Neoplasms
Conditions
Keywords
Adoptive T-cell therapy, Letetresgene autoleucel, Lete-cel, GSK3377794
Brief summary
This trial will evaluate safety and efficacy of human engineered T-cell therapies, in participants with advanced tumors. This trial is a sub study of the Master study NCT03967223.
Interventions
Letetresgene autoleucel will be administered.
DRUGCyclophosphamide
Cyclophosphamide will be used as a lymphodepleting chemotherapy.
DRUGFludarabine
Fludarabine will be used as a lymphodepleting chemotherapy.
Sponsors
USWM, LLC (dba US WorldMeds)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be greater than or equal to 10 years of age on the day of signing informed consent. * Participant scheduled to receive clinical drug product supply must also weigh ≥40 kg * Participant must be positive for HLA-A\*02:01, HLA-A\*02:05, and/or HLA-A\*02:06 alleles by a designated central laboratory * Participant's tumor is positive for NY-ESO-1 expression by a designated central laboratory. * Participant has a diagnosis of synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) * Performance status: dependent on age - Lansky \> 60, Karnofsky \> 60, Eastern * Cooperative Oncology Group 0-1. * Participant must have adequate organ function and blood cell counts, within 7 days prior to leukapheresis. * At time of treatment, participant has measurable disease according to RECIST v1.1. * Male or female. Contraception requirements will apply at the time of leukapheresis and treatment. * Consultation for prior history per protocol specifications.
Exclusion criteria
* Central nervous system metastases. * Any other prior malignancy that is not in complete remission. * Clinically significant systemic illness (.(Serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the participant's ability to tolerate protocol therapy or significantly increase the risk of complications) * Prior or active demyelinating disease. * History of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn's disease, systemic lupus) requiring steroids or other immunosuppressive treatments. * 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. * Previous allogeneic hematopoietic stem cell transplant. * Washout periods for prior radiotherapy and systemic chemotherapy must be followed. * Participant had major surgery in less than or equal to 28 days of first dose of study intervention. * Prior radiation exceeds protocol specified limits.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to approximately 36 months | ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) via investigator assessment per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1 relative to the total number of participants in the analysis population. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). 95% CI is based on Clopper-Pearson exact confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response (TTR) | Up to approximately 54 months | 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. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). |
| Duration of Response (DOR) | Up to approximately 54 months | Duration of response was defined as the interval between the initial date of confirmed response (PR/CR) and the date of progressive disease as assessed by local investigators, or death among participants with a confirmed response per RECIST 1.1. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). |
| Disease Control Rate (DCR) | Up to approximately 36 months | DCR is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) with a minimal 12 weeks (84 days ± 7 day window) duration relative to the total number of participants within the analysis population at the time of primary analysis as determined by local investigators per RECIST v1.1. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. The disease progression (PD) is defined as the date of radiological disease progression based on imaging data per RECIST v1.1. 95% CI is based on Clopper-Pearson exact confidence interval. |
| Progression Free Survival (PFS) | Up to approximately 54 months | PFS is defined as the interval of time between from the date of T-cell infusion to the earliest date of radiological progression of disease (PD) as assessed by local investigator per RECIST v1.1, or death due to any cause. The PD is defined as the date of radiological disease progression based on imaging data per RECIST v1.1. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Up to approximately 54 months | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. |
| Number of Participants With AEs of Special Interest (AESIs) | Up to approximately 54 months | An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days. |
| Number of Participants With TEAEs and TESAEs by Severity | Up to approximately 54 months | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. AEs and SAEs were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences; Grade 5- Death related to AE. |
| Number of Participants With AESIs by Severity | Up to approximately 54 months | An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days. |
| Percentage of Participants With Replication Competent Lentivirus (RCL) Positive | Up to approximately 54 months | 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). |
| Instances of Insertional Oncogenesis (IO) | Up to approximately 54 months | Instances of Insertional Oncogenesis (IO) was summarized descriptively. |
| Maximum Transgene Expansion (Cmax) | Day 1 to Day 14 | Cmax was defined as maximum observed persistence, determined directly from the persistence-time data. Blood samples were collected for PK analysis. |
| Time to Cmax (Tmax) | Day 1 to Day 14 | Tmax was defined as time to reach Cmax, determined directly from the persistence-time data. Blood samples were collected for PK analysis. |
| Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28]) | Up to 28 days | Area under the persistence-time curve from time zero to Day 28. Blood samples were collected for PK analysis. |
Countries
Canada, France, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
This study is a sub study of the master protocol (NCT03967223). The results presented are until the primary completion date. Data collection is still ongoing and additional results will be provided after study completion.
