Pilot Immunotherapy Study With Letetresgene Autoleucel (Lete-cel, GSK3377794)T-cells Specific in NY-ESO-1/ LAGE-1a-positive Advanced Non-small Cell Lung Cancer (NSCLC) Either Alone or in Combination With Pembrolizumab

• ClinicalTrials.gov Identifier: NCT03709706
• Recruitment Status: Active, not recruiting
• First Posted: October 17, 2018
• Last Update Posted: January 19, 2022
• Sponsor: GlaxoSmithKline
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

This trial will evaluate safety and efficacy of letetresgene autoleucel (GSK3377794) with or without pembrolizumab in participants with non-small cell lung cancer.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: Lete-cel; Drug: Pembrolizumab	Phase 1; Phase 2

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/LAGE-1a have shown objective responses. Letetresgene autoleucel (GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor (TCR) engineered T-cells. This protocol investigates Letetresgene autoleucel treatment in Human Leukocyte Antigen (HLA)-A*02+ participants with NY-ESO1+ advanced myxoid/round cell liposarcoma or high-grade myxoid liposarcoma.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will receive GSK3377794, either as monotherapy or in combination with pembrolizumab.
• Masking: None (Open Label)
• Masking Description: This will be an open-label study. Hence, there will be no masking.
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2a Pilot Study to Evaluate the Safety and Tolerability of Autologous T-Cells Expressing Enhanced TCRs (T Cell Receptors) Specific for NY-ESO-1/LAGE-1a (GSK3377794) Alone, or in Combination With Pembrolizumab in HLA-A2+ Participants With NY-ESO-1- or LAGE-1a-Positive Advanced or Recurrent Non-Small Cell Lung Cancer
• Actual Study Start Date: December 31, 2018
• Estimated Primary Completion Date: May 30, 2025
• Estimated Study Completion Date: May 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: lete-cel monotherapy; In Arm A, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel monotherapy. Participants who subsequently progress by Week 25 will be offered pembrolizumab.	Drug: Lete-cel; lete-cel will be administered to eligible participants.; Drug: Pembrolizumab; Pembrolizumab will be administered to eligible participants.
Experimental: Arm B: lete-cel plus pembrolizumab; In Arm B, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.	Drug: Lete-cel; lete-cel will be administered to eligible participants.; Drug: Pembrolizumab; Pembrolizumab will be administered to eligible participants.
Experimental: Arm C: lete-cel plus pembrolizumab; In Arm C, participants with NSCLC (with actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.	Drug: Lete-cel; lete-cel will be administered to eligible participants.; Drug: Pembrolizumab; Pembrolizumab will be administered to eligible participants.

Outcome Measures

Primary Outcome Measures :

1. Number of participants with adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESIs) based on severity [ Time Frame: Up to 106 weeks ]
2. AEs and SAEs leading to dose delays and/or withdrawals [ Time Frame: Up to 106 weeks ]
3. Overall response rate (ORR) [ Time Frame: Up to 106 weeks ]

Secondary Outcome Measures :

1. Progression-Free Survival (PFS) [ Time Frame: Up to 106 weeks ]
2. Disease Control Rate (DCR) [ Time Frame: Up to 106 weeks ]
3. Duration of Response (DoR) [ Time Frame: Up to 106 weeks ]
4. Time to Response (TTR) [ Time Frame: Up to 106 weeks ]
5. Maximum transgene expansion (Cmax) for lete-cel [ Time Frame: Up to 106 weeks post-dose ]
6. Time to Cmax (Tmax) for lete-cel [ Time Frame: Up to 106 weeks post-dose ]
7. Area under the time curve from zero to time t (AUC[0 to t]) of GSK3377794 [ Time Frame: Up to 106 weeks post-dose ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age >=18 years on the day of signing informed consent.
• Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Participant is positive for any of the following alleles: human leukocyte antigen (HLA)-A*02:01, HLA-A*02:05, and a) or HLA-A*02:06 by a validated test.
• Participant's tumor meets the pre-defined threshold for expression of NY-ESO-1 and/or LAGE-1a.
• Adequate organ function and blood cell counts, as defined in the protocol.
• Predicted life expectancy that is >=24 weeks from leukapheresis.
• Left ventricular ejection fraction >=45%.
• Prior therapies prior to lymphodepletion: a) All participants with NSCLC lacking actionable genetic aberrations, per National Comprehensive Cancer Network (NCCN) guidelines (Arms A and B), need to have received at least one line of programmed death protein 1/programmed death protein 1 ligand (PD-1/PD-L1) checkpoint blockade therapy. For participants in the metastatic setting, PD-1/PD-L1 checkpoint blockade therapy must have been received either alone, in combination or sequentially with platinum-containing chemotherapy. OR b) All participants with NSCLC with actionable genetic aberrations, per NCCN guidelines (Arm C only), should have received appropriate targeted therapy following NCCN or equivalent country-level guidelines.
• Disease progression at time of treatment, as defined in the protocol.
• Measurable disease at time of treatment per response evaluation criteria in solid tumors (RECIST) version 1.1 as assessed by local site investigator/radiology.

