samples were collected for the analysis of clinical chemistry parameters. No data collected separately for this outcome measure as any abnormal value would be recorded as an adverse event. | Up to 4.5 years | 
| Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-infused (NY-ESO-1 Genetically Engineered T) Cell Antibody Result | Serum samples were collected for the determination of anti-infused (NY-ESO-1 genetically engineered T) cell antibodies (ATA) using a validated electrochemiluminescent (ECL) immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. A participant was considered to have a confirmed positive ATA result if they have a positive screening assay result and a positive confirmation assay result. | Up to 4.5 years | 
| Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 1: High NY-ESO-1 Expression Treated With Regimen A | CRS is a potentially life-threatening toxicity that is observed following administration of antibodies and adoptive T-cell therapies for cancer. Serum samples were collected to analyze the concentration of cytokines using the electrochemiluminescent tagged detection antibodies. The correlation between cytokines and cytokine release syndrome was considered between participants who had serious CRS vs no CRS or Non-serious CRS. There were only 4 participants across the whole study that had serious CRS and cytokine data was available for 3 of these participants. Due to the limited number of participants that had serious CRS no statistical correlations in cytokine levels and CRS could be performed. A listing of the levels of cytokines for the 3 participants with serious CRS is available/provided. | Up to Week 4 | 
| Concentration of Cytokines in CRS by CRS Status: Cohort 2: Low NY-ESO-1 Expression Treated With Regimen A | CRS is a potentially life-threatening toxicity that is observed following administration of antibodies and adoptive T-cell therapies for cancer. Serum samples were collected to analyze the concentration of cytokines using the electrochemiluminescent tagged detection antibodies. The correlation between cytokines and cytokine release syndrome was considered between participants who had serious CRS vs no CRS or Non-serious CRS. There were only 4 participants across the whole study that had serious CRS and cytokine data was available for 3 of these participants. Due to the limited number of participants that had serious CRS no statistical correlations in cytokine levels and CRS could be performed. A listing of the levels of cytokines for the 3 participants with serious CRS is available/provided. | Up to Week 4 | 
| Concentration of Cytokines in CRS by CRS Status: Cohort 3: High NY-ESO-1 Expression Treated With Regimen B | CRS is a potentially life-threatening toxicity that is observed following administration of antibodies and adoptive T-cell therapies for cancer. Serum samples were collected to analyze the concentration of cytokines using the electrochemiluminescent tagged detection antibodies. The correlation between cytokines and cytokine release syndrome was considered between participants who had serious CRS vs no CRS or Non-serious CRS. There were only 4 participants across the whole study that had serious CRS and cytokine data was available for 3 of these participants. Due to the limited number of participants that had serious CRS no statistical correlations in cytokine levels and CRS could be performed. A listing of the levels of cytokines for the 3 participants with serious CRS is available/provided. | Up to Week 4 | 
| Concentration of Cytokines in CRS by CRS Status: Cohort 4: High NY-ESO-1 Expression Treated With Regimen C | CRS is a potentially life-threatening toxicity that is observed following administration of antibodies and adoptive T-cell therapies for cancer. Serum samples were collected to analyze the concentration of cytokines using the electrochemiluminescent tagged detection antibodies. The correlation between cytokines and cytokine release syndrome was considered between participants who had serious CRS vs no CRS or Non-serious CRS. There were only 4 participants across the whole study that had serious CRS and cytokine data was available for 3 of these participants. Due to the limited number of participants that had serious CRS no statistical correlations in cytokine levels and CRS could be performed. A listing of the levels of cytokines for the 3 participants with serious CRS is available/provided. | Up to Week 4 | 
| Time to Maximum Persistence of NY-ESO-1 Genetically Engineered T Cells | Time to maximum persistence is defined as date of maximum persistence for infusion visit minus date of first T cell infusion visit plus 1. Median and full range of time to maximum persistence are presented. | Up to 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NY-ESO-1, T Cell Receptor, Sarcoma, Cell Therapy, T Cell Therapy, Previously treated, Metastatic, Immuno-oncology