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

• ClinicalTrials.gov Identifier: NCT04526509
• Recruitment Status: Recruiting
• First Posted: August 25, 2020
• Last Update Posted: April 22, 2022
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: August 21, 2020
• First Posted Date: August 25, 2020
• Last Update Posted Date: April 22, 2022
• Actual Study Start Date: December 21, 2020
• Estimated Primary Completion Date: February 13, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2022)

• Substudy 1, 2 and 3: Frequency of dose limiting toxicities (DLTs) [ Time Frame: Until disease progression (up to 4 years) ]
  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.
• Substudy 1, 2 and 3:Frequency of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI) according to severity [ Time Frame: Until disease progression (up to 4 years) ]
  AEs, SAEs and AESIs will be collected. Severity of AEs and SAEs will be summarized using NCI-CTCAE, version 5.0.

Original Primary Outcome Measures (submitted: August 21, 2020)

• Substudy 1 and 2: Number of participants with dose limiting toxicities (DLTs) [ Time Frame: Until disease progression (up to 4 years) ]
  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.
• Substudy 1 and 2: Severity of DLTs [ Time Frame: Until disease progression (up to 4 years) ]
  Severity of DLTs will be summarized using National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Substudy 1 and 2: Number of participants with adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI) [ Time Frame: Until disease progression (up to 4 years) ]
  AEs, SAEs and AESIs will be collected.
• Substudy 1 and 2: Severity of AEs, SAEs and AESIs [ Time Frame: Until disease progression (up to 4 years) ]
  Severity of AEs, SAEs and AESIs will be summarized using NCI-CTCAE, version 5.0.

Current Secondary Outcome Measures (submitted: April 14, 2022)

• Substudy 1, 2 and 3: Overall response rate (ORR) [ Time Frame: Until disease progression (up to 4 years) ]
  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 analysis population at any time per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by the local investigators.
• Substudy 1, 2 and 3: Duration of response (DOR) [ Time Frame: Until disease progression (up to 4 years) ]
  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.
• Substudy 1, 2 and 3: Maximum expansion/persistence (Cmax) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of Cmax.
• Substudy 1, 2 and 3 : Time to Cmax (Tmax) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of Tmax.
• Substudy 1, 2 and 3: Area under the concentration/persistence time curve from zero to time t (AUC[0-t]) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of AUC (0 to t).

Original Secondary Outcome Measures (submitted: August 21, 2020)

• Substudy 1 and 2: Overall response rate [ Time Frame: Until disease progression (up to 4 years) ]
  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 analysis population at any time per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by the local investigators.
• Substudy 1 and 2: Duration of response [ Time Frame: Until disease progression (up to 4 years) ]
  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.
• Substudy 2: Progression free survival [ Time Frame: Until disease progression (up to 4 years) ]
  Progression free survival is defined as the time from the date of T-cell infusion until the first documented sign of disease progression per RECIST version 1.1 as determined by the local investigators or death due to any cause.
• Substudy 2: Disease control rate [ Time Frame: Until disease progression (up to 4 years) ]
  Disease control rate is defined as the percentage of patients 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 any time per RECIST version 1.1 as determined by the local investigators.
• Substudy 2: Time to response [ Time Frame: Until disease progression (up to 4 years) ]
  Time to response is defined as, in the subset of patients who achieved a confirmed PR or CR as assessed by local investigators per Response evaluation criteria in solid tumors (RECIST) version 1.1, the time from the date of T-cell infusion to first documented evidence of confirmed CR or PR.
• Substudy 1 and 2: Maximum expansion/persistence (Cmax) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of Cmax.
• Substudy 1 and 2: Time to Cmax (Tmax) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of Tmax.
• Substudy 1 and 2: Area under the concentration/persistence time curve from zero to time t (AUC[0-t]) [ Time Frame: Until disease progression (up to 4 years) ]
  Whole blood samples will be collected at indicated time points for evaluation of AUC (0 to t).
• Substudy 1 and 2: Phenotype of transduced T cells [ Time Frame: Until disease progression (up to 4 years) ]
  Tumor samples will be collected to assess phenotype of transduced T cells.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: This trial will evaluate the safety and efficacy of first time in human engineered T-cell therapies, in participants with advanced tumors.
• 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 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).
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

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

This will be an open-label study. Hence, there will be no masking

Primary Purpose: Treatment

• Condition: Neoplasms

Intervention

• Drug: GSK3901961
  GSK3901961 as an IV infusion.
• Drug: GSK3845097
  GSK3845097 as an IV infusion.
• Drug: GSK4427296
  GSK4427296 as an IV infusion.
• Drug: Cyclophosphamide
  Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.
• Drug: Fludarabine
  Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.

Study Arms

• Experimental: Substudy 1: Cohort 1 - GSK3901961 in previously treated metastatic NSCLC
  Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as intravenous (IV) infusion after completing lymphodepleting chemotherapy.
  Interventions:

  • Drug: GSK3901961
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: Substudy 1: Cohort 2 - GSK3901961 in previously treated advanced SS or MRCLS
  Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as IV infusion after completing lymphodepleting chemotherapy.
  Interventions:

  • Drug: GSK3901961
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: Substudy 2: GSK3845097 in previously treated advanced SS or MRCLS
  Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3845097, as IV infusion after completing lymphodepleting chemotherapy.
  Interventions:

  • Drug: GSK3845097
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: Substudy 3: GSK4427296 in previously treated advanced SS or MRCLS
  Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK4427296, as IV infusion after completing lymphodepleting chemotherapy.
  Interventions:

  • Drug: GSK4427296
  • Drug: Cyclophosphamide
  • Drug: Fludarabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 14, 2022): 50
• Original Estimated Enrollment (submitted: August 21, 2020): 38
• Estimated Study Completion Date: February 13, 2024
• Estimated Primary Completion Date: February 13, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Eligibility Criteria:

Inclusion criteria:

• Participant must be >=18 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
• Participant's tumor must have tested positive for NY-ESO-1/ 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 synovial sarcoma/ MRCLS:

• Participant has advanced (metastatic or unresectable) synovial sarcoma or MRCLS confirmed by local histopathology with evidence of disease-specific translocation
• Participant has received/completed treatment with anthracycline or with ifosfamide if intolerant to anthracycline for advanced (metastatic or unresectable) disease and progressed

Additional criteria for participants with non-small cell lung cancer (NSCLC):

• Participant has Stage IV NSCLC as confirmed by histology or cytology
• 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. For NSCLC that harbors an actionable genetic aberration (BRAF, anaplastic lymphoma kinase [ALK]/ c-ros oncogene 1 [ROS1]) per National Comprehensive Cancer Network (NCCN) guidelines, participant has also been previously treated with or is intolerant to the standard of care targeted therapy as recommended by NCCN or equivalent country-level guidelines (European Society for Medical Oncology [ESMO], National Institute for Health & Care Excellence [NICE])

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: US GSK Clinical Trials Call Center; 877-379-3718; GSKClinicalSupportHD@gsk.com

Contact: EU GSK Clinical Trials Call Center; +44 (0) 20 89904466; GSKClinicalSupportHD@gsk.com

• Listed Location Countries: Australia, Canada, Germany, Netherlands, Sweden, United States

Administrative Information

• NCT Number: NCT04526509
• Other Study ID Numbers: 209012; 2019-004446-14 ( EudraCT Number )
• 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

• 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

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Same as current
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: April 2022