Clinical trial NCT03709706: Pilot Immunotherapy Study With Letetresgene Autoleucel (Lete-cel, GSK3377794)T-cells in New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1)/ LAGE-1a-positive Advanced Non-small Cell Lung Cancer (NSCLC) Either Alone or in Combination With Pembrolizumab
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Neoplasms
Keywords: GSK3377794
Pembrolizumab
T Cell Receptors
Adoptive T-cell therapy
Non-Small Cell Lung Cancer
Immuno-oncology
NY-ESO-1
LAGE-1a
Leukapheresis
Letetresgene autoleucel
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2018-10-17
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will receive GSK3377794, either as monotherapy or in combination with pembrolizumab.
Primary purpose: TREATMENT

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

Detailed description: New York esophageal squamous cell carcinoma-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 is a multi-arm, open-label study of letetresgene autoleucel (lete-cel, GSK3377794) in Human Leukocyte Antigen (HLA)-A\*02:01, HLA-A\*02:05 and/or HLA-A\*02:06 positive adults whose tumors express NY-ESO-1 and/or LAGE-1a. This study will enroll participants who have unresectable Stage IIIb or Stage IV NSCLC.

Eligibility 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 treatment: 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.
* 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 that involves the lung (Percentage of normal lung receiving at least 20 Gray \[Gy\] during radiotherapy \[V20\] exceeding 30% lung volume or mean heart dose \>20 Gy) within 3 months or radiotherapy (including but not limited to palliative radiotherapy) to lung/mediastinum with V20 less than 30% lung volume and with mean heart dose \<=20 Gy within 4 weeks (+/- 3 days).
* Radiotherapy of \>=50 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 participants to prolonged cytopenia after lymphodepletion.
* All of the participant's measurable lesions have been irradiated within 3 months before lymphodepletion.
* Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to approximately 10 months
measure: Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESI)
timeFrame: Up to approximately 10 months
measure: Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events Based on Maximum Severity Grades
timeFrame: Up to approximately 10 months
measure: Number of Participants With AEs Leading to Dose Delays
timeFrame: Up to approximately 10 months
measure: Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
timeFrame: Up to approximately 10 months
Secondary outcomes:
measure: Progression-free Survival (PFS) Per RECIST Version 1.1 by Investigator Assessment
timeFrame: Up to approximately 10 months
measure: Disease Control Rate (DCR) Per RECIST Version 1.1 by Investigator Assessment
timeFrame: Up to approximately 10 months
measure: Duration of Response (DOR) Per RECIST Version 1.1 by Investigator Assessment
timeFrame: Up to approximately 10 months
measure: Time to Response (TTR) Per RECIST Version 1.1 by Investigator Assessment
timeFrame: Up to approximately 10 months
measure: Maximum Transgene Expansion (Cmax) of Lete-cel
timeFrame: Day 1 to Day 15
measure: Time to Cmax (Tmax) of Lete-cel
timeFrame: Day 1 to Day 15
measure: Area Under the Plasma Concentration-time Curve to Day 28 (AUC0-28d) of Lete-cel
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Duarte
country: United States
facility: GSK Investigational Site
state: California
city: La Jolla
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Stanford
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Lexington
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montréal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: