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 (study 208471)

Adoptive T-cell therapy (ACT) is a therapeutic approach that uses a cancer
patient*s own T lymphocytes obtained by leukapheresis, engineered to express a
tumor specific T-cell receptor, expanded in vitro and re-infused into the
participant, with the aim of generating an anti-tumor T-cell immune response.
NY-ESO-1 and LAGE-1a antigens are tumor-associated proteins that have been
found in several tumor types, including non-small cell lung cancer (NSCLC).
Previous clinical trials using ACT with T-cells directed against
NY-ESO-1/LAGE-1a have shown objective responses between 40-60% in participants
with synovial sarcoma, metastatic melanoma, and multiple myeloma. Pembrolizumab
is a monoclonal antibody that acts specifically on tumor targeting T-cells to
block PD-1/PD-L1 interaction and increase T-cell anti-tumor function;
pembrolizumab will be used in combination with NY-ESO-1/LAGE-1a TCR engineered
patient T-cells (GSK3377794) to potentially further improve therapy for
patients.
The ability of GSK3377794 to achieve objective responses in diverse tumor types
supports a hypothesis that HLA and antigen expression are biomarkers that
identify a population of participants that may benefit from GSK3377794.
This study will further assess the effects of GSK3377794 monotherapy and the
combination of GSK3377794 and pembrolizumab in HLA-A*02:01, HLA-A*02:05 and/or
HLA-A*02:06 patients with NY-ESO-1- or LAGE-1a-positive advanced or recurrent
NSCLC.

Protocol amendment 5 27-03-2020; main changes: Randomisation has been dropped.
At screening fresh biopsy tumour tissue may be considered if no achival
material is available. New inclusion criterion platinum-based chemotherapy.
Clarification exisiting inclusion criterion measurable disease. Removal
exclusion criterion docetaxel treatment. Removal supportive therapy with
docetaxel between leukapheresis and the start of lymphodepletion.

Protocol amendment 6 dd 19-05-2021; main changes: Simplify/enhance screening
and enrollment efforts. Broaden patient eligibility. Include additional safety
tests and measures.

Protocol amendment 7 November 2021. Main changes:
1. Implementation of additional safety monitoring measures in accordance with a
recent Dear Investigator Letter and safety events for GSK3377794.
2. For participants treated as of protocol amendment 7, the upper end of the
target dose range of transduced T cells was increased from to 8×109 to 15×109
in order to maximize the delivery of cells for participants whose manufacture
yields >8×109 transduced T cells.

Primary:
• To evaluate the safety and tolerability of autologous genetically modified
T-cells (GSK3377794) in human leukocyte antigen (HLA) HLA-A*02:01, HLA-A*02:05
and/or HLA-A*02:06 positive participants with NY-ESO-1 and/or LAGE-1a positive
advanced NSCLC alone [Arm A1] or GSK3377794 in combination with pembrolizumab
[Arm A].
• To determine the response to GSK3377794 alone [Arm A] or in combination with
pembrolizumab [Arm B].
Secondary:
• To further investigate the anti-tumor activity of GSK3377794.
• To describe the persistence of GSK3377794 over time.
NB: exploratory objectives, see protocol paragraph 3.

Parallel group, open-label, study of GSK3377794.
Screening.
Leucapheresis.
Standard of care until disease progression.
When disease progression has been confirmed: wash-out from previous standard of
care.
Four days chemotherapy with fluderabine (4 days) and cyclophosphamide (3 days).
Start study treatment:
Allocation to Arm /B or C, based on changes in tumour genes No (Arm A/B) or Yes
(Arm C).
Arm A/B: First Arm A will be filled, thereafter Arm B will be filled
Arm A: GSK3377794 will be administered as a single intravenous (IV) infusion of
1 to 6 x109 transduced cells. Participants who subsequently progress may
optionally receive rescue therapy with pembrolizumab 200 mg Q3W for up to 35
cycles at or until disease progression.
In Arm B, participants will receive a single IV infusion of GSK3377794 on Day 1
followed by pembrolizumab 200 mg starting on Day 22. Pembrolizumab will be
administered for up to 35 cycles Q3W or until disease progression.
Arm C: All participants will be treated with GSK3377794 plus pembrolizumab.
After the study participants will be entered into a long term follow up
protocol.
Approx. 55 participants.

Treatment with GSK3377794 with or without pembrolizumab.

Risk: Adverse events of the study medication. Combination
GSK3377794-pembrolizumab has not been administered before.
Burden:
Pre-selection: 1-2 visits, 60 ml blood.
Visits from screening onwards:
3 visits before the start of the study treatment (including screening and
leukapheresis).
Chemotherapy: fludarabine (3-4 days, 30 mg/m2 in 50-100 ml NaCl 0,9% in 30
min.) and cyclophosphamide (3 days, 900 mg/m2 in 100-250 ml Na Cl 0,9% in 60
min.). Administration GSK3377794 (1 day, 5 x 109 T-cells in 100 ml in 15-30
min.). Admission to hospital 3-7 days. Thereafter 7 weeks every week and
thereafter from week 8 until week 25 every 3 weeks.
Pembrolizumab (max. 35 days with an interval of 3 weeks, 200 mg in 100 ml in 30
min.)
From week 25 onwards the number of visits differs from one treatment group to
the other:
• Group 1: every 12 weeks from week 34 until the end of treatment.
• Group 2 and 3: every 3 weeks from week 28 until the end of treatment (because
of the pembrolizumab infusions).
Tests:
• Physical examination: during screening and during every visit during
treatment period.
• Blood pressure, pulse, pulse oximetry etc.: every visit.
• Blood draws 15-240 ml, 800 ml in first 6 months.
• ECG: 5x.
• Echocardiography (alternative: MUGA scan): 2x.
• CT/MRI scan: every 6-12 weeks (cf. standard).
• Tumor biopsy: 3x.
• Additional renal function tests in the elderly.
Optional:
• Blood test for pharmacogenetic research (6 ml).
• Photographs of skin abnormalities in case of adverse events.
• Interview during week 3 and end of trial.