A Phase 1b/2a Pilot Study to Evaluate the Safety and Tolerability of Autologous T-Cells Expressing Enhanced TCRs (T Cell Receptors) Specific for NY-ESO-1/LAGE-1a (GSK3377794) Alone, or in Combination With Pembrolizumab in HLA-A2+ Participants With NY-ESO-1- or LAGE-1a-Positive Advanced or Recurrent Non-Small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
This trial will evaluate safety and tolerability of letetresgene autoleucel (GSK3377794) with or without pembrolizumab in participants with non-small cell lung cancer.
详细描述
New York esophageal squamous cell carcinoma-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 (GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor (TCR) engineered T-cells. This is a multi-arm, open-label study of letetresgene autoleucel (lete-cel, GSK3377794) in Human Leukocyte Antigen (HLA)-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 positive adults whose tumors express NY-ESO-1 and/or LAGE-1a. This study will enroll participants who have unresectable Stage IIIb or Stage IV NSCLC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This will be an open-label study. Hence, there will be no masking.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >=18 years on the day of signing informed consent.
- •Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Participant is positive for any of the following alleles: human leukocyte antigen (HLA)-A*02:01, HLA-A*02:05, and a) or HLA-A*02:06 by a validated test.
- •Participant's tumor meets the pre-defined threshold for expression of NY-ESO-1 and/or LAGE-1a.
- •Adequate organ function and blood cell counts, as defined in the protocol.
- •Predicted life expectancy that is >=24 weeks from leukapheresis.
- •Left ventricular ejection fraction >=45%.
- •Prior therapies prior to lymphodepletion: a) All participants with NSCLC lacking actionable genetic aberrations, per National Comprehensive Cancer Network (NCCN) guidelines (Arms A and B), need to have received at least one line of programmed death protein 1/programmed death protein 1 ligand (PD-1/PD-L1) checkpoint blockade therapy. For participants in the metastatic setting, PD-1/PD-L1 checkpoint blockade therapy must have been received either alone, in combination or sequentially with platinum-containing chemotherapy. OR b) All participants with NSCLC with actionable genetic aberrations, per NCCN guidelines (Arm C only), should have received appropriate targeted therapy following NCCN or equivalent country-level guidelines.
- •Disease progression at time of treatment, as defined in the protocol.
- •Measurable disease at time of treatment per response evaluation criteria in solid tumors (RECIST) version 1.1 as assessed by local site investigator/radiology.
排除标准
- •Prior treatment: 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.
- •Prior allogeneic/autologous bone marrow or solid organ transplantation.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, dimethylsulfoxide (DMSO) or other agents used in the study.
- •Severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients.
- •Active autoimmune disease that has required systemic treatment in past 2 years.
- •History of chronic or recurrent (within the last year prior to enrollment) severe autoimmune or active immune-mediated disease requiring steroids or other immunosuppressive treatments.
- •Uncontrolled intercurrent illness.
- •Participant has active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein Barr virus (EBV), cytomegalovirus (CMV), syphilis, or human T lymphotropic virus (HTLV), as defined in protocol.
- •Known psychiatric or substance abuse disorders.
- •Symptomatic or untreated central nervous system (CNS) metastases.
- •Radiotherapy that involves the lung (Percentage of normal lung receiving at least 20 Gray [Gy] during radiotherapy [V20] exceeding 30% lung volume or mean heart dose >20 Gy) within 3 months or radiotherapy (including but not limited to palliative radiotherapy) to lung/mediastinum with V20 less than 30% lung volume and with mean heart dose <=20 Gy within 4 weeks (+/- 3 days).
- •Radiotherapy of >=50 Gy to a significant volume of the pelvis, long bones or spine, or a cumulative dose of radiation that, in the investigator's opinion would predispose participants to prolonged cytopenia after lymphodepletion.
- •All of the participant's measurable lesions have been irradiated within 3 months before lymphodepletion.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Arm A: lete-cel monotherapy
In Arm A, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel monotherapy. Participants who subsequently progress by Week 25 will be offered pembrolizumab.
干预措施: Lete-cel (Drug)
Arm A: lete-cel monotherapy
In Arm A, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel monotherapy. Participants who subsequently progress by Week 25 will be offered pembrolizumab.
干预措施: Pembrolizumab (Drug)
Arm B: lete-cel plus pembrolizumab
In Arm B, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.
干预措施: Lete-cel (Drug)
Arm B: lete-cel plus pembrolizumab
In Arm B, participants with NSCLC (lacking actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.
干预措施: Pembrolizumab (Drug)
Arm C: lete-cel plus pembrolizumab
In Arm C, participants with NSCLC (with actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.
干预措施: Lete-cel (Drug)
Arm C: lete-cel plus pembrolizumab
In Arm C, participants with NSCLC (with actionable genetic aberrations) will receive lete-cel followed by pembrolizumab.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Up to approximately 10 months
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. AEs which start or worsen on or after T-cell infusion are defined as treatment-emergent.
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESI)
时间窗: Up to approximately 10 months
AESI included cytokine release syndrome (CRS), pneumonitis/pneumonia, graft vs host disease (GvHD), guillain barre syndrome (GBS) or acute inflammatory demyelinating polyneuropathy (AIDP), pancytopenia/aplastic anemia (including analysis of all hematopoietic cytopenias), immune effector cell-associated neurotoxicity syndrome (ICANS) and treatment-related inflammatory response at tumor site. AEs which start or worsen on or after T-cell infusion are defined as treatment-emergent.
Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events Based on Maximum Severity Grades
时间窗: Up to approximately 10 months
An AE is any untoward medical occurrence in a clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. AEs which start or worsen on or after T-cell infusion are defined as TE. Severity was reported during study and was assigned a grade according to the National Institutes of Health National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). SAEs are subset of AEs. AEs and SAEs severity graded on a 5-point scale as: 1 = mild, 2 = moderate discomfort, 3 = severe, 4 = life-threatening and 5 = death due to AE.
Number of Participants With AEs Leading to Dose Delays
时间窗: Up to approximately 10 months
An AE is any untoward medical occurrence in a clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with AEs leading to dose delays were summarized.
Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
时间窗: Up to approximately 10 months
Overall response rate (ORR) defined as the percentage of participants with a complete response (CR) or partial response (PR) via investigator assessment per RECIST (Response Evaluation Criteria in Solid Tumors Criteria) v1.1 relative to the total number of participants in the analysis population. Partial response is 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 is 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.
次要结局
- Time to Cmax (Tmax) of Lete-cel(Day 1 to Day 15)
- Progression-free Survival (PFS) Per RECIST Version 1.1 by Investigator Assessment(Up to approximately 10 months)
- Disease Control Rate (DCR) Per RECIST Version 1.1 by Investigator Assessment(Up to approximately 10 months)
- Duration of Response (DOR) Per RECIST Version 1.1 by Investigator Assessment(Up to approximately 10 months)
- Time to Response (TTR) Per RECIST Version 1.1 by Investigator Assessment(Up to approximately 10 months)
- Maximum Transgene Expansion (Cmax) of Lete-cel(Day 1 to Day 15)
- Area Under the Plasma Concentration-time Curve to Day 28 (AUC0-28d) of Lete-cel(Up to 28 days)