Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Pembrolizumab

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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, followed by pembrolizumab 200 mg every 3 weeks.

Letetresgene autoleucel (GSK3377794) as an IV infusion

Letetresgene autoleucel

Letetresgene autoleucel (GSK3377794) as an IV infusion, followed by pembrolizumab every 3 weeks

Letetresgene autoleucel with pembrolizumab

Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.

Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.

Pembrolizumab is available as an IV infusion

GSK Clinical Trials

This trial will evaluate safety, tolerability, and efficacy of letetresgene autoleucel (GSK3377794) with or without pembrolizumab in participants with relapsed and refractory multiple myeloma.

Letetresgene Autoleucel Engineered T Cells Alone and in Combination With Pembrolizumab in NY-ESO-1 Positive Multiple Myeloma

Open-Label Pilot Study to Assess the Safety, Tolerability and Antitumor Activity of Genetically Engineered NY-ESO-1 Specific (c259) T Cells Alone or in Combination With Pembrolizumab in HLA-A2+ Subjects With NY-ESO-1 and/or LAGE-1a Positive Relapsed and Refractory Multiple Myeloma

IPD for this study will be made available via the Clinical Study Data Request site.

An AE is any untoward medical occurrence in a participant or clinical investigation participant who received a study treatment and the event need not necessarily have a causal relationship with study treatment. An SAE is any AE that results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in a persistent or significant disability; is a congenital anomaly/birth defect; is clinically significant or requires intervention to prevent one of the outcomes listed before.

The following toxicities were considered to be treatment limiting toxicities: any \>=Grade 4 AE; Grade 3 non-infectious pneumonitis and any other Grade 3 AE (excluding pneumonitis), that did not improve to Grade 2 within 7 days after onset despite medical management and supportive care. Exceptions included the following: Grade 3 or 4 leukopenia, lymphopenia, neutropenia, or febrile neutropenia; Grade 3 or 4 thrombocytopenia not associated with significant bleeding; Grade 3 anemia; Grade 4 cytokine release syndrome (CRS) or toxicities related to CRS that resolved to Grade \<=2 within 7 days; other Grade 3 laboratory abnormality determined to be not clinically significant by the Investigator; Grade 3 or 4 fever and chills; Grade 3 or 4 hypoalbuminemia or abnormal electrolytes that responded to supplementation/correction; AE related to the cancer or its progression.

Blood samples were collected for the assessment of following clinical chemistry parameters: glucose, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, potassium, magnesium, phosphate, sodium and calcium. 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. 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.

Blood samples were collected for the assessment of following hematology parameters: hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. 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.

Blood samples were collected for the assessment of following coagulation parameters: prothrombin time and partial thromboplastin time (PTT). A laboratory value that is outside the normal range is considered either high abnormal (value above the upper limit of the normal range) or low abnormal (value below the lower limit of the normal range). Participants were counted twice if the participant had values in 'Decreased to low' and 'Increased to high' during the post-Baseline period. Data for worst case post Baseline is presented.

ECG was recorded 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 clinically significant ECG findings for worst case post-Baseline has 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.

Overall response rate is defined as the percentage of participants with a best overall response (BOR) of confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per International Myeloma Working Group (IMWG) Response Criteria (2016); where, PR: \>=50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>=90% or to \<200 milligrams (mg) per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<= 5% plasma cells in bone marrow; or sCR: CR as defined by normal free light chain (FLC) ratio and absence of clonal cells by immunohistochemistry. Confidence intervals were calculated using the exact (Clopper-Pearson) method.

Time to response is defined as the time interval (in months) from T-cell infusion to initial date of documented confirmed response (PR or better) in the subset of participants who showed a confirmed BOR of PR or better by Investigator assessment per IMWG (2016).

Duration of response is defined as the interval between the initial date of the confirmed response (sCR, CR, VGPR, or PR) and the initial assesment date of confirmed progressive disease or death among participants with a confirmed response per IMWG (2016).

Progression Free Survival is defined as the interval between the date of T-cell infusion and the initial assessment date of confirmed progressive disease as assessed by the investigator per IMWG (2016) or date of death. Progressive disease is defined as an increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>=0.5 grams per deciliter (g/dL); Serum M-protein increase \>=1 g/dL if the lowest M-component was \>=5 g/dL; Urinary M-protein (absolute increase must be \>=200 mg per 24 hours).

Blood samples were collected to measure persistence of infused GSK3377794 using polymerase chain reaction of a vector specific sequence in deoxyribonucleic acid (DNA) extracted from peripheral blood mononuclear cell (PBMC).

Blood samples were collected to measure persistence of infused GSK3377794 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC.

Merck Sharp & Dohme LLC

GlaxoSmithKline

Non-serious AEs and SAEs were collected in the ITT Population. All-cause mortality was collected in the modified ITT Population.

Eligible participants underwent leukapheresis to manufacture engineered T-cells. Participants then underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single intravenous (IV) infusion of GSK3377794.

GSK3377794

Eligible participants underwent leukapheresis to manufacture engineered T-cells. Participants then underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single IV infusion of GSK3377794 in combination with pembrolizumab 200 milligrams (mg) administered as an IV infusion every 3 weeks up to Week 108.

GSK3377794+Pembrolizumab

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

GSK Response Center

Any AE

Any SAE

Intent-To-Treat (ITT) Population comprised of all participants who underwent leukapheresis

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

ITT Population. Treatment limiting toxicities were assessed in GSK3377794+pembrolizumab arm only.

