Adoptive T-cell therapy (ACT) is a therapeutic approach that uses T lymphocytes of subjects
with cancer, obtained by leukapheresis 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. Clinical trials using ACT with T-cells directed against NY-ESO-1/LAGE-1a
have shown objective responses in subjects 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 TCR engineered
subject T-cells (GSK3377794) to potentially further improve therapy for subjects. 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 plus NY-ES0-1/ LAGE-1
positive subjects alone or in combination with pembrolizumab. This study consists of
screening phase, Leukapheresis/ GSK3377794 manufacture, lymphodepletion/treatment phase and
follow-up. Subjects will receive GSK3377794 as monotherapy (Arm A) or as a combination
therapy with pembrolizumab (Arm B), subjects in Arm C will receive the same treatment as
subjects in the Arm B. Approximately 45 subjects will be enrolled into the study.
Inclusion Criteria:Screening (Part 1):
- The subject (or legally acceptable representative if applicable) provides written
informed consent for the trial.
- Age >=18 years on the day of signing informed consent for the screening process.
- Pending approval of Medical Monitor (or designee), subjects 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
with measurable disease per RECIST version1.1 as assessed by local site
- ECOG Performance Status of 0 or 1.
- Predicted life expectancy that is >=3 months.
- Subject has left ventricular ejection fraction >=50% or as per institution's
- Adequate venous access for leukapheresis.
- In the Investigator's opinion, the subject is fit for lymphodepleting chemotherapy and
infusion of GSK3377794.
- An archived biopsy of the tumor tissue obtained at any time from the initial diagnosis
of NSCLC to time of study entry is mandatory for expression of NY-ESO-1 and, when
Leukapheresis (Part 2):
- In the Investigator's opinion, the subject is suitable for leukapheresis including the
following laboratory parameters being above the thresholds: Absolute neutrophil count
(ANC) >=1.5 x 10^9 cells/Liter (L), cluster of differentiation 3 (CD3) count
>=200/microliter (μL) and Lymphocyte count >=0.5 x 10^9 cells/L.
- Leukapheresis can be collected as follows: Between the lines of therapies; after the
first 3 cycles of current systemic chemotherapy; During programmed death receptor-1
(PD-1)/PD-1 ligand (PD-L1) regimen (alone or in combination with chemotherapy) or
after the first 3 cycles of checkpoint blockade therapy. Wash-out for anti-PD-1/ PD-L1
monotherapy is not required; after 9 weeks of current tyrosine kinase inhibitor (TKI)
therapy; after radiotherapy; pending approval of Medical Monitor (or designee), if
standard of care (SoC) therapy is refused by the subject.
- An intermediate SoC line of therapy between leukapheresis (Part2)and treatment (Part3)
at the time of disease progression is allowed.
Lymphodepletion/Treatment (Part 3):
- Prior to lymphodepleting chemotherapy, subjects must meet all the criteria for
screening and Leukapheresis.This must be confirmed within 2 weeks before
- All subjects with NSCLC with wildtype epidermal growth factor receptor (WT EGFR) and
WT ALK/ c-ros oncogene 1(ROS1) (Arms A and B) should have received and failed at least
one line of PD-1/PD L-1 checkpoint blockade therapy (alone or in combination with
- All subjects with NSCLC with EGFR mutations or ALK/ROS1 aberration (Arm C only) should
have received and failed appropriate targeted therapy following NCCN guidelines. These
subjects could have received and failed PD 1/PD L1 checkpoint blockade therapy.
- Experimental systemic regimens are allowed.
- Must have received or are receiving at least 1 line of prior systemic therapy:
Subjects who received or are receiving a PD-1/PD-L1 checkpoint blocker alone or in
combination with other therapies; pending approval of Medical Monitor (or designee),
prior SoC therapy is refused by the subject, subjects not eligible for radical
chemo-radiotherapy, or have terminated prior treatment due to intolerable side
effects. Subjects "intolerant" to a chemo-radiotherapy are those who are either
ineligible to receive chemotherapy due to poor functional status OR have developed
Grade ≥3 toxicity necessitating discontinuation of chemotherapy, or dose modification,
and/or Grade ≥3 unplanned hospitalization to alleviate effects of toxicity.
- Following treatment with therapies other than PD-1/PD-L1 checkpoint blockade,
progression is defined by RECIST v1.1. Alternatively, lymphodepleting regimen may
start after clinical AND/OR radiographic disease progression without second
confirmatory imaging, based upon benefit-risk evaluation in agreement with the Medical
Monitor (or designee); following treatment with a PD-1/PD-L1 checkpoint blockade
therapy administered either as monotherapy or in combination with other checkpoint
inhibitors or other therapies, progression is defined by meeting all of the following
criteria; has received at least 2 doses of an approved PD-1/PD-L1 checkpoint blockade
therapy; progression has been documented within 12 weeks from the last dose of
PD-1/PD-L1 checkpoint blockade therapy, has demonstrated progression after PD-1/PD-L1
therapy as defined by RECIST v1.1. The initial evidence of disease progression is to
be confirmed by a second assessment no less than 4 weeks and no more than 8 weeks
after the date of the first documented progression, in the absence of rapid clinical
progression. Confirmatory imaging may not be required based upon a benefit-risk
evaluation in agreement with the Medical Monitor (or designee)
- Have at least 2 tumor lesions,1 measurable as a target lesion and the other one
required for biopsy.
