Adoptive T-cell therapy (ACT) is a therapeutic approach that uses T lymphocytes of participants with cancer, obtained by leukapheresis with the aim of generating an anti-tumor T-cell immune response. New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and cancer testis antigen 2 (LAGE-1a) antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using ACT with T-cells directed against NY-ESO-1/LAGE-1a have shown objective responses in participants with cancer. Pembrolizumab is a monoclonal antibody that acts specifically on tumor targeting T-cells and increases T-cell anti-tumor function. Pembrolizumab will be used in combination with NY-ESO-1/LAGE-1a T Cell Receptors (TCR) engineered participant T-cells (GSK3377794) to potentially further improve therapy for participants. The primary objective of the study is to evaluate the safety and tolerability of autologous genetically modified T-cells (GSK3377794) in human leukocyte antigen (HLA) positive participants with NY-ES0-1/ LAGE-1a positive advanced non-small cell lung cancer (NSCLC) alone (Arm A) or GSK3377794 in combination with pembrolizumab in participants with NSCLC with wildtype epidermal growth factor receptor (WT EGFR) and WT anaplastic lymphoma kinase/ c-ros oncogene 1 (ALK/ROS1) (Arm B) and participants with NSCLC with EGFR or ALK/ROS1 aberration (Arm C). This study consists of screening phase, Leukapheresis/ GSK3377794 manufacture, lymphodepletion/treatment phase and follow-up. Participants will receive GSK3377794 as monotherapy (Arm A); or as a combination therapy with pembrolizumab (Arm B), and participants in Arm C will receive the same treatment as participants in the Arm B. Approximately 54 participants will be enrolled into the study.
Name: letetresgene autoleucel
Name: Pembrolizumab
Description: An 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 any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment.
Measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs) in participants who received GSK3377794 alone or in combination with pembrolizumab Time: Up to 106 weeksDescription: The severity of AEs will be graded according to National Cancer Institute-Common terminology criteria for adverse events (NCI-CTCAE) version 4.03.
Measure: Number of participants with adverse events of different severity in participants who received GSK3377794 alone or in combination with pembrolizumab Time: Up to 106 weeksDescription: Number of participants with AEs and SAEs leading to dose delays will be reported.
Measure: Number of participants with AEs and SAEs leading to dose delays Time: Up to 106 weeksDescription: Number of participants with AEs and SAEs leading to withdrawals will be reported.
Measure: Number of participants with AEs and SAEs leading to withdrawals Time: Up to 106 weeksDescription: Blood samples will be collected for analysis of hematology parameters including platelet counts, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell count (RBC), hemoglobin and hematocrit.
Measure: Number of participants with abnormal findings for hematology parameters Time: Up to 106 weeksDescription: Blood samples will be collected for analysis of clinical chemistry parameters including blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total and direct bilirubin, creatinine, sodium, alanine aminotransferase (ALT), total protein, glucose, calcium, alkaline phosphatase, chloride, albumin, phosphorus, low density lipid (LDH), urea, potassium, magnesium and bicarbonate.
Measure: Number of participants with abnormal findings for clinical chemistry parameters Time: Up to 106 weeksDescription: Urine samples will be collected for the analysis of the following urine parameters: specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite and leukocyte esterase by dipstick.
Measure: Number of participants with abnormal findings for urinalysis parameters Time: Up to 106 weeksDescription: Vital sign parameters including systolic and diastolic blood pressure, respiratory rate, pulse rate, and temperature will be assessed.
Measure: Number of of participants with abnormal findings for vital signs Time: Up to 106 weeksDescription: ECOG performance status is a measure of the participant's ability to carry out activities of daily living on a 6-point scale ranging from 0 (fully active) to 5 (Dead).
Measure: Mean Eastern Cooperative Oncology Group (ECOG) performance status score Time: Up to 106 weeksDescription: Twelve-lead ECG will be obtained using an ECG machine.
Measure: Number of participants with abnormal electrocardiogram (ECG) findings Time: Up to 106 weeksDescription: ORR is the percentage of participants with a confirmed complete response (CR) or a partial response (PR) at any time as per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by the local investigators.
Measure: Overall response rate (ORR) Time: Up to 106 weeksDescription: PFS is defined as the time from the date of T-cell infusion until the earliest date of disease progression as per RECIST version 1.1 as determined by the local investigators, or death due to any cause.
Measure: Progression-Free Survival (PFS) Time: Up to 106 weeksDescription: DCR is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) for at least 6 months as per RECIST version 1.1 as determined by the local investigators.
Measure: Disease Control Rate (DCR) Time: Up to 106 weeksDescription: DoR is defined as, in the subset of participants who show a confirmed CR or PR as determined by the local investigators, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.
Measure: Duration of Response (DoR) Time: Up to 106 weeksDescription: TTR is the time from the date of T-cell infusion to the first documented evidence of response (PR or better) in the subset of participants who achieved a confirmed PR or CR as determined by the local investigators.
Measure: Time to Response (TTR) Time: Up to 106 weeksDescription: Blood samples will be collected for pharmacokinetic analysis.
Measure: Maximum observed concentration (Cmax) following administration of monotherapy of GSK3377794 Time: Up to 106 weeks post-doseDescription: Blood samples will be collected for pharmacokinetic analysis.
Measure: Cmax following administration of combination therapy of GSK3377794 Time: Up to 106 weeks post-doseDescription: Blood samples will be collected for pharmacokinetic analysis
Measure: Time to Cmax (Tmax) following administration of monotherapy of GSK3377794 Time: Up to 106 weeks post-doseDescription: Blood samples will be collected for pharmacokinetic analysis.
Measure: Tmax following administration of combination therapy of GSK3377794 Time: Up to 106 weeks post-doseDescription: Blood samples will be collected for pharmacokinetic analysis.
Measure: Area under the time curve from zero to time t (AUC[0 to t]) following administration of monotherapy of GSK3377794 Time: Up to 106 weeks post-doseDescription: Blood samples will be collected for pharmacokinetic analysis.
Measure: AUC(0 to t) following administration of combination therapy of GSK3377794 Time: Up to 106 weeks post-doseAllocation: Randomized
Parallel Assignment
There is one SNP
Exclusion Criteria: For Screening (Part 1): - NSCLC with B-Raf gene (BRAF) V600E mutation, Neurotrophic Tropomyosin-Related Kinase (NTRK) gene fusion, and/or any other actionable genetic aberration that can be treated with targeted SoC (NCCN recommended) therapy. --- V600E ---