Participants by arm
| Arm | Count |
|---|---|
| Letetresgene Autoleucel (Lete-cel) Eligible participants were leukapheresed to manufacture autologous lete-cel. Participants underwent lymphodepleting chemotherapy which generally consisted of fludarabine 30 mg/m\^2/day on day -7 through day -4 and cyclophosphamide 900 milligrams per meter square per day (mg/m\^2/day) on day -6 through day -4. followed by a single infusion of lete-cel on Day 1. The dose of lete-cel was within the range of 1×10\^9 to 15×10\^9 transduced T cells. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Letetresgene Autoleucel (Lete-cel) |
|---|---|
| Age, Continuous | 49.4 years STANDARD_DEVIATION 16.7 |
| Age, Customized <=18 years | 1 Participants |
| Age, Customized 19-64 years | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment Netherlands | 2 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 7 |
| other Total, other adverse events | 5 / 7 |
| serious Total, serious adverse events | 4 / 7 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) via investigator assessment per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1 relative to the total number of participants in the analysis population. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). 95% CI is based on Clopper-Pearson exact confidence interval.
Time frame: Up to approximately 36 months
Population: Modified intent-to-treat (mITT) population included all participants who received any dose of Lete-cel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letetresgene Autoleucel (Lete-cel) | Overall Response Rate (ORR) | 80 percentage of participants |
Secondary
Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28])
Area under the persistence-time curve from time zero to Day 28. Blood samples were collected for PK analysis.
Time frame: Up to 28 days
Population: Pharmacokinetic (PK) population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letetresgene Autoleucel (Lete-cel) | Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28]) | 1911782.96 Days*copies per microgram genomic DNA | Geometric Coefficient of Variation 53.709 |
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) with a minimal 12 weeks (84 days ± 7 day window) duration relative to the total number of participants within the analysis population at the time of primary analysis as determined by local investigators per RECIST v1.1. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. The disease progression (PD) is defined as the date of radiological disease progression based on imaging data per RECIST v1.1. 95% CI is based on Clopper-Pearson exact confidence interval.
Time frame: Up to approximately 36 months
Population: Modified intent-to-treat (mITT) population included all participants who received any dose of Lete-cel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letetresgene Autoleucel (Lete-cel) | Disease Control Rate (DCR) | 80.0 Percentage of Participants |
Secondary
Duration of Response (DOR)
Duration of response was defined as the interval between the initial date of confirmed response (PR/CR) and the date of progressive disease as assessed by local investigators, or death among participants with a confirmed response per RECIST 1.1. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline).
Time frame: Up to approximately 54 months
Secondary
Instances of Insertional Oncogenesis (IO)
Instances of Insertional Oncogenesis (IO) was summarized descriptively.
Time frame: Up to approximately 54 months
Secondary
Maximum Transgene Expansion (Cmax)
Cmax was defined as maximum observed persistence, determined directly from the persistence-time data. Blood samples were collected for PK analysis.
Time frame: Day 1 to Day 14
Population: Pharmacokinetic (PK) population included participants in the safety population from whom at least one persistence sample was obtained, analyzed and was measurable.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letetresgene Autoleucel (Lete-cel) | Maximum Transgene Expansion (Cmax) | 119701.64 Copies per microgram genomic DNA | Geometric Coefficient of Variation 68.267 |
Secondary
Number of Participants With AESIs by Severity
An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days.
Time frame: Up to approximately 54 months
Secondary
Number of Participants With AEs of Special Interest (AESIs)
An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included cytokine release syndrome (CRS), hematopoietic cytopenias (including pancytopenia and aplastic anemia), graft vs host disease (GVHD), ICANS, Guillain-Barre syndrome, treatment-related inflammatory response at tumor site(s), and neutropenia Grade 4 lasting ≥28 days.
Time frame: Up to approximately 54 months
Secondary
Number of Participants With TEAEs and TESAEs by Severity
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. AEs and SAEs were graded according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences; Grade 5- Death related to AE.
Time frame: Up to approximately 54 months
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function.
Time frame: Up to approximately 54 months
Secondary
Percentage of Participants With Replication Competent Lentivirus (RCL) Positive
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).
Time frame: Up to approximately 54 months
Secondary
Progression Free Survival (PFS)
PFS is defined as the interval of time between from the date of T-cell infusion to the earliest date of radiological progression of disease (PD) as assessed by local investigator per RECIST v1.1, or death due to any cause. The PD is defined as the date of radiological disease progression based on imaging data per RECIST v1.1.
Time frame: Up to approximately 54 months
Secondary
Time to Cmax (Tmax)
Tmax was defined as time to reach Cmax, determined directly from the persistence-time data. Blood samples were collected for PK analysis.
Time frame: Day 1 to Day 14
Population: Pharmacokinetic (PK) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letetresgene Autoleucel (Lete-cel) | Time to Cmax (Tmax) | 6.90 Days |
Secondary
Time to Response (TTR)
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. CR is defined as 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). PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline).
Time frame: Up to approximately 54 months