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Letetresgene Autoleucel Engineered T Cells in NY-ESO-1 Positive Participants With Advanced Myxoid/ Round Cell Liposarcoma

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ClinicalTrials.gov Identifier: NCT02992743
Recruitment Status : Active, not recruiting
First Posted : December 14, 2016
Last Update Posted : October 18, 2021
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE December 12, 2016
First Posted Date  ICMJE December 14, 2016
Last Update Posted Date October 18, 2021
Actual Study Start Date  ICMJE December 6, 2016
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2021)
Overall Response Rate (ORR) per response evaluation criteria in solid tumors (RECIST) version 1.1 criteria by investigator assessment [ Time Frame: Up to 1 year ]
ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) per RECIST version 1.1 criteria by investigator assessment relative to the total number of participants in the analysis population.
Original Primary Outcome Measures  ICMJE
 (submitted: December 12, 2016)
Proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR). [ Time Frame: 1 Year ]
Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2021)
  • Overall Response Rate (ORR) per RECIST version 1.1 criteria by independent review [ Time Frame: Up to 1 year ]
    ORR is defined as the proportion of participants with a confirmed CR or PR per RECIST version 1.1 criteria by independent review relative to the total number of participants in the analysis population.
  • Time to response (TTR) [ Time Frame: Up to 1 year ]
    Time to Response is defined as the interval between T-cell infusion to the initial date of the confirmed response.
  • Duration of response (DOR) [ Time Frame: Up to 1 year ]
    Duration of response is defined as the interval between the initial date of the confirmed response to the date of progressive disease or death.
  • Progression Free Survival (PFS) [ Time Frame: Up to 1 year ]
    Progression free survival is defined as the interval between the date of T cell infusion and the earliest date of disease progression or death due to any cause.
  • Number of participants with adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). [ Time Frame: Up to 1 year ]
    AEs, SAEs, and AESIs will be collected.
  • Number of participants with clinically significant changes in hematology and clinical chemistry [ Time Frame: Up to 1 year ]
    Blood samples will be collected for assessment of hematology and clinical chemistry.
  • Number of participants with replication competent lentivirus (RCL) [ Time Frame: Upto 1 year ]
    RCL exposure will be assessed by polymerase chain reaction (PCR) based assay
  • Number of participants with insertional oncogenesis [ Time Frame: Upto 1 year ]
    Peripheral blood mononuclear cells (PBMC) samples will be collected for monitoring insertional oncogenesis by PCR for gene modified cells in the blood
  • Number of participants with positive anti-drug antibodies (ADA) and titers of ADA against letetresgene autoleucel [ Time Frame: Up to 1 year ]
    Serum samples will be collected to analyze for the presence of ADAs using validated immunoassays.
  • Maximum transgene expansion (Cmax) of letetresgene autoleucel [ Time Frame: Up to 1 year ]
    Blood samples will be collected to measure Cmax
  • Time to Cmax (Tmax) [ Time Frame: Up to 1 year ]
    Blood samples will be collected to measure Tmax
  • Area under the time curve from zero to time t AUC(0-t) of letetresgene autoleucel [ Time Frame: Up to 1 year ]
    Blood samples will be collected to measure AUC (0-t)
  • Number of participants with abnormal electrocardiogram (ECG) parameters [ Time Frame: Up to 1 year ]
    Participants with abnormal ECG parameters will be assessed.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2016)
  • Interval between the date of first T cell infusion dose and first documented evidence of CR or PR. [ Time Frame: 1 Year ]
    Evaluation of the efficacy of the treatment by assessment of time to first response.
  • Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause. [ Time Frame: 1 Year ]
    Evaluation of the efficacy of the treatment by assessment of duration of response.
  • Interval between the date of first documented evidence of SD until first documented disease progression or death due to any cause. [ Time Frame: 1 Year ]
    Evaluation of the efficacy of the treatment by assessment of duration of stable disease.
  • Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause. [ Time Frame: 1 Year ]
    Evaluation of the efficacy of the treatment by assessment of progression-free survival.
  • Interval between the date of first T cell infusion and date of death due to any cause. [ Time Frame: 1 Year ]
    Evaluation of the efficacy of the treatment by assessment of overall survival.
  • Number of subjects with adverse events (AE), including serious adverse events (SAE). [ Time Frame: 1 Year ]
    Determine if treatment with autologous genetically modified T cells (NY-ESO-1ᶜ²⁵⁹T) is safe and tolerable through laboratory assessments, including chemistry and hematology, and anti-NY-ESO-1 antibodies; and cardiac assessments, including ECG.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: December 12, 2016)
  • Evaluation of the persistence of genetically modified T cells. [ Time Frame: 1 Year ]
    Evaluation of the persistence of the infused T cells in the periphery.
  • Measurement of RCL in genetically modified T cells. [ Time Frame: 1 Year ]
    Evaluation of RCL in Subject PBMCs using PCR-based assay.
  • Mean fluorescence intensity (expression) of specific surface markers on gene-modified T cells [ Time Frame: 1 Year ]
    Killing profile and cytokine profile of genetically modified T cells will be evaluated using flow cytometry.
  • Percentage of total gene modified T cells with memory subtype [ Time Frame: 1 Year ]
    Memory phenotype of genetically modified T cells will be evaluated using flow cytometry.
  • Percentage of total gene modified T cells with exhaustion marker expression [ Time Frame: 1 Year ]
    Exhaustion profile of genetically modified T cells will be evaluated using flow cytometry
  • Evaluation of NY-ESO-1 expression pre and post infusion using IHC [ Time Frame: 1 Year ]
    NY-ESO-1 will be assessed in tumor biopsies taken at baseline, Week 8 and at the time of disease progression by measuring frequency (percentage of positive cells) and intensity of expression (e.g. 1+, 2+, 3+). The results will be correlated to clinical outcome.
  • Correlation of candidate biomarkers with clinical response to treatment [ Time Frame: 1 Year ]
    Biomarkers will be assessed in tumor biopsies taken at baseline, Week 8 and at the time of disease progression, and in peripheral blood by protein or gene expression analysis. Leukocyte infiltration (percentage); tumor microenvironment markers (expression level); epitope spreading (length and number of unique T cell CDR3 sequences); function and phenotype of TILs and gene-modified T cells will be assessed. The results will be correlated to clinical outcome.
  • Evaluation of cytokine levels [ Time Frame: 1 Year ]
    Analysis of serum cytokine levels taken before and after T cell infusion
  • Evaluation of germline polymorphisms in IL-6, TNF-α, IL-10, INF-γ and TGF-β and their association with cytokine release syndrome [ Time Frame: 1 Year ]
    Assessment of germline polymorphisms in the listed cytokines though analysis of peripheral blood sample
 
