Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumors
- Conditions
- Neoplasms
- Interventions
- Registration Number
- NCT03967223
- Lead Sponsor
- Adaptimmune
- Brief Summary
This trial will evaluate safety and efficacy of human engineered T-cell therapies, in participants with advanced tumors.
- Detailed Description
New York esophageal antigen-1 (NY-ESO-1) and LAGE-1a antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using adoptively transferred T cells directed against NY-ESO-1/LAGE-1a have shown objective responses. Letetresgene autoleucel (lete-cel, GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor engineered T cells. This is a master protocol investigating T-cell therapies. It will initially consist of a core protocol with two independent substudies investigating Letetresgene autoleucel in previously untreated (1L) Human Leukocyte Antigen (HLA)-A\*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) (Substudy 1) and Letetresgene autoleucel as second line or higher (2L+) treatment in HLA-A\*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) SS or MRCLS who have progressed following treatment with anthracycline based chemotherapy (Substudy 2).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 103
- Participant must be greater than or equal to 10 years of age on the day of signing informed consent.
- Participant scheduled to receive clinical drug product supply must also weigh ≥40 kg
- Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a designated central laboratory
- Participant's tumor is positive for NY-ESO-1 expression by a designated central laboratory.
- Participant has a diagnosis of synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS)
- Performance status: dependent on age - Lansky > 60, Karnofsky > 60, Eastern Cooperative Oncology Group 0-1.
- Participant must have adequate organ function and blood cell counts, within 7 days prior to leukapheresis.
- At time of treatment, participant has measurable disease according to RECIST v1.1.
- Male or female. Contraception requirements will apply at the time of leukapheresis and treatment.
- Consultation for prior history per protocol specifications.
- Central nervous system metastases.
- Any other prior malignancy that is not in complete remission.
- Clinically significant systemic illness (Serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the participant's ability to tolerate protocol therapy or significantly increase the risk of complications).
- Prior or active demyelinating disease.
- History of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn's disease, systemic lupus) requiring steroids or other immunosuppressive treatments.
- Previous treatment with genetically engineered NY-ESO-1-specific T cells.
- Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
- Prior gene therapy using an integrating vector.
- Previous allogeneic hematopoietic stem cell transplant.
- Washout periods for prior radiotherapy and systemic chemotherapy must be followed.
- Participant had major surgery in less than or equal to 28 days of first dose of study intervention.
- Prior radiation exceeds protocol specified limits.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Substudy 1: lete-cel in previously untreated advanced (metastatic or unresectable) SS or MRCLS Letetresgene autoleucel (lete-cel, GSK3377794) Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. Substudy 2: lete-cel in advanced (metastatic or unresectable) SS or MRCLS post anthracycline chemo Letetresgene autoleucel (lete-cel, GSK3377794) Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. Substudy 1: lete-cel in previously untreated advanced (metastatic or unresectable) SS or MRCLS Fludarabine Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. Substudy 1: lete-cel in previously untreated advanced (metastatic or unresectable) SS or MRCLS Cyclophosphamide Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. Substudy 2: lete-cel in advanced (metastatic or unresectable) SS or MRCLS post anthracycline chemo Fludarabine Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel. Substudy 2: lete-cel in advanced (metastatic or unresectable) SS or MRCLS post anthracycline chemo Cyclophosphamide Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel.
- Primary Outcome Measures
Name Time Method Substudy 1: Overall response rate (ORR) Until disease progression (up to 5 years) Overall response rate is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) relative to the total number of participants within the analysis population at any time per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. as determined by the local investigators.
Substudy 2: Overall response rate (ORR) as assessed by central independent review Up to 5 years Overall response rate is defined as the percentage of participants with a confirmed CR or PR relative to the total number of participants within the analysis population at any time per RECIST v1.1. as assessed by central independent review.
- Secondary Outcome Measures
Name Time Method Substudy 1 and 2: Time to response (TTR) Until disease progression (up to 5 years) Time to response is defined as time from date of T-cell administration to first documented evidence of confirmed (CR or PR) as assessed by local investigators per RECIST v1.1.
Substudy 1 and 2: Duration of response (DOR) Until disease progression (up to 5 years) Duration of response is defined as, in the subset of participants who show a confirmed CR or PR as assessed by local investigators, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.
