Study of GSK3901961 In Previously Treated Advanced (Metastatic OR Unresectable) Synovial Sarcoma/ Myxoid/Round Cell Liposarcoma, and Previously Treated Metastatic Non-Small Cell Lung Cancer

Phase 1

Terminated

Conditions: Neoplasms

Interventions: Drug: GSK3901961
Drug: Cyclophosphamide
Drug: Fludarabine

Registration Number: NCT06048705

Lead Sponsor: Adaptimmune

Brief Summary: The primary purpose of this sub study is to assess the safety, tolerability and determine recommended Phase 2 dose (RP2D) of GSK3901961 in HLA A\*02:01, HLA-A\*02:05 and/or HLA A\*02:06 positive participants with New York esophageal squamous cell carcinoma (NY ESO 1) and/or Cancer testis antigen 2 (LAGE 1a) positive previously treated metastatic Non-Small Cell Lung Cancer (NSCLC) and previously treated, advanced (metastatic or unresectable) Synovial Sarcoma/ Myxoid/Round Cell Liposarcoma SS/MRCLS.

Detailed Description: This study is a substudy of the Master record - (209012) NCT04526509.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Participant must be >=18 years of age and weighs ≥40 kg on the day of signing informed consent
Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles
Participant's tumor must have tested positive for NY-ESO-1 and/or LAGE-1a expression by a GSK designated laboratory
Performance status: Eastern Cooperative Oncology Group of 0-1
Participant must have adequate organ function and blood cell counts 7 days prior to leukapheresis
Participant must have measurable disease according to RECIST v1.1.
Participant has advanced (metastatic or unresectable) SS or MRCLS confirmed by local histopathology with evidence of disease-specific translocation
Participant has completed at least one standard of care (SOC) treatment including anthracycline containing regimen unless intolerant to or ineligible to receive the therapy.
Participants who are not candidates to receive anthracycline should have received ifosfamide unless also intolerant to or ineligible to receive ifosfamide. Participants who received neoadjuvant/adjuvant anthracycline or ifosfamide based therapy and progressed will be eligible
Participant has histologically or cytologically confirmed Stage IV NSCLC
Participant has been previously treated with SOC for Stage IV NSCLC

Exclusion Criteria

Central nervous system (CNS) metastases, with certain exceptions for CNS metastases in NSCLC as specified in the protocol
Any other prior malignancy that is not in complete remission
Clinically significant systemic illness
Prior or active demyelinating disease
History of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments
Previous treatment with genetically engineered NY-ESO-1-specific T cells, NY-ESO-1 vaccine or NY-ESO-1 targeting antibody
Prior gene therapy using an integrating vector
Previous allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplant
Washout periods for prior radiotherapy and systemic chemotherapy must be followed
Major surgery within 4 weeks prior to lymphodepletion
Pregnant or breastfeeding females

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GSK3901961	GSK3901961	Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive high dose of GSK3901961 after completing lymphodepleting chemotherapy. The first study participant receiving GSK3901961 will receive the total assigned dose as 2 separate infusions 7 days apart, in aliquots of 30% (first infusion) and 70% (second infusion) of the total target dose, respectively. Based on the dose limiting toxicities reported in the first participant, then all subsequent participants treated with GSK3901961 will receive the full dose as a single, i.e., one-time, infusion.
GSK3901961	Fludarabine	Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive high dose of GSK3901961 after completing lymphodepleting chemotherapy. The first study participant receiving GSK3901961 will receive the total assigned dose as 2 separate infusions 7 days apart, in aliquots of 30% (first infusion) and 70% (second infusion) of the total target dose, respectively. Based on the dose limiting toxicities reported in the first participant, then all subsequent participants treated with GSK3901961 will receive the full dose as a single, i.e., one-time, infusion.
GSK3901961	Cyclophosphamide	Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive high dose of GSK3901961 after completing lymphodepleting chemotherapy. The first study participant receiving GSK3901961 will receive the total assigned dose as 2 separate infusions 7 days apart, in aliquots of 30% (first infusion) and 70% (second infusion) of the total target dose, respectively. Based on the dose limiting toxicities reported in the first participant, then all subsequent participants treated with GSK3901961 will receive the full dose as a single, i.e., one-time, infusion.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs Based on Maximum Severity	Up to approximately 21 months	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any untoward medical occurrence that, at any dose can result in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth or is medically significant or requires intervention to prevent one or the outcomes listed above. AEs and SAEs were graded according to NCI-CTCAE v5.0. Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences; Grade 5- Death related to AE. AEs which start or worsen on or after T-cell infusion are classified as treatment emergent. SAEs are subset of AEs. Results for maximum severity grades has been presented.
Number of Participants With Dose Limiting Toxicities (DLTs)	Up to 28 days	DLT events were graded according to NCI-CTCAE v5.0. DLTs were defined as Grade (Gr) 4 (life-threatening and death) related to GSK3901961 2) Gr 3 (Severe or medically significant) at least possibly related to GSK3901961 and do not resolve to Gr \<=1 (or Baseline) within 7 days from the onset of the event 3) Gr \>=3 non-infectious pneumonitis not responding to oxygen supplementation and systemic steroid treatment 4) Any Gr 3 cytokine release syndrome (CRS) at least possibly related to GSK3901961 that does not improve to Gr \<2 (moderate) toxicity within 7 days with or without dexamethasone 5) Any Gr 4 CRS at least possibly related to study product that does not improve to Gr \<=2 (or Baseline) within 7 days 6) Any Gr 3 or greater neurotoxicity that does not resolve to Gr \<=2 within 72 hours 7) Any Gr \>=3 organ toxicity (exclusive of CRS toxicity) involving major organ systems that persists for \>72 hours and occurs within 28 days of infusion.
Number of Participants With Treatment Emergent Adverse Events of Special Interest (AESI)	Up to approximately 21 months	An AESI may be of scientific and medical concern related to the treatment, monitored, and rapidly communicated by investigator to sponsor. AESIs included events of Cytokine Release Syndrome (CRS), Haematopoietic cytopenias (including pancytopenia and aplastic anaemia), Graft versus Host Disease (GvHD), Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS), Guillain-Barre Syndrome (GBS), Pneumonitis and treatment-related inflammatory response at tumor site(s) and Neutropenia Grade 4 lasting more than or equal to 28 days. AEs which start or worsen on or after T-cell infusion are classified as treatment emergent.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR)	Up to approximately 21 months	DoR is defined as the interval of time (in months) from first documented evidence of the confirmed response (PR or CR) as assessed by local investigators to the date of disease progression per RECIST v1.1 or death due to any cause, among participants with a confirmed response of PR or CR. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.
Maximum Transgene Expansion (Cmax) of GSK3901961	Up to 21 days	Cmax was defined as peak cell expansion during the interventional phase. Blood samples were collected to measure Cmax.
Overall Response Rate (ORR) Assessed by Investigator According to RECIST v1.1	Up to approximately 21 months	Overall response rate (ORR) defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) via investigator assessment per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1 relative to the total number of participants in the analysis population. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response (CR) was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). Confidence intervals (CI) were calculated using the exact (Clopper-Pearson) method.
Time to Cmax (Tmax) of GSK3901961	Up to 21 days	Tmax was defined as time to peak cell expansion during the interventional phase. Blood samples were collected to measure Tmax.
Area Under the Time Curve From Zero to Time 28 Days AUC(0-28)	Up to 28 days	Area under the cell expansion-time curve from first T-cell infusion to Day 28. Blood samples were collected to measure AUC (0-28 days).