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

NCT03168438 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: 208470ADP-0011-008KEYNOTE-487
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 5

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.

Conditions

Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (7)

• Overall Response Rate

  Up to 108 weeks

• Time to Response

  Up to 108 weeks

• Duration of Response

  Up to 108 weeks

• Progression-free Survival

  Up to 108 weeks

• Maximum Persistence (Cmax) of GSK3377794

  Up to 108 weeks

Study Arms (2)

Arm 1: Letetresgene autoleucel (GSK3377794)

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cyclophosphamide

Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Pembrolizumab

Interventions

Letetresgene autoleucel DRUG

Letetresgene autoleucel (GSK3377794) as an IV infusion

Arm 1: Letetresgene autoleucel (GSK3377794)

Letetresgene autoleucel with pembrolizumab DRUG

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

Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Fludarabine DRUG

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

Arm 1: Letetresgene autoleucel (GSK3377794); Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Cyclophosphamide DRUG

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

Arm 1: Letetresgene autoleucel (GSK3377794); Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Pembrolizumab DRUG

Pembrolizumab is available as an IV infusion

Arm 2: Letetresgene autoleucel (GSK3377794) with pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (5)

GSK Investigational Site

Duarte, California, 91010, United States

Location

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

Tampa, Florida, 33612-9497, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30322, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21201, United States

Location

Related Publications (1)

• Nishihori T, Hoffman JE, Huff A, Kapoor GS, Eleftheriadou I, Zajic S, Urbano A, Suchindran S, Chisamore M, D'Souza JW, Faitg T, Rapoport AP. Safety and efficacy of letetresgene autoleucel alone or with pembrolizumab for relapsed/refractory multiple myeloma. Blood Adv. 2023 Apr 11;7(7):1168-1177. doi: 10.1182/bloodadvances.2022008460.

  PMID: 36534160 DERIVED

MeSH Terms

Conditions

Neoplasms; Recurrence; Multiple Myeloma

Interventions

pembrolizumab; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2017
• First Posted: May 30, 2017
• Study Start: August 18, 2017
• Primary Completion: July 13, 2020
• Study Completion: November 5, 2020
• Last Updated: January 11, 2022
• Results First Posted: January 11, 2022

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (5)