A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
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.
详细描述
Design
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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.
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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.
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Cohort 1: Complete
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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.
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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)
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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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
入排标准
- 年龄范围
- 4 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Cohort 1 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: NY-ESO-1(c259)T Cells (Drug)
Cohort 1 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: Fludarabine (Drug)
Cohort 1 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: Cyclophosphamide (Drug)
Cohort 2 treated with NY-ESO-1 T Cells
Low NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: NY-ESO-1(c259)T Cells (Drug)
Cohort 2 treated with NY-ESO-1 T Cells
Low NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: Fludarabine (Drug)
Cohort 2 treated with NY-ESO-1 T Cells
Low NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine as the lymphodepleting chemotherapy.
干预措施: Cyclophosphamide (Drug)
Cohort 3 treated with NY-ESO-1 T Cells
High NYESO-1 expression and the use of cyclophosphamide only for lymphodepletion rather than fludarabine as the lymphodepleting chemotherapy.
干预措施: NY-ESO-1(c259)T Cells (Drug)
Cohort 3 treated with NY-ESO-1 T Cells
High NYESO-1 expression and the use of cyclophosphamide only for lymphodepletion rather than fludarabine as the lymphodepleting chemotherapy.
干预措施: Cyclophosphamide (Drug)
Cohort 4 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of reduced dose cyclophosphamide plus fludarabine regimen as the lymphodepleting chemotherapy.
干预措施: NY-ESO-1(c259)T Cells (Drug)
Cohort 4 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of reduced dose cyclophosphamide plus fludarabine regimen as the lymphodepleting chemotherapy.
干预措施: Fludarabine (Drug)
Cohort 4 treated with NY-ESO-1 T Cells
High NY-ESO-1 expression and the use of reduced dose cyclophosphamide plus fludarabine regimen as the lymphodepleting chemotherapy.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to 4.5 years
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.
次要结局
- Progression Free Survival(Up to 4.5 years)
- Best Overall Response(Up to 4.5 years)
- Concentration of Cytokines in CRS by CRS Status: Cohort 4: High NY-ESO-1 Expression Treated With Regimen C(Up to Week 4)
- Time to Maximum Persistence of NY-ESO-1 Genetically Engineered T Cells(Up to 4.5 years)
- Duration of Overall Response(Up to 4.5 years)
- Overall Survival(Up to 4.5 years)
- Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)(Up to 5 years)
- Number of Participants With Worst Post-Baseline Grade Results for Hematology Parameters(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(Up to Week 4)
- Concentration of Cytokines in CRS by CRS Status: Cohort 2: Low NY-ESO-1 Expression Treated With Regimen A(Up to Week 4)
- Number of Participants With Worst Post-Baseline Grade Results for Clinical Chemistry Parameters(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(Up to 4.5 years)
- Concentration of Cytokines in CRS by CRS Status: Cohort 3: High NY-ESO-1 Expression Treated With Regimen B(Up to Week 4)