Substudy 1 and 2: Disease control rate (DCR) Until disease progression (up to 5 years) Disease control rate is defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) with minimal 12 weeks duration relative to the total number of participants within the analysis population at the time of primary analysis as determined by Investigators per RECIST v1.1.
Substudy 1 and 2: Progression free survival (PFS) Until disease progression (up to 5 years) Progression free survival is defined as the time from the date of T-cell administration until first documented sign of disease progression per RECIST v1.1, or death.
Substudy 1 and 2: Maximum transgene expansion (Cmax) of letetresgene autoleucel Until disease progression (up to 5 years) Whole blood samples will be collected at indicated time points for evaluation of Cmax.
Substudy 1 and 2: Time to Cmax (Tmax) of letetresgene autoleucel Until disease progression (up to 5 years) Whole blood samples will be collected at indicated time points for evaluation of Tmax.
Substudy 1 and 2: Frequency of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI) according to severity Until disease progression (up to 5 years) AEs, SAEs and AESIs will be collected. Severity of AEs and SAEs will be summarized using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
Substudy 1 and 2: Number of participants with replication competent lentivirus (RCL) Until disease progression (up to 5 years) RCL exposure will be assessed by polymerase chain reaction (PCR) based assay.
Substudy 1 and 2: Area under the concentration/persistence time curve from zero to time t (AUC[0-t]) of letetresgene autoleucel Until disease progression (up to 5 years) Whole blood samples will be collected at indicated time points for evaluation of AUC(0-t).
Substudy 2: Overall Survival (OS) Up to 5 years Overall Survival is defined as the interval of time between the date of T-cell infusion and the date of death.
Substudy 2: Overall response rate (ORR) as determined by the local investigators Up to 5 years Overall response rate is defined as the percentage of participants with a confirmed CR or PR relative to the total number of participants within the analysis population at any time per RECIST v1.1. as determined by the local investigators.
Substudy 2: Number of participants with positive anti-drug antibodies (ADA) and titers of ADA against letetresgene autoleucel Up to 36 months Serum samples will be collected to analyze for the presence of ADAs using validated immunoassays.
Substudy 1 and 2: Number of participants with insertional oncogenesis (IO) Until disease progression (up to 5 years) Peripheral blood mononuclear cells (PBMC) samples will be collected for monitoring insertional oncogenesis by PCR for gene modified cells in the blood.
Substudy 2: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis parameters Until disease progression (up to 5 years) Blood and urine samples will be collected for assessment of hematology, clinical chemistry and urinalysis parameters.
Trial Locations
- Locations (37)
Hospital Virgen Del Rocio
🇪🇸Sevilla, Spain
Stanford Hospital and Clinics
🇺🇸Stanford, California, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Memorial Sloan Kettering cancer center
🇺🇸New York, New York, United States
Ico Duran y Reynals l'Hospitalet de Llobrega
🇪🇸Hospitalet de Llobregat, Barcelona, Spain
University of Iowa College of Medicine
🇺🇸Iowa City, Iowa, United States
Hospital Universitario Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Hospital Santa Creu Y Sant Pau
🇪🇸Barcelona, Spain
The Netherlands Cancer Institute
🇳🇱Amsterdam, Netherlands
University of Chicago
🇺🇸Chicago, Illinois, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Minnesota Oncology Hematology
🇺🇸Minneapolis, Minnesota, United States
Ohio State University-Columbus
🇺🇸Columbus, Ohio, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
University of Pittsburgh, Hillman Cancer Centre
🇺🇸Pittsburgh, Pennsylvania, United States
Fred Hutchinson Cancer Research
🇺🇸Seattle, Washington, United States
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Christie Hospital NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University Of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
CHU de Bordeaux GH Sud Hôpital Haut Lévêque
🇫🇷Pessac cedex, France
CIUSSS de L'Est-De-Lile-De-Montreal
🇨🇦Montreal, Quebec, Canada
Centre Léon Bérard
🇫🇷Lyon cedex 08, France
Ircss Istituto Clinico Humanitas
🇮🇹Rozzano (MI), Lombardia, Italy
Fondazione IRCCS Instituto Nazionale Dei Tumori
🇮🇹Milano, Lombardia, Italy
University College Hospital-London
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧London, United Kingdom
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
University of Michigan Medical Center
🇺🇸Ann Arbor, Michigan, United States