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

• ClinicalTrials.gov Identifier: NCT05993299
• Recruitment Status: Active, not recruiting
• First Posted: August 15, 2023
• Results First Posted: October 16, 2023
• Last Update Posted: October 16, 2023
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: Letetresgene autoleucel; Drug: Cyclophosphamide; Drug: Fludarabine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 31, 2019
• Actual Primary Completion Date: October 12, 2022
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Letetresgene autoleucel	Drug: Letetresgene autoleucel; Letetresgene autoleucel will be administered.; Drug: Cyclophosphamide; Cyclophosphamide will be used as a lymphodepleting chemotherapy.; Drug: Fludarabine; Fludarabine will be used as a lymphodepleting chemotherapy.

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: Up to approximately 36 months ]
   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.

Secondary Outcome Measures :

1. Time to Response (TTR) [ Time Frame: Up to approximately 54 months ]
   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).
2. Duration of Response (DOR) [ Time Frame: Up to approximately 54 months ]
   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).
3. Disease Control Rate (DCR) [ Time Frame: Up to approximately 36 months ]
   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.
4. Progression Free Survival (PFS) [ Time Frame: Up to approximately 54 months ]
   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.
5. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to approximately 54 months ]
   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.
6. Number of Participants With AEs of Special Interest (AESIs) [ Time Frame: Up to approximately 54 months ]
   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.
7. Number of Participants With TEAEs and TESAEs by Severity [ Time Frame: Up to approximately 54 months ]
   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.
8. Number of Participants With AESIs by Severity [ Time Frame: Up to approximately 54 months ]
   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.
9. Percentage of Participants With Replication Competent Lentivirus (RCL) Positive [ Time Frame: Up to approximately 54 months ]
   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).
10. Instances of Insertional Oncogenesis (IO) [ Time Frame: Up to approximately 54 months ]
    Instances of Insertional Oncogenesis (IO) was summarized descriptively.
11. Maximum Transgene Expansion (Cmax) [ Time Frame: Day 1 to Day 14 ]
    Cmax was defined as maximum observed persistence, determined directly from the persistence-time data. Blood samples were collected for PK analysis.
12. Time to Cmax (Tmax) [ Time Frame: Day 1 to Day 14 ]
    Tmax was defined as time to reach Cmax, determined directly from the persistence-time data. Blood samples were collected for PK analysis.
13. Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28]) [ Time Frame: Up to 28 days ]
    Area under the persistence-time curve from time zero to Day 28. Blood samples were collected for PK analysis.

Eligibility Criteria

• Ages Eligible for Study: 10 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Pennsylvania

GSK Investigational Site

Pittsburgh, Pennsylvania, United States, 15232

United States, Texas

GSK Investigational Site

Dallas, Texas, United States, 75390-9063

United States, Wisconsin

GSK Investigational Site

Milwaukee, Wisconsin, United States, 53226

Canada, Quebec

GSK Investigational Site

Montreal, Quebec, Canada, H1T 2M4

Netherlands

GSK Investigational Site

Amsterdam, Netherlands, 1066 CX

United Kingdom

GSK Investigational Site

London, United Kingdom, SW3 6JJ

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] November 4, 2021

Statistical Analysis Plan  [PDF] December 7, 2022

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT05993299
• Other Study ID Numbers: 208467 Substudy 1
• First Posted: August 15, 2023
• Results First Posted: October 16, 2023
• Last Update Posted: October 16, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an 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 may be granted, when justified, for up to 6 months.
• URL: http://www.gsk.com/en-gb/innovation/trials/data-transparency/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:

Adoptive T-cell therapy; Letetresgene autoleucel; Lete-cel; GSK3377794

Additional relevant MeSH terms:

Liposarcoma; Sarcoma, Synovial; Liposarcoma, Myxoid; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Adipose Tissue; Neoplasms, Connective Tissue; Cyclophosphamide; Fludarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists