Master Protocol to Assess Safety and Dose of First Time in Human Next Generation Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Advanced Solid Tumors

Study Overview
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Brief Summary
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This trial will evaluate the safety and efficacy of first time in 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 have shown objective responses. GSK3901961, GSK3845097 and GSK4427296 are next generation engineered T-cell receptor (TCR) T-cells, co-expressing the cluster of differentiation 8 (CD8) alpha cell surface receptor, targeting NY-ESO-1, co-expressing the dominant-negative TGF-beta receptor type II (dnTGF-beta RII) cell surface receptor, targeting NY-ESO-1, and engineered using the Epigenetically Reprogrammed (Epi-R) manufacturing process, respectively to potentially improve function. This is a master protocol evaluating first time in human T-cell therapies. It currently consists of three independent substudies, investigating GSK3901961, GSK3845097 and GSK4427296 in human leukocyte antigen (HLA)-A*02 positive participants with NYESO1+ previously treated advanced (metastatic or unresectable) synovial sarcoma (SS)/myxoid/round cell liposarcoma (MRCLS) and/or previously treated metastatic non-small cell lung cancer (NSCLC).

Official Title
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Master Protocol to Assess the Safety and Recommended Phase 2 Dose of Next Generations of Autologous Enhanced NY-ESO-1/ LAGE-1a TCR Engineered T-cells, Alone or in Combination With Other Agents, in Participants With Advanced Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: GSK3901961
* Drug: GSK3845097
* Drug: GSK4427296
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria: Inclusion criteria: Participant must be >=18 years of age and weighs ≥40 kg 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 Participant's tumor must have tested positive for NY-ESO-1 and/or LAGE-1a expression by a GSK designated laboratory Performance status: Eastern Cooperative Oncology Group of 0-1 Participant must have adequate organ function and blood cell counts 7 days prior to leukapheresis Participant must have measurable disease according to RECIST v1.1. Additional criteria for participants with SS/ MRCLS: Participant has advanced (metastatic or unresectable) SS or MRCLS confirmed by local histopathology with evidence of disease-specific translocation Participant has completed at least one standard of care (SOC) treatment including anthracycline containing regimen unless intolerant to or ineligible to receive the therapy. Participants who are not candidates to receive anthracycline should have received ifosfamide unless also intolerant to or ineligible to receive ifosfamide. Participants who received neoadjuvant/adjuvant anthracycline or ifosfamide based therapy and progressed will be eligible Additional criteria for participants with non-small cell lung cancer (NSCLC): Participant has Stage IV NSCLC as confirmed by histology or cytology Prior therapies for participants lacking actionable genetic aberrations (i.e., wild type), per National Comprehensive Cancer Network (NCCN) guidelines: participant has been previously treated with or is intolerant to programmed death receptor-1 (PD)-1/Programmed death ligand 1 (PD-L1) checkpoint blockade therapy and has been previously treated with or is intolerant to a platinum-based chemotherapy. Adjuvant therapy will count as a regimen if completed within 6 months before relapse. Or for participants that harbors an actionable genetic aberration (e.g. BRAF, anaplastic lymphoma kinase [ALK]/ c-ros oncogene 1 [ROS1] etc.), per NCCN guidelines: participants has been previously treated with or is intolerant to SOC therapy, including targeted therapy, as recommended by NCCN or equivalent country-level guidelines (European Society for Medical Oncology [ESMO], National Institute for Health & Care Excellence [NICE]) . Or Investigator has decided that additional lines of SOC therapy after the first line are not in the participant's best interest. Exclusion criteria: Central nervous system (CNS) metastases, with certain exceptions for CNS metastases in NSCLC as specified in the protocol 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 requiring steroids or other immunosuppressive treatments Previous treatment with genetically engineered NY-ESO-1-specific T cells, NY-ESO-1 vaccine or NY-ESO-1 targeting antibody Prior gene therapy using an integrating vector Previous allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplant Washout periods for prior radiotherapy and systemic chemotherapy must be followed Major surgery within 4 weeks prior to lymphodepletion Pregnant or breastfeeding females

Ages Eligible for Study
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Minimum Age: 18 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: Cohort 1 - GSK3901961 in previously treated metastatic NSCLC<br>Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as intravenous (IV) infusion after completing lymphodepleting chemotherapy. | Drug: GSK3901961<br>* GSK3901961 as an IV infusion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>|
| Experimental: Substudy 1: Cohort 2 - GSK3901961 in previously treated advanced SS or MRCLS<br>Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as IV infusion after completing lymphodepleting chemotherapy. | Drug: GSK3901961<br>* GSK3901961 as an IV infusion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>|
| Experimental: Substudy 2: GSK3845097 in previously treated advanced SS or MRCLS<br>Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3845097, as IV infusion after completing lymphodepleting chemotherapy. | Drug: GSK3845097<br>* GSK3845097 as an IV infusion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>|
| Experimental: Substudy 3: GSK4427296 in previously treated advanced SS or MRCLS<br>Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK4427296, as IV infusion after completing lymphodepleting chemotherapy. | Drug: GSK4427296<br>* GSK4427296 as an IV infusion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy 1, 2 and 3: Frequency of dose limiting toxicities (DLTs) | Toxicities will be considered DLTs if they are considered at least possibly related to transduced T-cells; and they occur within the DLT-assessment period. | Until disease progression (up to 4 years) | 
| Substudy 1, 2 and 3: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 NCI-CTCAE, version 5.0. | Until disease progression (up to 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy 1, 2 and 3: Overall response rate (ORR) | Overall response rate is defined as the percentage of participants with a confirmed complete response (CR) or a confirmed partial response (PR) relative to the total number of participants within the relevant cohort and analysis population at any time per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by the local investigators. | Until disease progression (up to 4 years) | 
| Substudy 1, 2 and 3: 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 4 years) | 
| Substudy 1, 2 and 3: Maximum expansion/persistence (Cmax) | Whole blood samples will be collected at indicated time points for evaluation of Cmax. | Until disease progression (up to 4 years) | 
| Substudy 1, 2 and 3 : Time to Cmax (Tmax) | Whole blood samples will be collected at indicated time points for evaluation of Tmax. | Until disease progression (up to 4 years) | 
| Substudy 1, 2 and 3: Area under the concentration/persistence time curve from zero to time t (AUC[0-t]) | Whole blood samples will be collected at indicated time points for evaluation of AUC (0 to t). | Until disease progression (up to 4 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced tumors, GSK3901961, GSK4427296, T cell receptors, Leukapheresis, Advanced myxoid/round cell liposarcoma, Adoptive T-cell therapy, Advanced synovial sarcoma, Advanced non-small cell lung cancer, GSK3845097