Letetresgene Autoleucel Engineered T Cells in NY-ESO-1 Positive Participants With Advanced Myxoid/ Round Cell Liposarcoma

Study Overview
=================
Brief Summary
-----------------
This trial will evaluate safety and efficacy of Letetresgene autoleucel (GSK3377794) in participants with advanced myxoid/round cell liposarcoma or high-grade myxoid liposarcoma.

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.

Official Title
-----------------
A Pilot Study of NY-ESO-1c259T Cells in Subjects With Advanced Myxoid/ Round Cell Liposarcoma

Conditions
-----------------
Neoplasms

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is greater than equal to (>=)18 years of age at the time of signing the study informed consent. Participant has a diagnosis of advanced (metastatic or inoperable) high grade myxoid liposarcoma / myxoid round cell liposarcoma confirmed histologically and by the presence of the reciprocal chromosomal translocation t(12;16) (q13;p11) or t(12; 22) (q13;q12). Participant has measurable disease according to RECIST v1.1 criteria. Participant must have previously received or be intolerant to anthracycline based therapy for advanced (metastatic or inoperable) disease. Participants who received neoadjuvant/adjuvant anthracycline based therapy and progressed within 6 months of completion of therapy will be eligible. Participant must be HLA A*02:01, HLA A*02:05 and/or HLA-A*02:06 positive. Participant's tumor (either the most recent archival specimen or a fresh biopsy) is positive for NY-ESO-1 expression by a designated central laboratory. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Participant has a left ventricular ejection fraction >=45%. Participant is fit for apheresis and has adequate venous access for the cell collection. Participants must satisfy pregnancy and contraceptive requirements per protocol and have adequate organ function per protocol specified values. Exclusion Criteria: Any previous gene therapy using an integrating vector. Any previous allogeneic hematopoietic stem cell transplant. Participant has history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study. Participant has history of chronic or recurrent (within the last year prior to screening) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments. Participant has known active brain or leptomeningeal metastases. Participant has other prior malignancy that is not in complete remission. Participant has uncontrolled intercurrent illness including, but not limited to: (i) Ongoing or active infection. (ii) Clinically significant cardiac disease (iii) Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded, however, participants must not be oxygen dependent). Participant has active infection with Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), ), Hepatitis C virus (HCV) or human T-lymphotropic virus (HTLV).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment | 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 RECIST (Response Evaluation Criteria In Solid Tumors Criteria) v1.1 relative to the total number of participants in the analysis population. 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 (mm). Confidence intervals (CI) were calculated using the exact (Clopper-Pearson) method. | Up to 24 months | 
| Best Overall Response (BOR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment | The Best Overall Response (BOR) with confirmation for a participant is defined as the best confirmed response (Confirmed Complete Response [CR] > Confirmed Partial Response [PR] > Stable Disease [SD] > Progressive Disease [PD] > Not Evaluable [NE]) from first T cell infusion until disease progression or initiation of new anti-cancer therapy, whichever is earlier, as assessed by the investigator per RECIST v1.1 Criteria. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response (TTR) Assessed by Investigator | Time to response was defined as the interval of time between the date of T-cell infusion and the first documented evidence of the confirmed response (PR or CR), in the subset of participants with a confirmed PR or CR as their best confirmed overall response. 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 mm. | Up to 24 months | 
| Duration of Response (DOR) Assessed by Investigator | Duration of response was defined as the interval between the initial date of confirmed response (PR/CR) and the date of progressive disease or death among participants with a confirmed response per RECIST 1.1. 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. Kaplan-Meier Median and 95% confidence intervals are presented. Confidence intervals were calculated using the Brookmeyer-Crowley method. | Up to 24 months | 
| Progression Free Survival (PFS) Assessed by Investigator | Progression free survival was defined as the interval between the date of T cell infusion and the earliest date of disease progression or 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. Kaplan-Meier Median and 95% confidence intervals are presented. Confidence intervals were calculated using the Brookmeyer-Crowley method. | Up to 24 months | 
| Best Overall Response (BOR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Independent Reviewer Assessment | The Best Overall Response (BOR) with confirmation for a participant is defined as the best confirmed response (Confirmed Complete Response [CR] > Confirmed Partial Response [PR] > Stable Disease [SD] > Progressive Disease [PD] > Not Evaluable [NE]) from first T cell infusion until disease progression or initiation of new anti-cancer therapy, whichever is earlier, as assessed by independent reviewer per RECIST v1.1 criteria. | Up to 24 months | 
| Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Independent Reviewer | Overall response rate (ORR) defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) via independent reviewer assessment per RECIST v1.1 relative to the total number of participants in the analysis population. 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 (mm). Confidence intervals (CI) were calculated using the exact (Clopper-Pearson) method. | Up to 24 months | 
| Time to Response (TTR) Assessed by Independent Reviewer | Time to response was defined as the interval of time between the date of T-cell infusion and the first documented evidence of the confirmed response (PR or CR), in the subset of participants with a confirmed PR or CR as their best confirmed overall response. 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 mm. | Up to 24 months | 
| Duration of Response (DOR) Assessed by Independent Reviewer | Duration of response was defined as the interval between the initial date of confirmed response (PR/CR) and the date of progressive disease or death among participants with a confirmed response per RECIST 1.1. 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 mm. Kaplan-Meier Median and 95% confidence intervals are presented. Confidence intervals were calculated using the Brookmeyer-Crowley method. | Up to 24 months | 
| Progression Free Survival (PFS) Assessed by Independent Reviewer | Progression free survival was defined as the interval between the date of T cell infusion and the earliest date of disease progression or 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 independent reviewer per RECIST v1.1 is presented. Kaplan-Meier Median and 95% confidence intervals are presented. Confidence intervals were calculated using the Brookmeyer-Crowley method. | Up to 24 months | 
| Number of Participants With Serious Adverse Events (SAEs) and Non-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. 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. | Up to 24 months | 
| Number of Participants With Adverse Event 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. The AESI 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), and Guillain-Barre syndrome. | Up to 24 months | 
| Number of Participants With Any Grade Increase in Hematology Results at Worst-case Post-baseline | Blood samples were collected for the analysis of following hematology parameters: hemoglobin, lymphocytes, neutrophils, platelets, leukocytes. Laboratory parameters were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0, 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 of number of participants with any grade increase at worst-case post-baseline (maximum grade increase post-baseline) is presented. | Up to 24 months | 
| Number of Participants With Any Grade Increase in Clinical Chemistry Results at Worst-case Post-baseline | Blood samples were collected for the analysis clinical chemistry parameters: glucose, albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, potassium, magnesium, sodium, phosphate, calcium. Laboratory parameters were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0, 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 of number of participants with any grade increase at worst-case post-baseline (maximum grade increase post-baseline) is presented. | Up to 24 months | 
| Number of Participants With Replication Competent Lentivirus (RCL) | RCL was monitored using a polymerase chain reaction (PCR)-based assay that detects and measures copies of the gene coding for the vector's envelope protein, namely vesicular stomatitis virus G protein (VSV-G). | Day 1 (pre-infusion), and at Week 12, Week 24, and 1 year post-infusion | 
| Number of Participants With Insertional Oncogenesis | Peripheral blood mononuclear cells (PBMC) samples were collected for monitoring insertional oncogenesis by PCR for gene modified cells in the blood. DNA from participant identified with >1% PBMC at >=1 year post T-cell infusion was sent for integration site analysis. Integration site analysis was used to assess the possibility of insertional oncogenesis. Participants with insertional oncogenesis were participants with any clones representing >20% of the total. | Up to 2 years | 
| Number of Participants With Positive Anti-drug Antibodies (ADAs) | Serum samples were collected to analyze for the presence of ADAs using validated immunoassays. | Up to 24 Months | 
| Maximum Transgene Expansion (Cmax) of GSK3377794 | Cmax was defined as peak cell expansion during the interventional phase. Blood samples were collected to measure Cmax. | Day 2 to Day 15 | 
| Time to Cmax (Tmax) | Tmax was defined as time to peak cell expansion during the interventional phase. Blood samples were collected to measure Tmax. | Day 2 to Day 15 | 
| Area Under the Time Curve From Zero to Time 28 Days AUC(0-28) of GSK3377794 | 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 | 
| Change From Baseline in Electrocardiogram (ECG) Parameters- PR Interval, QRS Duration, QT Interval, QTcB Interval, QTcF Interval and RR Interval | Triplicate 12-Lead ECGs were collected at baseline visit and single ECGs at other timepoints. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline is the most recent, non-missing value within 7 days prior to the lymphodepleting chemotherapy. Change from baseline was to be calculated by subtracting post-dose value from baseline value. | Baseline, Day 1, Day 4 and Day 8 | 
| Change From Baseline in ECG Mean Heart Rate | Single 12-lead ECG was to be obtained at designated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Baseline is the most recent, non-missing value within 7 days prior to the lymphodepleting chemotherapy. Change from baseline was to be calculated by subtracting post-dose value from baseline value. | Baseline, Day 1 (Pre-dose), Day 4 and Day 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myxoid/ round cell liposarcoma, Letetresgene autoleucel, Immuno-oncology, T Cell Receptor, Leukapheresis, NY-ESO-1, Adoptive TCR T-cell therapy