Exclusion Criteria:

• Prior gene therapy using an integrating vector.
• Prior allogeneic/autologous bone marrow or solid organ transplantation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, dimethylsulfoxide (DMSO) or other agents used in the study
• Severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients.
• Active autoimmune disease that has required systemic treatment in past 2 years.
• History of chronic or recurrent (within the last year prior to enrollment) severe autoimmune or active immune-mediated disease requiring steroids or other immunosuppressive treatments.
• Uncontrolled intercurrent illness.
• Participant has active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein Barr virus (EBV), cytomegalovirus (CMV), syphilis, or human T lymphotropic virus (HTLV), as defined in protocol.
• Known psychiatric or substance abuse disorders.
• Symptomatic or untreated central nervous system (CNS) metastases.
• Radiotherapy meeting any of the following criteria: a. >=50 Gray (Gy) to a significant volume of the pelvis, long bones or spine, or a cumulative dose of radiation that, in the investigator's opinion would predispose patients to prolonged cytopenia after lymphodepletion. b. Radiotherapy to the target lesions within 3 months before lymphodepletion. A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy dose.
• Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

United States, California

GSK Investigational Site

Duarte, California, United States, 91010

GSK Investigational Site

La Jolla, California, United States, 92093-0987

GSK Investigational Site

Sacramento, California, United States, 95817

GSK Investigational Site

Stanford, California, United States, 94305

United States, Colorado

GSK Investigational Site

Denver, Colorado, United States, 80218

United States, Florida

GSK Investigational Site

Hollywood, Florida, United States, 33021

United States, Georgia

GSK Investigational Site

Atlanta, Georgia, United States, 30322

United States, Illinois

GSK Investigational Site

Chicago, Illinois, United States, 60637

United States, Iowa

GSK Investigational Site

Iowa City, Iowa, United States, 52242

United States, Kentucky

GSK Investigational Site

Lexington, Kentucky, United States, 40536

United States, Maryland

GSK Investigational Site

Baltimore, Maryland, United States, 21201

United States, Missouri

GSK Investigational Site

Saint Louis, Missouri, United States, 63110

United States, New York

GSK Investigational Site

New York, New York, United States, 10065

United States, North Carolina

GSK Investigational Site

Durham, North Carolina, United States, 27710

United States, Ohio

GSK Investigational Site

Columbus, Ohio, United States, 43210

United States, Pennsylvania

GSK Investigational Site

Philadelphia, Pennsylvania, United States, 19111

GSK Investigational Site

Pittsburgh, Pennsylvania, United States, 15232

United States, Tennessee

GSK Investigational Site

Nashville, Tennessee, United States, 37203

United States, Texas

GSK Investigational Site

Houston, Texas, United States, 77030

United States, Utah

GSK Investigational Site

Salt Lake City, Utah, United States, 84112-5550

Canada, Ontario

GSK Investigational Site

Toronto, Ontario, Canada, M5G 1X6

Canada, Quebec

GSK Investigational Site

Montréal, Quebec, Canada, H2X 0A9

Netherlands

GSK Investigational Site

Amsterdam, Netherlands, 1066 CX

GSK Investigational Site

Groningen, Netherlands, 9713 GZ

GSK Investigational Site

Rotterdam, Netherlands, 3015 GD

GSK Investigational Site

Utrecht, Netherlands, 3584 CX

Spain

GSK Investigational Site

Barcelona, Spain, 08035

GSK Investigational Site

Madrid, Spain, 28040

GSK Investigational Site

Madrid, Spain, 28050

GSK Investigational Site

Pamplona, Spain, 31008

United Kingdom

GSK Investigational Site

London, United Kingdom, WC1E 6AG

GSK Investigational Site

Manchester, United Kingdom, M20 4BX

Sponsors and Collaborators

GlaxoSmithKline

Merck Sharp & Dohme Corp.

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03709706
• Other Study ID Numbers: 208471
• First Posted: October 17, 2018
• Last Update Posted: January 19, 2022
• Last Verified: January 2022

Individual Participant Data (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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); 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

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

Keywords provided by GlaxoSmithKline:

GSK3377794; Pembrolizumab; T Cell Receptors; Adoptive T-cell therapy; Non-Small Cell Lung Cancer; Immuno-oncology; NY-ESO-1; LAGE-1a; Leukapheresis; Letetresgene autoleucel

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents