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
Adoptive T-cell therapy (ACT) is a therapeutic approach that uses T lymphocytes of participants with cancer, obtained by leukapheresis with the aim of generating an anti-tumor T-cell immune response. New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and cancer testis antigen 2 (LAGE-1a) antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using ACT with T-cells directed against NY-ESO-1/LAGE-1a have shown objective responses in participants with cancer. Pembrolizumab is a monoclonal antibody that acts specifically on tumor targeting T-cells and increases T-cell anti-tumor function. Pembrolizumab will be used in combination with NY-ESO-1/LAGE-1a T Cell Receptors (TCR) engineered participant T-cells (GSK3377794) to potentially further improve therapy for participants. The primary objective of the study is to evaluate the safety and tolerability of autologous genetically modified T-cells (GSK3377794) in human leukocyte antigen (HLA) positive participants with NY-ES0-1/ LAGE-1a positive advanced non-small cell lung cancer (NSCLC) alone (Arm A) or GSK3377794 in combination with pembrolizumab in participants with NSCLC with wildtype epidermal growth factor receptor (WT EGFR) and WT anaplastic lymphoma kinase/ c-ros oncogene 1 (ALK/ROS1) (Arm B) and participants with NSCLC with EGFR or ALK/ROS1 aberration (Arm C). This study consists of screening phase, Leukapheresis/ GSK3377794 manufacture, lymphodepletion/treatment phase and follow-up. Participants will receive GSK3377794 as monotherapy (Arm A); or as a combination therapy with pembrolizumab (Arm B), and participants in Arm C will receive the same treatment as participants in the Arm B. Approximately 54 participants will be enrolled into the study.
18 Years and up
Accepting Healthy Volunteers?
Screening (Part 1):
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
- Participant must be positive for Human leukocyte antigen (HLA)-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a designated central laboratory.
- Participant's tumor has been pathologically reviewed by a designated central laboratory with confirmed positive expression of NY-ESO-1 and/or, if tested, LAGE-1a.
- Age >=18 years on the day of signing informed consent for the screening process.
- Pending approval of Medical Monitor (or designee), participants can be enrolled in other experimental interventional clinical studies during the screening and leukapheresis stages of this study (GSK208471).
- Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC.
- ECOG Performance Status of 0 or 1.
- Predicted life expectancy that is >=3 months.
- Participant has left ventricular ejection fraction >=50 percent (%) or as per institution's guidelines.
- Adequate venous access for leukapheresis.
- In the Investigator's opinion, the participant is fit for lymphodepleting chemotherapy and infusion of GSK3377794.
Leukapheresis (Part 2):
- In the Investigator's opinion, the participant is suitable for leukapheresis including laboratory parameters as described in the protocol.
- Leukapheresis can be collected between the lines of therapies
- An intermediate standard of care (SoC) line of therapy between leukapheresis (Part 2) and treatment (Part 3) at the time of disease progression is allowed.
Lymphodepletion/Treatment (Part 3):
- All participants with NSCLC with WT EGFR and WT ALK/ ROS1 (Arms A and B) should have received and failed at least one line of programmed death protein 1/programmed death protein 1 ligand (PD-1/PD-L1) checkpoint blockade therapy (alone or in combination with systemic chemotherapy).
- All participants with NSCLC with EGFR or ALK/ROS1 aberration (Arm C only) should have received and failed appropriate targeted therapy following National Comprehensive Cancer Network (NCCN) guidelines. These participants could have received and failed PD-1/PD-L1 checkpoint blockade therapy.
- Experimental systemic regimens are allowed.
- Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC with measurable disease per RECIST version 1.1 as assessed by local site investigator/radiology.
- Central nervous system (CNS) metastases with low CNS disease burden are allowed on a case by case basis after benefit-risk evaluation in consultation with the Sponsor Medical Monitor (or designee).
- A biopsy of tumor tissue obtained following cessation of the last line of treatment for NSCLC but within 2 weeks prior to initiating lymphodepleting chemotherapy is required unless clinically unsafe to do so.
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- A female participants are eligible to participate if they are not pregnant or breastfeeding and if she is not of childbearing potential.
- Participant must have adequate organ function as described in the protocol.
Pembrolizumab therapy following disease progression after GSK3377794 infusion (Arm A only, Part 4):
- Participants who have received GSK3377794 in Arm A are eligible for therapy with pembrolizumab 200 milligrams flat dose once every 3 weeks if they fulfil certain criteria.
For Screening (Part 1):
- NSCLC with B-Raf gene (BRAF) V600E mutation, Neurotrophic Tropomyosin-Related Kinase (NTRK) gene fusion, and/or any other actionable genetic aberration that can be treated with targeted SoC (NCCN recommended) therapy.
- Prior therapies: Arm A and B: Has received and failed >=3 lines of systemic therapy. Arm C: Has received >=4 lines of systemic therapy.
- Any prior treatment with oncology cell therapy (TCR-T-cell therapy or chimeric antigen receptor [CAR]-T therapy); Prior gene therapy using an integrating vector.
- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
- Prior malignancy other than NSCLC, with exceptions: agreed upon consultation between the Investigator and Sponsor Medical Monitor (or designee).
- Participant has an active autoimmune disease that has required systemic treatment in past 2 years.
- Participant has a 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.
- Prior allogeneic/autologous bone marrow or solid organ transplantation with some exceptions if occurred more than 5 years ago.
- Uncontrolled intercurrent illness.
- Prior or active demyelinating disease.
- Current unstable liver or biliary disease per Investigator assessment.
- Participant has positive viral serology as defined in protocol.
- Participant is pregnant or breastfeeding.
- Has known psychiatric or substance abuse disorders.
Leukapheresis (Part 2):
- Toxicity from previous anti-cancer therapy that has not recovered to CTCAE version 4.03 Grade <=1 prior to enrollment (except for non-clinically significant toxicities, e.g.,alopecia, vitiligo). Participants with existing pneumonitis because of radiation are not excluded; however, participants cannot be oxygen-dependent. Participants with Grade 2 toxicities that are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Medical Monitor (or designee).
- Investigational treatment within 30 days or 5 half-lives (whichever is shorter) prior to leukapheresis.
- Radiotherapy that involves >25% bone marrow exposure.
Lymphodepletion/ Treatment (Part 3):
- Has received a live vaccine within 30 days prior to the first dose of study drug.
- Major surgery <=28 days before first dose of study treatment.