Back to results

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

Primary Purpose

Neoplasms

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Letetresgene autoleucel

Letetresgene autoleucel with pembrolizumab

Fludarabine

Cyclophosphamide

Pembrolizumab

About this trial

This is an interventional treatment trial for Neoplasms focused on measuring Relapsed and Refractory Multiple Myeloma, T Cell Receptor, Immuno-oncology, NY-ESO-1, Leukapheresis, Adoptive TCR T-cell therapy, Letetresgene autoleucel

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm 1: Letetresgene autoleucel (GSK3377794)

Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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).

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).

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).

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).

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.

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.

Full Information

NCT ID

NCT03168438

First Posted

May 24, 2017

Last Updated

November 9, 2021

Sponsor

GlaxoSmithKline

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT03168438

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Terminated

Why Stopped

The study was terminated following an internal review of the company's research and development portfolio

Study Start Date

August 18, 2017 (Actual)

Primary Completion Date

July 13, 2020 (Actual)

Study Completion Date

November 5, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms

Keywords

Relapsed and Refractory Multiple Myeloma, T Cell Receptor, Immuno-oncology, NY-ESO-1, Leukapheresis, Adoptive TCR T-cell therapy, Letetresgene autoleucel

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Letetresgene autoleucel (GSK3377794)

Arm Type

Experimental

Arm Description

Arm Title

Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Letetresgene autoleucel

Intervention Description

Letetresgene autoleucel (GSK3377794) as an IV infusion

Intervention Type

Drug

Intervention Name(s)

Letetresgene autoleucel with pembrolizumab

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Pembrolizumab

Intervention Description

Pembrolizumab is available as an IV infusion

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Up to 108 weeks

Title

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

Description

Time Frame

Up to 3 weeks

Title

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

Description

Time Frame

Up to 108 weeks

Title

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

Description

Time Frame

Up to 108 weeks

Title

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

Description

Time Frame

Up to 108 weeks

Title

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

Description

Time Frame

Up to 108 weeks

Secondary Outcome Measure Information:

Title

Overall Response Rate

Description

Time Frame

Up to 108 weeks

Title

Time to Response

Description

Time Frame

Up to 108 weeks

Title

Duration of Response

Description

Time Frame

Up to 108 weeks

Title

Progression-free Survival

Description

Time Frame

Up to 108 weeks

Title

Maximum Persistence (Cmax) of GSK3377794

Description

Time Frame

Up to 108 weeks

Title

Time to Maximum Persistence

Description

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

Time Frame

Up to 108 weeks

Title

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

Description

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

Time Frame

Up to Day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Duarte

State/Province

California

ZIP/Postal Code

91010

Country

United States

Facility Name

GSK Investigational Site

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

GSK Investigational Site

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612-9497

Country

United States

Facility Name

GSK Investigational Site

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

GSK Investigational Site

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

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

IPD Sharing 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.

IPD Sharing 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.

IPD Sharing URL

http://clinicalstudydatarequest.com

Learn more about this trial

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

We'll reach out to this number within 24 hrs