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

• ClinicalTrials.gov Identifier: NCT03168438
• Recruitment Status: Terminated
• First Posted: May 30, 2017
• Results First Posted: January 11, 2022
• Last Update Posted: January 11, 2022
• Sponsor: GlaxoSmithKline
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: May 24, 2017
• First Posted Date: May 30, 2017
• Results First Submitted Date: November 9, 2021
• Results First Posted Date: January 11, 2022
• Last Update Posted Date: January 11, 2022
• Actual Study Start Date: August 18, 2017
• Actual Primary Completion Date: July 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 9, 2021)

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

Original Primary Outcome Measures (submitted: May 24, 2017)

Number of subjects with Treatment Limiting Toxicities (TLT), adverse events (AE), including serious adverse events (SAE). [ Time Frame: 3.5 years ]

Adverse events (AEs), including serious adverse event (SAEs) and treatment limiting toxicities (TLTs with combination only); laboratory assessments including chemistry, hematology and coagulation; and cardiac assessments by electrocardiogram (ECG).

Current Secondary Outcome Measures (submitted: November 9, 2021)

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

Original Secondary Outcome Measures (submitted: May 24, 2017)

• Proportion of subjects with a positive response : Partial Response (PR), Very Good Partial response (VGPR), Complete Response (CR) or stringent CR (sCR) [ Time Frame: 3.5 years ]
  Evaluation of the efficacy of the treatment by assessment of the Overall Response rate (ORR) according to International Myeloma Working Group (IMWG) Uniform Response Criteria.
• Interval between the date of T-cell infusion and first documented evidence of positive response (PR, VGPR, CR, sCR) [ Time Frame: 3.5 years ]
  Evaluation of the efficacy of the treatment by assessment of time to first response (Time to Response (TTR))
• Interval between the date of first documented evidence of response (PR, VGPR, CR, sCR) until first documented disease progression (PD) or death due to any cause [ Time Frame: 5 years ]
  Evaluation of the efficacy of the treatment by assessment of duration of response.
• Interval between the date of T cell infusion and the earliest date of disease progression or death due to any cause [ Time Frame: 5 years ]
  Evaluation of the efficacy of the treatment by assessment of progression-free survival (PFS).
• Interval between the date of T cell infusion and the earliest date of death due to any cause [ Time Frame: 7 years ]
  Evaluation of the efficacy of the treatment by assessment of overall survival (OS).

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: May 24, 2017)

• Assessment of response by correlating Minimal Residual Disease (MRD) with PFS and OS [ Time Frame: 4.5 years ]
  Molecular identification and quantification of the clonotypic sequence will be performed by Next-Gen Sequencing on bone marrow samples collected before and 100 days after T cell infusion.
• Correlation of NY-ESO-1ᶜ²⁵⁹T persistence, phenotype and functionality with response to treatment [ Time Frame: 4.5 years ]
  Flow cytometry will be used to assess the phenotype of transduced T cells in the manufactured product and in post-infusion samples.
• Assessment of loss of antigen expression as resistance mechanism [ Time Frame: 4.5 years ]
  Expression of NY-ESO-1, LAGE-1a and CD138 (marker of plasma cells) in bone marrow aspirates will be assessed by qRT-PCR at different time points after T cell infusion in order to assess tumor burden and antigen expression.
• Evaluation of potential antigenicity of NY-ESO-1ᶜ²⁵⁹T cell receptor [ Time Frame: 4.5 years ]
  The presence of antibodies directed against the NY-ESO-1ᶜ²⁵⁹T cell receptor in serum ("anti-drug antibodies") will be measured by ELISA using a custom assay and will be analyzed in relation to persistence of transduced T cells in peripheral blood.
• Evaluation of the role of expression of PD-1 and PD-L1 in bone marrow in response to treatment [ Time Frame: 4.5 years ]
  Expression of PD-1 and PD-L1 in Bone Marrow Mononuclear Cells (BMMC) isolated from BM aspirates will be measured by flow cytometry. When BM biopsies are collected, IHC will be used to assess expression of PD-L1 on plasma cells and in the microenvironment.
• Investigation of cellular and molecular biomarkers of response in BM samples [ Time Frame: 4.5 years ]
  BM aspirates will be analyzed at the cellular level (flow cytometry) and at the molecular level (gene expression profiling) to identify markers of immune response (immune cell subsets, immune-modulatory molecules, etc.)
• Correlation of clonal outgrowth of T-cell populations with response following T-cell infusion [ Time Frame: 4.5 years ]
  Assessment of the polyclonality status of the T cell population in peripheral blood and BM aspirates will be performed by TCR sequencing (NGS)
• Measurement of cytokines in relation to CRS [ Time Frame: 4.5 years ]
  Cytokines will be quantified in peripheral blood and BM serum before and after T-cell infusion using a multiplex assay (e.g. Luminex)

Descriptive Information

• Brief Title: Letetresgene Autoleucel Engineered T Cells Alone and in Combination With Pembrolizumab in NY-ESO-1 Positive Multiple Myeloma
• Official Title: 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
• Brief Summary: This trial will evaluate safety, tolerability, and efficacy of letetresgene autoleucel (GSK3377794) with or without pembrolizumab in participants with relapsed and refractory multiple myeloma.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasms

Intervention

• Drug: Letetresgene autoleucel
  Letetresgene autoleucel (GSK3377794) as an IV infusion
• Drug: Letetresgene autoleucel with pembrolizumab
  Letetresgene autoleucel (GSK3377794) as an IV infusion, followed by pembrolizumab every 3 weeks
• Drug: Fludarabine
  Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.
• Drug: Cyclophosphamide
  Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route.
• Drug: Pembrolizumab
  Pembrolizumab is available as an IV infusion

Study Arms

• Experimental: Arm 1: Letetresgene autoleucel (GSK3377794)
  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.
  Interventions:

  • Drug: Letetresgene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab
  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.
  Interventions:

  • Drug: Letetresgene autoleucel with pembrolizumab
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 23, 2021): 6
• Original Estimated Enrollment (submitted: May 24, 2017): 20
• Actual Study Completion Date: November 5, 2020
• Actual Primary Completion Date: July 13, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03168438
• Other Study ID Numbers: 208470; ADP-0011-008 ( Other Identifier: Adaptimmune Therapeutics ); KEYNOTE-487 ( Other Identifier: Merck Sharp and Dohme Corp. )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Adaptimmune
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Adaptimmune
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: October 2021