Descriptive Information
Brief Title  ICMJE Letetresgene Autoleucel Engineered T Cells in NY-ESO-1 Positive Participants With Advanced Myxoid/ Round Cell Liposarcoma
Official Title  ICMJE A Pilot Study of NY-ESO-1c259T Cells in Subjects With Advanced Myxoid/ Round Cell Liposarcoma
Brief Summary This trial will evaluate safety and efficacy of Letetresgene autoleucel (GSK3377794) in participants with advanced myxoid/round cell liposarcoma or high-grade myxoid liposarcoma.
Detailed Description New York esophageal antigen-1 (NY-ESO-1) and LAGE-1a antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using adoptively transferred T-cells directed against NY-ESO-1/LAGE-1a have shown objective responses. Letetresgene autoleucel (GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor (TCR) engineered T-cells. This protocol investigates Letetresgene autoleucel treatment in Human Leukocyte Antigen (HLA)-A*02+ participants with NY-ESO1+ advanced myxoid/round cell liposarcoma or high-grade myxoid liposarcoma.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: letetresgene autoleucel (GSK3377794)
    Letetresgene autoleucel (GSK3377794) as an IV infusion.
  • Drug: Cyclophosphamide
    Cyclophosphamide will be used as a lymphodepleting chemotherapy.
  • Drug: Fludarabine
    Fludarabine will be used as a lymphodepleting chemotherapy.
Study Arms  ICMJE Experimental: letetresgene autoleucel (GSK3377794)
Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive letetresgene autoleucel (GSK3377794), as a single intravenous (IV) infusion after completing lymphodepleting chemotherapy.
Interventions:
  • Drug: letetresgene autoleucel (GSK3377794)
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
Publications * Not Provided

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 23, 2021)
23
Original Estimated Enrollment  ICMJE
 (submitted: December 12, 2016)
15
Estimated Study Completion Date  ICMJE August 1, 2022
Estimated Primary Completion Date November 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participant is greater than equal to (>=)18 years of age at the time of signing the study informed consent.
  • Participant has a diagnosis of advanced (metastatic or inoperable) high grade myxoid liposarcoma / myxoid round cell liposarcoma confirmed histologically and by the presence of the reciprocal chromosomal translocation t(12;16) (q13;p11) or t(12; 22) (q13;q12).
  • Participant has measurable disease according to RECIST v1.1 criteria.
  • Participant must have previously received or be intolerant to anthracycline based therapy for advanced (metastatic or inoperable) disease.
  • Participants who received neoadjuvant/adjuvant anthracycline based therapy and progressed within 6 months of completion of therapy will be eligible.
  • Participant must be HLA A*02:01, HLA A*02:05 and/or HLA-A*02:06 positive.
  • Participant's tumor (either the most recent archival specimen or a fresh biopsy) is positive for NY-ESO-1 expression by a designated central laboratory.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
  • Participant has a left ventricular ejection fraction >=45%.
  • Participant is fit for apheresis and has adequate venous access for the cell collection.
  • Participants must satisfy pregnancy and contraceptive requirements per protocol and have adequate organ function per protocol specified values.

Exclusion Criteria:

  • Any previous gene therapy using an integrating vector.
  • Any previous allogeneic hematopoietic stem cell transplant.
  • Participant has history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
  • Participant has history of chronic or recurrent (within the last year prior to screening) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments.
  • Participant has known active brain or leptomeningeal metastases.
  • Participant has other prior malignancy that is not in complete remission.
  • Participant has uncontrolled intercurrent illness including, but not limited to:
  • (i) Ongoing or active infection.
  • (ii) Clinically significant cardiac disease
  • (iii) Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded, however, participants must not be oxygen dependent).
  • Participant has active infection with Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), ), Hepatitis C virus (HCV) or human T-lymphotropic virus (HTLV).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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  
 
Administrative Information
NCT Number  ICMJE NCT02992743
Other Study ID Numbers  ICMJE 208469
ADP-0011-007 ( Other Identifier: Adaptimmune Therapeutics )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date October 2021

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