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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01343043
Recruitment Status : Completed
First Posted : April 27, 2011
Results First Posted : July 9, 2020
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE April 26, 2011
First Posted Date  ICMJE April 27, 2011
Results First Submitted Date  ICMJE June 18, 2020
Results First Posted Date  ICMJE July 9, 2020
Last Update Posted Date July 9, 2020
Actual Study Start Date  ICMJE September 27, 2012
Actual Primary Completion Date June 18, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 18, 2020)
Objective Response Rate (ORR) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 26, 2011)
Determine the response rate. [ Time Frame: Day 28, 60, 100, 180; Month 9, 12, then q6 months x 3 yrs ]
Disease Staging Evaluation: CT scan chest, head, abdomen, pelvis. MRI of tumro, FDG-PET, Bone Scan if indicated.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 18, 2020)
  • Duration of Overall Response [ Time Frame: Up to 4.5 years ]
    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.
  • Progression Free Survival [ Time Frame: Up to 4.5 years ]
    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.
  • Best Overall Response [ Time Frame: Up to 4.5 years ]
    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.
  • Overall Survival [ Time Frame: Up to 4.5 years ]
    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.
  • Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 5 years ]
    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.
  • Number of Participants With Worst Post-Baseline Grade Results for Hematology Parameters [ Time Frame: Up to 4.5 years ]
    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.
  • Number of Participants With Worst Post-Baseline Grade Results for Clinical Chemistry Parameters [ Time Frame: Up to 4.5 years ]
    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.
  • Number of Participants With at Least One Confirmed Positive Post-Baseline Anti-infused (NY-ESO-1 Genetically Engineered T) Cell Antibody Result [ Time Frame: Up to 4.5 years ]
    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.
  • Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 1: High NY-ESO-1 Expression Treated With Regimen A [ Time Frame: Day 0 (pre-dose, 1, 2, 4, 8 and 12 hours post-dose), Day 1, Day 3, Day 4, Day 7, Week 2, Week 3 and Week 4 ]
    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 concentration of cytokines was analyzed by participant's CRS status which was categorized by 'CRS none or none serious adverse events' and 'CRS serious adverse events'. Data for concentration of different cytokines like interferon (IFN) gamma, interleukin (IL)12, IL13, IL6, IL8, and tumor necrosis factor (TNF) is presented by 'CRS none or none serious adverse events' and 'CRS serious adverse events' for cohort 1 'High NY-ESO-1 expression treated with Regimen A'.
  • Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 2: Low NY-ESO-1 Expression Treated With Regimen A [ Time Frame: Day 0 (pre-dose, 1, 2 and 4 hours post-dose), Day 1, Day 3, Day 4, Day 7, Week 2, Week 3 and Week 4 ]
    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 concentration of cytokines was analyzed by participant's CRS status which was categorized by 'CRS none or none serious adverse events' and 'CRS serious adverse events'. Data for concentration of different cytokines like IFN gamma, IL12, IL13, IL6, IL8, and TNF is presented by 'CRS none or none serious adverse events' and 'CRS serious adverse events' for cohort 2 'Low NY-ESO-1 expression treated with Regimen A'.
  • Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 3: High NY-ESO-1 Expression Treated With Regimen B [ Time Frame: Day 0 (pre-dose and post-dose), Day 1, Day 3, Day 4, Day 7, Week 2, Week 3 and Week 4 ]
    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 concentration of cytokines was analyzed by participant's CRS status which was categorized by 'CRS none or none serious adverse events'. Data for concentration of different cytokines like IFN gamma, IL12, IL13, IL6, IL8, and TNF is presented by 'CRS none or none serious adverse events' for Cohort 3 'High NY-ESO-1 expression treated with Regimen B'.
  • Concentration of Cytokines in Cytokine Release Syndrome (CRS) by CRS Status: Cohort 4: High NY-ESO-1 Expression Treated With Regimen C [ Time Frame: Day 0 (pre-dose, 1 and 2 hours post-dose), Day 1, Day 4, Day 7, Week 2, Week 3 and Week 4 ]
    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 concentration of cytokines was analyzed by participant's CRS status which was categorized by 'CRS none or none serious adverse events'. Data for concentration of different cytokines like IFN gamma, IL12, IL13, IL6, IL8, and TNF is presented by 'CRS none or none serious adverse events' for Cohort 4 'High NY-ESO-1 expression treated with Regimen C'.
  • Time to Maximum Persistence of NY-ESO-1 Genetically Engineered T Cells [ Time Frame: Up to 4.5 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2011)
Evaluate persistence and expansion of NY-ESO-1 cells [ Time Frame: Daily Days 0-14, D21, D28, D42, D60, Mo: 3, 4, 5, 6, 9, 12; q6mo for 3 yrs ]
Research Analysis
Current Other Pre-specified Outcome Measures
 (submitted: June 18, 2020)
  • Number of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: Up to Day 21 (from first dose) ]
    DLT was planned to be evaluated. An event was to be considered a DLT if it occurred within the first 21 days of treatment, and met one of the protocol defined DLT criteria.
  • Number of Participants With Clinically Significant Abnormal Electrocardiogram, Echocardiogram and Multigated Acquisition Scan Findings [ Time Frame: Up to 4.5 years ]
    Abnormal electrocardiogram, echocardiogram and multigated acquisition scan findings were planned to be evaluated. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee.
  • Percentage of Participants With Confirmed CR [ Time Frame: Up to 4.5 years ]
    Participants were planned to be evaluated for confirmed CR according to RECIST v1.1, after receiving a second dose of NY-ESO-1 genetically engineered T cell infusion
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma
Official Title  ICMJE A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma
Brief Summary 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

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE Biological: NY-ESO-1(c259)T Cells
Cytoreductive 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.
Study Arms  ICMJE
  • Experimental: Cohort 1 treated with NY-ESO-1 T Cells
    High NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine. (COMPLETE)
    Intervention: Biological: NY-ESO-1(c259)T Cells
  • Experimental: Cohort 2 treated with NY-ESO-1 T Cells
    Low NY-ESO-1 expression and the use of cyclophosphamide plus fludarabine.
    Intervention: Biological: NY-ESO-1(c259)T Cells
  • Experimental: Cohort 3 treated with NY-ESO-1 T Cells
    High NYESO-1 expression and the use of cyclophosphamide only for lymphodepletion rather than fludarabine. (COMPLETE)
    Intervention: Biological: NY-ESO-1(c259)T Cells
  • Experimental: Cohort 4 treated with NY-ESO-1 T Cells
    High NY-ESO-1 expression and the use of reduced dose cyclophosphamide plus fludarabine regimen.
    Intervention: Biological: NY-ESO-1(c259)T Cells
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 18, 2020)
50
Original Estimated Enrollment  ICMJE
 (submitted: April 26, 2011)
10
Actual Study Completion Date  ICMJE June 18, 2019
Actual Primary Completion Date June 18, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Canada,   France,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT01343043
Other Study ID Numbers  ICMJE 208466
ADP 04511 ( Other Identifier: Adaptimmune Therapeutics )
2015-005594-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP