Study of GSK3845097 in Previously Treated Participants With Advanced Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Assessment of Safety and Recommended Phase 2 Dose of Autologous T Cells Engineered With an Affinity-enhanced TCR Targeting NY ESO 1 and LAGE 1a, and Co-expressing the dnTGF-βRII (GSK3845097) in Participants With NY ESO 1 and/or LAGE 1a Positive Previously Treated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

To assess the safety, tolerability and determine recommended phase 2 dose (RP2D) of GSK3845097 in HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 positive participants with New York esophageal squamous cell carcinoma (NY-ESO)-1 and/or Cancer testis antigen 2 (LAGE-1a) positive, previously treated, advanced (metastatic or unresectable) Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCLS).

Study Overview

• Status: Terminated
• Conditions: Neoplasms
• Intervention / Treatment: Drug: GSK3845097; Drug: Cyclophosphamide; Drug: Fludarabine

Detailed Description

This study is a substudy of the Master record - (209012) NCT04526509.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • GSK Investigational Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • GSK Investigational Site
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • GSK Investigational Site
• Germany
  • Bayern
    • Muenchen, Bayern, Germany, 81377
      • GSK Investigational Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • GSK Investigational Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • GSK Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • GSK Investigational Site
• Sweden
  • Stockholm, Sweden, SE-171 64
    • GSK Investigational Site
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • GSK Investigational Site
  • Florida
    • Jacksonville, Florida, United States, 32224
      • GSK Investigational Site
    • Tampa, Florida, United States, 33612
      • GSK Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • GSK Investigational Site
  • Kansas
    • Westwood, Kansas, United States, 66205
      • GSK Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • GSK Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • GSK Investigational Site
  • New York
    • New York, New York, United States, 10032
      • GSK Investigational Site
    • New York, New York, United States, 10065
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • GSK Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.
• 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GSK3845097; Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive high dose of GSK3845097 after completing lymphodepleting chemotherapy. The first study participant receiving GSK3845097 will receive the total assigned dose as 2 separate infusions 7 days apart, in aliquots of 30% (first infusion) and 70% (second infusion) of the total target dose , respectively. Based on the dose limiting toxicities reported in the first participant, then all subsequent participants treated with GSK3845097 will receive the full dose as a single, i.e., one-time, infusion.

Drug: GSK3845097; GSK3845097 was administered.; Drug: Cyclophosphamide; Cyclophosphamide was administered as lymphodepleting chemotherapy.; Drug: Fludarabine; Fludarabine was administered as lymphodepleting chemotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs)	DLT events were graded according to NCI-CTCAE v5.0. DLTs were defined as Grade (Gr) 4 (life-threatening and death) related to GSK3845097 2) Gr 3 (Severe or medically significant) at least possibly related to GSK3845097 and do not resolve to Gr <=1 (or Baseline) within 7 days from the onset of the event 3) Gr >=3 non-infectious pneumonitis not responding to oxygen supplementation and systemic steroid treatment 4) Any Gr 3 cytokine release syndrome (CRS) at least possibly related to GSK3845097 that does not improve to Gr <2 (moderate) toxicity within 7 days with or without dexamethasone 5) Any Gr 4 CRS at least possibly related to study product that does not improve to Gr <=2 (or Baseline) within 7 days 6) Any Gr 3 or greater neurotoxicity that does not resolve to Gr <=2 within 72 hours 7) Any Gr >=3 organ toxicity (exclusive of CRS toxicity) involving major organ systems that persists for >72 hours and occurs within 28 days of infusion.	Up to 28 days
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs Based on Maximum Severity	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any untoward medical occurrence that, at any dose can result in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth or is medically significant or requires intervention to prevent one or the outcomes listed above. AEs and SAEs were graded according to NCI-CTCAE v5.0. 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. AEs which start or worsen on or after T-cell infusion are classified as treatment emergent. SAEs are subset of AEs. Results for maximum severity grades has been presented.	Up to approximately 21 months
Number of Participants With Treatment Emergent Adverse Events of Special Interest (AESI)	An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included events of Cytokine Release Syndrome (CRS), Haematopoietic cytopenias (including pancytopenia and aplastic anaemia), Graft versus Host Disease (GvHD), Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS), Guillain-Barre Syndrome (GBS), Pneumonitis and treatment-related inflammatory response at tumor site(s) and Neutropenia Grade 4 lasting more than or equal to 28 days. AEs which start or worsen on or after T-cell infusion are classified as treatment emergent.	Up to approximately 21 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Assessed by Investigator According to RECIST v1.1	Overall response rate (ORR) 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. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response (CR) was defined as the 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). Confidence intervals (CI) were calculated using the exact (Clopper-Pearson) method.	Up to approximately 21 months
Duration of Response (DoR)	DoR is defined as the interval of time (in months) from first documented evidence of the confirmed response (PR or CR) as assessed by local investigators to the date of disease progression per RECIST v1.1 or death due to any cause, among participants with a confirmed response of PR or CR. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.	Up to approximately 21 months
Maximum Transgene Expansion (Cmax) of GSK3845097	Cmax was defined as peak cell expansion during the interventional phase. Blood samples were collected to measure Cmax.	Up to 21 days
Time to Cmax (Tmax) of GSK3845097	Tmax was defined as time to peak cell expansion during the interventional phase. Blood samples were collected to measure Tmax.	Up to 21 days
Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28])	Area under the cell expansion-time curve from first T-cell infusion to Day 28. Blood samples were collected to measure AUC (0-28 days).	Up to 28 days

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2020
• Primary Completion (Actual): October 24, 2022
• Study Completion (Actual): October 24, 2022

Study Registration Dates

• First Submitted: July 5, 2023
• First Submitted That Met QC Criteria: July 5, 2023
• First Posted (Actual): July 13, 2023

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: September 1, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Leukapheresis; Advanced tumors; Adoptive T-cell therapy; Advanced synovial sarcoma; GSK3845097; T cell receptor; Advanced Myxoid/Round Cell Liposarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Adipose Tissue; Sarcoma; Liposarcoma; Liposarcoma, Myxoid; Sarcoma, Synovial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 209012 Substudy 2; 2019-004446-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No