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

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

Official Title
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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

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Letetresgene autoleucel
* Drug: Letetresgene autoleucel with pembrolizumab
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >=18 years of age or older on the date of signing informed consent. Histologically confirmed diagnosis of secretory multiple myeloma with myeloma markers at levels defined in the protocol. Documented diagnosis of relapsed and refractory multiple myeloma (RRMM) (at least 3 prior regimens and responsive to at least 1, and refractory to most recent prior therapies, which must have included one or more than one drug from each of the following drug classes: an immunomodulatory imide drug (IMiD), proteasome inhibitor, alkylator (unless the participant is ineligible or contraindicated to receive an alkylator), CD 38 monoclonal antibody, and glucocorticoid as separate lines or a combined line of therapy.- Left ventricular ejection fraction (LVEF) >= 50%. Lower LVEF (>= 40%) permissible if formal cardiologic evaluation reveals no evidence for clinically significant functional impairment. Meets protocol criteria for patients who have previously received checkpoint inhibitors or other immuno-oncology agents. ECOG Performance Status 0 or 1. Participant is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive as determined by a designated central laboratory. Participant has confirmed sufficient expression of NY-ESO-1 and/or LAGE-1a as determined by a designated central laboratory. In the Investigator's opinion, the participant is fit for cell collection. Participant has adequate organ function and cell counts as described in the protocol. Participants previously treated with BCMA therapy (BCMA chimeric antigen receptor (CAR)-T, antibody-drug conjugate (ADC), or other type of BCMA-targeted therapy) must have progressed from this therapy prior to attending the Baseline visit prior to beginning lymphodepletion. Contraception use by male and female participant meets protocol requirements. Exclusion Criteria: Has only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), non-secretory myeloma or primarily amyloidosis. Previously received anti- programmed death (PD)-1, anti-PD-ligand (L)1, or anti-PD-L2 inhibitor. Previously participated in Merck pivotal trial NCT02576977: Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab in Refractory or RRMM. Had a prior allogeneic stem cell transplant. Has ongoing toxicity from previous anticancer therapy. Had a major surgery within 4 weeks prior to enrollment. Has history of allergic reactions to fludarabine, cyclophosphamide or agents similar to fludarabine, cyclophosphamide or other agents used in the study. Known history of myelodysplasia. Current active liver or biliary disease. Known history of chronic active hepatitis or liver cirrhosis. Participant has an active viral infection. History of severe immune disease, including non-infectious pneumonitis, requiring steroids or other immunosuppressive treatments. Active immune-mediated diseases. Prior or active demyelinating disease. Evidence or history of significant cardiac disease. Evidence or history of other significant, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease. Participants with concomitant second malignancies (except adequately treated non-melanomatous skin cancers, carcinoma in situ of the breast, treated superficial bladder cancer or prostate cancer, or in situ cervical cancers ) not in complete remission. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may be eligible. Active bacterial or systemic viral or fungal infections. Pregnant or breastfeeding. Cannot meet washout periods for prior radiotherapy, chemotherapy or other protocol-specified therapies. More than 2 years have passed since the participant's last leukapheresis collection.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: 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<br>* Letetresgene autoleucel (GSK3377794) as an IV infusion<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>|
| Experimental: Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab<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, followed by pembrolizumab 200 mg every 3 weeks. | Drug: Letetresgene autoleucel with pembrolizumab<br>* Letetresgene autoleucel (GSK3377794) as an IV infusion, followed by pembrolizumab every 3 weeks<br>Drug: Fludarabine<br>* Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.<br>Drug: Pembrolizumab<br>* Pembrolizumab is available as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Up to 108 weeks | 
| Number of Participants With Treatment Limiting Toxicities-GSK3377794+Pembrolizumab Arm Only | 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. | Up to 3 weeks | 
| Number of Participants With Worst-case Chemistry Results by Any Grade Increase Post-Baseline Relative to Baseline | 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. | Up to 108 weeks | 
| Number of Participants With Worst-case Hematology Results by Any Grade Increase Post-Baseline Relative to Baseline | 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. | Up to 108 weeks | 
| Number of Participants With Worst-case Results for Coagulation Parameters Relative to Normal Range Post-Baseline Relative to Baseline | 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. | Up to 108 weeks | 
| Number of Participants With Worst-case Post Baseline Abnormal Electrocardiogram (ECG) Findings | 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. | Up to 108 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | 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. | Up to 108 weeks | 
| Time to Response | 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). | Up to 108 weeks | 
| Duration of Response | 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). | Up to 108 weeks | 
| Progression-free Survival | 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). | Up to 108 weeks | 
| Maximum Persistence (Cmax) of GSK3377794 | 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). | Up to 108 weeks | 
| Time to Maximum Persistence | Blood samples were collected to measure persistence of infused GSK3377794 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC. | Up to 108 weeks | 
| Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC[0-28]) | Blood samples were collected to measure persistence of infused GSK3377794 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC. | Up to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed and Refractory Multiple Myeloma, T Cell Receptor, Immuno-oncology, NY-ESO-1, Leukapheresis, Adoptive TCR T-cell therapy, Letetresgene autoleucel