Letetresgene Autoleucel Engineered T Cells in NY-ESO -1 Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This trial will evaluate safety and efficacy of letetresgene autoleucel (GSK3377794) in participants with metastatic NSCLC.

Detailed Description
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New York esophageal antigen-1 (NY-ESO-1) and L antigen family member (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 engineered TCR T-cells. This protocol investigates letetresgene autoleucel treatment in Human Leukocyte Antigen (HLA)*-A*02+ participants with NY-ESO1+ advanced metastatic non-small cell lung cancer as second line treatment.

Official Title
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A Pilot Open-Label Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Subjects With Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: letetresgene autoleucel (GSK3377794)
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is >=18 years of age on the day of signing informed consent. Participant has a diagnosis of histologically or cytologically confirmed advanced non-small cell lung cancer (Stage IIIB or IV) or recurrent disease. Participants with known epidermal growth factor receptor (EGFR) mutations or Anaplastic lymphoma kinase receptor (ALK) or ROS1 gene rearrangements must have failed (disease progression [PD] or unacceptable toxicity) prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively (PD or unacceptable toxicity). There is no limit to lines of prior anti-cancer therapy. Participant has measurable disease according RECIST v1.1 criteria. Participant is HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 positive. Participant's tumor is positive for NYESO and/or LAGE-1a expression by a designated central laboratory. Participant has Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Participant has an anticipated life expectancy >3 months. Participant has left ventricular ejection fraction >=50 percent(%). Participant is fit for leukapheresis and has adequate venous access for the cell collection. Male or Female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Participant must have adequate organ function. Exclusion Criteria: Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per Investigator assessment). Washout periods for prior radiotherapy and chemotherapy and other systemic therapy must be followed. Experimental anti-cancer vaccine within 2 months prior to leukapheresis in the absence of response or in the opinion of the Investigator is responding to an experimental vaccine given within 6 months prior to leukapheresis. Any prior gene therapy using an integrating vector. Toxicity from previous anti-cancer therapy that has not recovered to less than or equal to (<=)Grade 1 prior to enrollment (with exceptions). History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, or other agents used in the study. Central nervous system (CNS) metastases. Active brain metastases or leptomeningeal metastases. 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. Other active malignancies besides NSCLC within 3 years prior to Screening not in complete remission. Unintended weight loss >10% in 6 months preceding study entry. Corrected QT interval (QTc) >450 milliseconds (msec) or QTc >480 msec for participants with Bundle Branch Block (BBB). Uncontrolled intercurrent illness. Participants who in the opinion of the Investigator will be unlikely to fully comply with protocol requirements. Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or human T-cell lymphotropic virus (HTLV). Participant is pregnant or breastfeeding. Major surgery within 4 weeks prior to lymphodepleting chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: letetresgene autoleucel (GSK3377794)<br>Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive letetresgene autoleucel (GSK3377794), as a single intravenous (IV) infusion after completing lymphodepleting chemotherapy. | Drug: letetresgene autoleucel (GSK3377794)<br>* letetresgene autoleucel (GSK3377794) as an IV infusion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as a lymphodepleting chemotherapy.<br>Drug: Fludarabine<br>* Fludarabine will be used as a lymphodepleting chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or is clinically significant or requires intervention to prevent one of the outcomes listed before. Number of participants with common (greater than or equal to [>=]5 percent[%]) non-serious AEs and SAEs are presented. | Up to 24 months | 
| Number of Participants With Hematology Results by Maximum Grade Increase Post-Baseline | Blood samples were collected for the analysis of following hematology parameters: hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. Laboratory parameters were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.03 where, Grade1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline is the most recent, non-missing value from a central laboratory within 7 days prior to the lymphodepleting chemotherapy. An increase in grade is defined as an increase in CTCAE grade relative to Baseline grade. Data for any grade increase at worst-case post-Baseline is presented | Up to 24 months | 
| Number of Participants With Any Grade Increase in Clinical Chemistry Parameters | Blood samples were collected for analysis of clinical chemistry parameters: glucose (Gl), albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (Bil), creatinine (Creat), potassium (Pot), magnesium (Mg), phosphate (Ph), sodium (Sod) and calcium. Laboratory parameters were graded according to NCI-CTCAE version 4.03 where, Grade1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. An increase in grade is defined as an increase in CTCAE grade relative to Baseline grade. Data for any grade increase at worst-case post-Baseline is presented. | Up to 24 months | 
| Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings | 12-lead ECGs were recorded in semi-supine position after 5 minutes rest using an ECG machine that automatically calculated the heart rate and measured PR, RR, QRS and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Data for number of participants with abnormal not clinically significant (NCS) and clinically significant (CS) ECG findings for worst case post-Baseline have been presented. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. | Up to 24 months | 
| Change From Baseline in Oxygen Saturation | Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen saturation was measured using a pulse oximeter. Baseline is the most recent, non-missing value within 7 days prior to initiating the lymphodepleting chemotherapy. Change from Baseline is the post-Baseline visit value minus Baseline value. | Baseline, Day 1 (pre-dose, 5, 15, and 30 minutes, 1, 1.5, 2, and 4 hours post dose), Days 2, 3, 4, 5, 8 and Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a confirmed Partial response (PR) or Complete response (CR) as the Best overall response (BOR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Confidence Interval (CI) was calculated using the exact method. Partial response is 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 is 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. | Up to 24 Months | 
| Time to Response | Time to response is defined as the interval of time (in months) between the date of T-cell infusion and the first documented evidence of response (PR or CR) in the subset of participants with a confirmed PR or CR as the BOR as assessed by the investigator per RECIST v1.1. | Up to 24 months | 
| Duration of Response | Duration of response (DoR), defined as the interval of time in months from first documented evidence of PR or better to the time when disease progression is documented as assessed by RECIST v1.1 or death due to any cause among participants with a confirmed PR or CR as the BOR. | Up to 24 months | 
| Disease Control Rate (DCR) | DCR is defined as the percentage of participants with a stable disease (SD) or better as the BOR (Confirmed PR, confirmed CR, or SD >=12 weeks), as assessed by the investigator per RECIST v1.1. CI was calculated using the exact method. | Up to 24 months | 
| Progression-Free Survival (PFS) by Investigator Assessment | Progression-free survival (PFS) is defined as the interval of time (in months) between the date of T-cell infusion and the earlier of the date of disease progression as assessed by the investigator and the date of death due to any cause. Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. PFS based on responses assessed by investigator per RECIST v1.1 is presented. Median and inter-quartile range (first quartile and third quartile) are presented. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letetresgene autoleucel, Adoptive TCR T-cell therapy, NY-ESO-1, T Cell Receptor, Non-Small Cell Lung Cancer, Leukapheresis