Master Protocol to Assess the Safety and Recommended Phase 2 Dose of Next Generations of Autologous Enhanced NY-ESO-1/ LAGE-1a TCR Engineered T-cells, alone or in combination with other agents, in Participants with Advanced Tumors (study 209012)

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. In 2020 two
clinical trials have been started in The Netherlands with GSK3377794, a form of
ACT (study 208467, NL70428.000.19 and study 208471, NL69764.000.19). GSK3377794
is able 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 is a platform study, that will assess the effects of so called next
generations of NY-ESO-1/LAGE-1a TCR engineered T cells that are efficacy
enhanced using advances in technology (incl. multi-component engineering)
and/or innovative ways of manufacturing. Each substudy will be performed with a
next generation ACT alone or in combination with other agents, in
HLA-A2-positive participants with NY-ESO-1 and/or LAGE-1a-positive advanced
tumors.

At present 2 substudies are open:
Substudy 1:
GSK3901961 in previously treated advanced (metastatic or unresectable) synovial
sarcoma and previously treated metastatic NSCLC.
Substudy 2:
GSK3845097 in previously treated advanced synovial sarcoma.

Protocol amendment 1: July 1, 2021 Main changes:
1. Changes to Substudy 1 and 2 Inclusion criteria relative to disease status
requirements to allow participants with advanced disease diagnosis to undergo
target expression screening; participants with evidence of radiological or
clinical disease progression will be able to undergo leukapheresis; initiation
of lymphodepletion will require evidence of disease progression from prior line
of therapy by RECIST v1.1.
2. Changes to Substudy 1 Inclusion and Exclusion criteria language relative to
prior lines of treatments for NSCLC participants to allow those who have
received any PD-1/PD-L1 checkpoint blockade therapy and, in the same or
different line of treatment, any platinum containing chemotherapy. NSCLC
participants with actionable genetic aberrations may also be included if they
have exhausted the targeted standard of care therapy.
3. Clarifications to Substudy 1 and 2 lymphodepleting chemotherapy dose
adjustments to ensure adequate consideration given to prior anti-cancer
therapies (systemic and radiation exposure), renal function (for fludarabine)
as well as use of adjusted body weight (for cyclophosphamide when necessary).
4. Allowing potential future inclusion of a limited number of patients who
progressed following clinical benefit (PR, CR, SD >=3 months) from infusion with
GSK3377794 (letetresgene autoleucel, lete-cel) on a GSK sponsored trial.

Protocol amendment 2: November 4, 2021; Main changes:
1. Implementation of additional safety monitoring measures in accordance with a
recent Dear Investigator Letter and safety events.
2. For participants treated as of protocol amendment 2, the cyclophosphamide
dose in the lymphodepleting chemotherapy was reduced on Day -7 thru Day -4 to
further optimize and reduce potential for acute and prolonged cytopenias while
also minimizing impact on efficacy.
3. For NSCLC participants in Substudy 1 Cohort 2 treated as of Protocol
Amendment 2, the lymphodepleting chemotherapy schedule was changed from Day -8
through Day -5 to Day -7 through Day -4 to align with the schedule for the
sarcoma participant cohort.
4. Inclusion of myxoid/round cell liposarcoma as a second translation-related
sarcoma indication.

Protocol amendment 4 dated 27-05-2022:
This amendment concerns the Master protocol and sub-studies 1 and 2
(worldwide); in the US this amendment also concerns substudy 3. Protocol
amendment 3 concerned changes related to substudy 3 which is only being
conducted in the US.
Main changes of amendment 4:
- Change of inclusion and exclusion criteria; a detailed overview of the
changes can be found on page 2-4 of the clean version of the Master protocol.
- Changes to the protocol amendment have been incorporated into the ICF
A detailed overview of the changes can be found on page 2-4 of the clean
version of the Master protocol.

Primary:
To assess the safety, tolerability and determine recommended phase 2 dose
(RP2D) of NY-ESO-1 and LAGE-1a specific T cells, alone or in combination with
other agents, in HLA-A*02-positive participants with NY-ESO-1 and/or LAGE-1a
positive advanced tumors
Secondary:
To investigate the efficacy of NY-ESO-1 and LAGE-1a specific T cells, alone or
in combination with other agents, in HLA-A*02+ participants with NYESO-1 and/or
LAGE-1a positive advanced tumors. To describe the expansion and persistence of
NYESO-1 and LAGE-1a specific T cells, alone or in combination with other
agents, over time. To evaluate T cell trafficking to and activity at tumor site.

Substudy objectives: see protocol chapter 13.

This is a master protocol (platform study).
The protocol will evaluate next generation NY-ESO-1/LAGE-1a specific TCR
engineered T cells in HLA-A*02-positive participants with NY-ESO-1 and/or
LAGE-1a-positive previously treated advanced synovial sarcoma, myxoid/round
cell liposarcoma and NSCLC (substudy 1) or advanced synovial sarcoma or myxoïd/
rondcel liposarcoom (substudy 2).

Steps: Preselection (HLA-A*02 and NY-ESO-1 and LAGE-1a) and further screening -
Leukapheresis - 3 days of chemotherapy (fludarabine and cyclophosphamide) - 1
infusion of GSK3901961 (substudy 1) or GSK3845097 (substudy 2) - Follow-up max.
1 year.

The protocol may be amended later to investigate other next generations of
NY-ESO-1/LAGE-1a TCR engineered T cells and/or other NY-ESO-1+ or LAGE-1a
positive tumor types and/or combinations with other agents.
After the study participants will be entered into a long term follow up
protocol.
Approx. 20 participants in substudy 1 and 10 in substudy 2. The total number
may be increased to 48.

Treatment with NY-ESO-1 and LAGE-1a specific T cells, alone or in combination
with other agents.
Substudy 1: GSK3901961 and substudy 2: GSK3845097.

Risk: Adverse events of the study medication.
Burden:
Pre-selection: 1-2 visits, 10 ml blood and (if no archival material available)
1 tumor biopsy.
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 (2-3 days, 1200-1800 mg/m2 in 200-500 ml NaCl 0,9%
in 60 min.). Administration GSK3901961 or GSK3845097 (1 day, 1 x 109 - 8 x 109
cells) *). Hospital stay min. 3 days *). Thereafter 2 weeks with regular
hospital visits. In total 17 hospital visits during the first 6 months and
every 3 months thereafter.
*) For the first patient receiving GSK3901961 and the first patient receiving
GSK3845097: 30% of the dose will be administered. The remaining 70% will be
administered one week later. Both patients will stay in the hospital for 10
consecutive days.
Tests:
• Physical examination: every visit during treatment period.
• Blood pressure, pulse, pulse oximetry etc.: every visit.
• ECG: 6 times.
• Echocardiography (alternative: MUGA scan): twice.
• Telemetry (if tumor location near heart): 3-7 days post administration of
study medication.
• Blood draws: every visit. 5-110 mL blood per occasion; total during first 6
months (excl. 210-300 mL for leukaferesis): 820 mL.
• CT/MRI scan: every 6-12 weeks.
• Tumor biopsy: 3x.
Optional:
• Blood test for pharmacogenetic research (6 ml).
• Photographs of skin abnormalities in case of adverse events.