Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Study Overview
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Brief Summary
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This trial will evaluate safety and efficacy of human engineered T-cell therapies, in participants with advanced tumors. This trial is a sub study of the Master study NCT03967223.

Official Title
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Evaluation of Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Letetresgene autoleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be greater than or equal to 10 years of age on the day of signing informed consent. Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a designated central laboratory Participant's tumor is positive for NY-ESO-1 expression by a designated central laboratory. Participant has a diagnosis of synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) Performance status: dependent on age - Lansky > 60, Karnofsky > 60, Eastern Cooperative Oncology Group 0-1. Participant must have adequate organ function and blood cell counts, within 7 days prior to leukapheresis. At time of treatment, participant has measurable disease according to RECIST v1.1. Consultation for prior history per protocol specifications. Exclusion Criteria: Central nervous system metastases. Any other prior malignancy that is not in complete remission. Clinically significant systemic illness. Prior or active demyelinating disease. History of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn's disease, systemic lupus) requiring steroids or other immunosuppressive treatments. Previous treatment with genetically engineered NY-ESO-1-specific T cells. Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody. Prior gene therapy using an integrating vector. Previous allogeneic hematopoietic stem cell transplant. Washout periods for prior radiotherapy and systemic chemotherapy must be followed. Participant had major surgery in less than or equal to 28 days of first dose of study intervention. Prior radiation exceeds protocol specified limits.

Ages Eligible for Study
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Minimum Age: 10 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letetresgene autoleucel<br> | Drug: Letetresgene autoleucel<br>* Letetresgene autoleucel will be administered.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as a lymphodepleting chemotherapy.<br>Drug: Fludarabine<br>* Fludarabine will be used as a lymphodepleting chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) via investigator assessment per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1 relative to the total number of participants in the analysis population. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). 95% CI is based on Clopper-Pearson exact confidence interval. | Up to approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response (TTR) | Time to response was defined as the interval of time between the date of T-cell infusion and the first documented evidence of the confirmed response (PR or CR), in the subset of participants with a confirmed PR or CR as their best confirmed overall response. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). | Up to approximately 54 months | 
| Duration of Response (DOR) | Duration of response was defined as the interval between the initial date of confirmed response (PR/CR) and the date of progressive disease as assessed by local investigators, or death among participants with a confirmed response per RECIST 1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). | Up to approximately 54 months | 
| Disease Control Rate (DCR) | DCR is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) with a minimal 12 weeks (84 days ± 7 day window) duration relative to the total number of participants within the analysis population at the time of primary analysis as determined by local investigators per RECIST v1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. The disease progression (PD) is defined as the date of radiological disease progression based on imaging data per RECIST v1.1. 95% CI is based on Clopper-Pearson exact confidence interval. | Up to approximately 36 months | 
| Progression Free Survival (PFS) | PFS is defined as the interval of time between from the date of T-cell infusion to the earliest date of radiological progression of disease (PD) as assessed by local investigator per RECIST v1.1, or death due to any cause. The PD is defined as the date of radiological disease progression based on imaging data per RECIST v1.1. | Up to approximately 54 months | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An AE is any untoward medical occurrence in a clinical investigation 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, at any dose 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 which involve medical or scientific judgment or is associated with liver injury and impaired liver function. | Up to approximately 54 months | 
| Number of Participants With AEs of Special Interest (AESIs) | An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days. | Up to approximately 54 months | 
| Number of Participants With TEAEs and TESAEs by Severity | An AE is any untoward medical occurrence in a clinical investigation 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, at any dose 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 which involve medical or scientific judgment or is associated with liver injury and impaired liver function. AEs and SAEs were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences; Grade 5- Death related to AE. | Up to approximately 54 months | 
| Number of Participants With AESIs by Severity | An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days. | Up to approximately 54 months | 
| Percentage of Participants With Replication Competent Lentivirus (RCL) Positive | RCL was monitored using a polymerase chain reaction (PCR)-based assay that detects and measures copies of the gene coding for the vector's envelope protein, namely vesicular stomatitis virus G protein (VSV-G). | Up to approximately 54 months | 
| Instances of Insertional Oncogenesis (IO) | Instances of Insertional Oncogenesis (IO) was summarized descriptively. | Up to approximately 54 months | 
| Maximum Transgene Expansion (Cmax) | Cmax was defined as maximum observed persistence, determined directly from the persistence-time data. Blood samples were collected for PK analysis. | Day 1 to Day 14 | 
| Time to Cmax (Tmax) | Tmax was defined as time to reach Cmax, determined directly from the persistence-time data. Blood samples were collected for PK analysis. | Day 1 to Day 14 | 
| Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28]) | Area under the persistence-time curve from time zero to Day 28. Blood samples were collected for PK analysis. | Up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adoptive T-cell therapy, Letetresgene autoleucel, Lete-cel, GSK3377794