Number of Participants With Treatment Limiting Toxicities-GSK3377794+Pembrolizumab Arm Only

Glucose (Hyperglycemia)

Glucose (Hypoglycemia)

Albumin (Hypoalbuminemia)

ALP increased

ALT increased

AST increased

Bilirubin increased

Creatinine increased

Potassium (Hyperkalemia)

Potassium (Hypokalemia)

Magnesium (Hypermagnesemia)

Magnesium (Hypomagnesemia)

Phosphate (Hypophosphatemia)

Sodium (Hypernatremia)

Sodium (Hyponatremia)

Calcium (Hypercalcemia)

Calcium (Hypocalcemia)

Modified ITT Population comprised of all participants in the ITT Population who received the NY-ESO-1c259T infusion.

Number of Participants With Worst-case Chemistry Results by Any Grade Increase Post-Baseline Relative to Baseline

Hemoglobin (Anemia)

Hemoglobin increased

Lymphocyte count decreased

Lymphocyte count increased

Neutrophil count decreased

Platelet count decreased

Leukocyte count decreased

Number of Participants With Worst-case Hematology Results by Any Grade Increase Post-Baseline Relative to Baseline

Prothrombin Time; decrease to low

Prothrombin Time; To normal or no change

Prothrombin Time; increase to high

PTT; decrease to low

PTT; To normal or no change

PTT; increase to high

Modified ITT Population. Only those participants with data available at the specified time point is reported

Number of Participants With Worst-case Results for Coagulation Parameters Relative to Normal Range Post-Baseline Relative to Baseline

Number of Participants With Worst-case Post Baseline Abnormal Electrocardiogram (ECG) Findings

Overall Response Rate

Modified ITT Population. Only those participants with a confirmed response per IMWG 2016 were analyzed.

Time to Response

Duration of Response

Progression-free Survival

Maximum Persistence (Cmax) of GSK3377794

Time to Maximum Persistence

Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC[0-28])

Overall Study

Skin and Connective Tissue Diseases

Sarcoma

Liposarcoma

Sarcoma, Synovial

Liposarcoma, Myxoid

Neoplasms, Connective and Soft Tissue

Neoplasms, Adipose Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Synovial Sarcoma

Myxoid Liposarcoma

Letetresgene autoleucel will be administered.

Cyclophosphamide will be used as a lymphodepleting chemotherapy.

Fludarabine will be used as a lymphodepleting chemotherapy.

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.

Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Evaluation of Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

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 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 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).

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.

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.

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.

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.

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.

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) was summarized descriptively.

Cmax was defined as maximum observed persistence, determined directly from the persistence-time data. Blood samples were collected for PK analysis.

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 persistence-time curve from time zero to Day 28. Blood samples were collected for PK analysis.

All-Cause mortality, Non-SAEs and SAEs were collected for intent-to-treat population that included all participants who started leukapheresis procedure.

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.

Letetresgene Autoleucel (Lete-cel)

<=18 years

19-64 years

Age, Customized

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

Netherlands

United Kingdom

United States

Region of Enrollment

Modified intent-to-treat (mITT) population included all participants who received any dose of Lete-cel.

Overall Response Rate (ORR)

Time to Response (TTR)

Duration of Response (DOR)

Disease Control Rate (DCR)

Progression Free Survival (PFS)

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Number of Participants With AEs of Special Interest (AESIs)

Number of Participants With TEAEs and TESAEs by Severity

Number of Participants With AESIs by Severity

Percentage of Participants With Replication Competent Lentivirus (RCL) Positive

Instances of Insertional Oncogenesis (IO)

Pharmacokinetic (PK) population included participants in the safety population from whom at least one persistence sample was obtained, analyzed and was measurable.

Maximum Transgene Expansion (Cmax)

Time to Cmax (Tmax)

Area Under the Time Curve From Zero to Time 28 Days (AUC[0-28])

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Recurrence

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Squamous Cell

Lung Neoplasms

Esophageal Squamous Cell Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Immunomodulating Agents

In Arm A, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel monotherapy. Participants who subsequently progress by Week 25 will be offered pembrolizumab.

In Arm B, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.

In Arm C, participants with NSCLC (with actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.

lete-cel will be administered to eligible participants.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Letetresgene Autoleucel Engineered T Cells Alone and in Combination With Pembrolizumab in NY-ESO-1 Positive Multiple Myeloma	NCT03168438	Neoplasms	Letetresgene au... Letetresgene au... Fludarabine Cyclophosphamid... Pembrolizumab	18 Years -	GlaxoSmithKline
Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma	NCT05993299	Neoplasms	Letetresgene au... Cyclophosphamid... Fludarabine	10 Years -	GlaxoSmithKline
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	NCT03709706	Neoplasms	Lete-cel Pembrolizumab	18 Years -	GlaxoSmithKline
Letetresgene Autoleucel Engineered T Cells Alone and in Combination With Pembrolizumab in NY-ESO-1 Positive Multiple Myeloma	NCT03168438	Neoplasms	Letetresgene au... Letetresgene au... Fludarabine Cyclophosphamid... Pembrolizumab	18 Years -	GlaxoSmithKline
Letetresgene Autoleucel Engineered T Cells Alone and in Combination With Pembrolizumab in NY-ESO-1 Positive Multiple Myeloma	NCT03168438	Neoplasms	Letetresgene au... Letetresgene au... Fludarabine Cyclophosphamid... Pembrolizumab	18 Years -	GlaxoSmithKline
Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma	NCT05993299	Neoplasms	Letetresgene au... Cyclophosphamid... Fludarabine	10 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for letetresgene autoleucel