Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumors

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.

Detailed Description
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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 (lete-cel, GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor engineered T cells. This is a master protocol investigating T-cell therapies. It will initially consist of a core protocol with two independent substudies investigating Letetresgene autoleucel in previously untreated (1L) Human Leukocyte Antigen (HLA)-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) (Substudy 1) and Letetresgene autoleucel as second line or higher (2L+) treatment in HLA-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) SS or MRCLS who have progressed following treatment with anthracycline based chemotherapy (Substudy 2).

Official Title
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Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered NY-ESO-1-Specific (c259) T Cells, Alone or in Combination With Other Agents, in HLA-A2+ Participants With NY-ESO-1 and/or LAGE-1a Positive Solid Tumors (IGNYTE-ESO)

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Letetresgene autoleucel (lete-cel, GSK3377794)
* Drug: Fludarabine
* Drug: Cyclophosphamide


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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1: lete-cel in previously untreated advanced (metastatic or unresectable) SS or MRCLS<br>Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. | Drug: Letetresgene autoleucel (lete-cel, GSK3377794)<br>* letetresgene autoleucel will be administered.<br>Drug: Fludarabine<br>* Fludarabine will be used as the lymphodepleting chemotherapy<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as the lymphodepleting chemotherapy.<br>|
| Experimental: Substudy 2: lete-cel in advanced (metastatic or unresectable) SS or MRCLS post anthracycline chemo<br>Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. | Drug: Letetresgene autoleucel (lete-cel, GSK3377794)<br>* letetresgene autoleucel will be administered.<br>Drug: Fludarabine<br>* Fludarabine will be used as the lymphodepleting chemotherapy<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as the lymphodepleting chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy 1: Overall response rate (ORR) | Overall response rate is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) relative to the total number of participants within the analysis population at any time per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. as determined by the local investigators. | Until disease progression (up to 5 years) | 
| Substudy 2: Overall response rate (ORR) as assessed by central independent review | Overall response rate is defined as the percentage of participants with a confirmed CR or PR relative to the total number of participants within the analysis population at any time per RECIST v1.1. as assessed by central independent review. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy 1 and 2: Time to response (TTR) | Time to response is defined as time from date of T-cell administration to first documented evidence of confirmed (CR or PR) as assessed by local investigators per RECIST v1.1. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Duration of response (DOR) | Duration of response is defined as, in the subset of participants who show a confirmed CR or PR as assessed by local investigators, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Disease control rate (DCR) | Disease control rate is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) with minimal 12 weeks duration relative to the total number of participants within the analysis population at the time of primary analysis as determined by Investigators per RECIST v1.1. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Progression free survival (PFS) | Progression free survival is defined as the time from the date of T-cell administration until first documented sign of disease progression per RECIST v1.1, or death. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Frequency of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI) according to severity | AEs, SAEs and AESIs will be collected. Severity of AEs and SAEs will be summarized using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Number of participants with replication competent lentivirus (RCL) | RCL exposure will be assessed by polymerase chain reaction (PCR) based assay. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Number of participants with insertional oncogenesis (IO) | Peripheral blood mononuclear cells (PBMC) samples will be collected for monitoring insertional oncogenesis by PCR for gene modified cells in the blood. | Until disease progression (up to 5 years) | 
| Substudy 2: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis parameters | Blood and urine samples will be collected for assessment of hematology, clinical chemistry and urinalysis parameters. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Maximum transgene expansion (Cmax) of letetresgene autoleucel | Whole blood samples will be collected at indicated time points for evaluation of Cmax. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Time to Cmax (Tmax) of letetresgene autoleucel | Whole blood samples will be collected at indicated time points for evaluation of Tmax. | Until disease progression (up to 5 years) | 
| Substudy 1 and 2: Area under the concentration/persistence time curve from zero to time t (AUC[0-t]) of letetresgene autoleucel | Whole blood samples will be collected at indicated time points for evaluation of AUC(0-t). | Until disease progression (up to 5 years) | 
| Substudy 2: Overall response rate (ORR) as determined by the local investigators | Overall response rate is defined as the percentage of participants with a confirmed CR or PR relative to the total number of participants within the analysis population at any time per RECIST v1.1. as determined by the local investigators. | Up to 5 years | 
| Substudy 2: Overall Survival (OS) | Overall Survival is defined as the interval of time between the date of T-cell infusion and the date of death. | Up to 5 years | 
| Substudy 2: Number of participants with positive anti-drug antibodies (ADA) and titers of ADA against letetresgene autoleucel | Serum samples will be collected to analyze for the presence of ADAs using validated immunoassays. | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adoptive T-cell therapy, Advanced metastatic disease, Advanced unresectable disease, Synovial sarcoma, Myxoid/round cell liposarcoma, GSK3377794, Positive solid tumors, T-cell receptors, Leukapheresis, Letetresgene autoleucel, Lete-cel