- Prior radiotherapy is allowed if prior palliative or stereotactic radiosurgery to
solitary lesions outside of the chest (no wash-out required).
- 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)
- Lymphodepleting regimen initiation is allowed if: There is clinical and/or
radiographic evidence of disease progression; the wash-out period for supportive
therapy (chemotherapy or radiotherapy) has been fulfilled.
- Supportive radiotherapy has not affected >25% of bone marrow.
- An intermediate SoC line of therapy between leukapheresis (Part 2) and treatment (Part
3) at the time of disease progression is allowed based on the Investigator's
evaluation of benefits and risks.
- 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.
- Male subjects are eligible to participate if they agree to the following: during the
intervention period starting at the first dose of chemotherapy (lymphodepletion
regimen) for at least 12 months after receiving the T-cell (GSK3377794) infusion, or 4
months after there is no evidence of persistence/ gene modified cells in the
subjects's blood, whichever is longer, if receiving pembrolizumab, must use effective
contraception for at least 4 months after the last dose of pembrolizumab if this time
frame is longer than the duration of contraception required in the context of
chemotherapy (lymphodepletion regimen) and gene modified cells; refrain from donating
sperm plus either be abstinent from heterosexual or homosexual intercourse as their
preferred and usual lifestyle (abstinent on a long term and persistent basis) and
agree to remain abstinent or must agree to use contraception/barrier), agree to use a
male condom and should also be advised of the benefit for a female partner to use a
highly effective method of contraception as a condom may break or leak when having
sexual intercourse with a woman of childbearing potential who is not currently
- A female subject is eligible to participate if they are not pregnant or breastfeeding
and if she is not of childbearing potential.
- Adequate Organ Function is defined as following >=1.5x10^9 cells/L for absolute
neutrophil count, >=200microliter for CD3 count, >=0.5 x10^9 per liter for lymphocyte
count,>=9 g/L or >=5.6 millimoles (mmol)/L for Hemoglobin, >=75x10^9/L for Platelets,
>=2.5 grams/deciliter (g/dL) for albumin, <=1.5x upper limit of normal (ULN) (isolated
bilirubin >=1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
<35%) for total bilirubin, <=2.5xULN (or <=5 x ULN if documented history of liver
metastases for ALT, >=50 milliliters/minute/1.73 square meters for calculated
creatinine clearance (CrCl) and <=1.5×ULN unless subject is receiving anticoagulant
therapy as long as International normalized ratio (INR)/ prothrombin time (PT) or
activated partial thromboplastin time (aPTT) is within therapeutic range.
Pembrolizumab therapy following disease progression after GSK3377794(Arm A only, Part 4):
- Subjects who have received GSK3377794 in Arm A are eligible for anti-PD-1 rescue
therapy with pembrolizumab 200 milligrams flat dose once every 3 weeks (Q3W) if they
fulfil all the following criteria:
- Radiographically confirmed progressive disease following treatment with GSK3377794 at
or before the scheduled Week 25 scan.
- Any toxicity must be <= Grade 1 Common Terminology Criteria for Adverse Events (CTCAE)
v4.03 at the time of first/dose (except for non-clinically significant toxicities
e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or
irreversible (e.g., non-demyelinating peripheral neuropathy) can be enrolled on a
case-by-case basis with prior consultation and agreement with the Sponsor's Medical
- Treatment with anti-PD-1 rescue therapy with pembrolizumab is deemed appropriate by
the Investigator and in agreement with the Sponsor Medical Monitor (or designee).
Exclusion Criteria:For screening (Part 1):
- NSCLC with BRAF, HER2, and/or any other actionable genetic aberration that can be
treated with targeted standard of care (NCCN recommended) therapy.
- Prior therapies: Arm A and B: Has received and failed ≥3 lines of systemic therapy.
Subjects who are receiving a second line of systemic therapy during the study
screening period can be eligible if they have an expected time to progression of at
least four months per investigator assessment, a positive benefit-risk evaluation is
provided by the investigator, and there is agreement with the Sponsor Medical Monitor
or designee (all parameters are necessary), Arm C: Has received ≥4 lines of systemic
therapy, Arm C: Subjects with NSCLC with EGFR or ALK/ROS1 aberration who are receiving
a fourth line of systemic therapy during the study screening period can be eligible if
all the following parameters apply: Have an expected time to progression of at least
four months per investigator assessment, a positive benefit-risk evaluation is
provided by the investigator, In agreement with the Sponsor Medical Monitor (or
- 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.
- Docetaxel therapy after having failed either doublet platinum-based chemotherapy or
PD-1/PD-L1 checkpoint blockade therapy treatment: 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
- Prior malignancy other than NSCLC, with exceptions agreed upon consultation between
the Investigator and Sponsor Medical Monitor (or designee).
- Subject has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to agents used in the study.
- Subject has severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its
- Subject has an active autoimmune disease that has required systemic treatment in past
- Subject 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 including, but not limited to: Ongoing or active
infection; Clinically significant cardiac disease defined by congestive heart failure
New York Heart Association (NYHA) Class >; Uncontrolled clinically significant
arrhythmia in last 6 months; acute coronary syndrome (angina or myocardial infarction)
in last 6 months; Severe aortic stenosis, symptomatic mitral stenosis; Inadequate
pulmonary function with mechanical parameters <40% predicted (forced expiratory volume
in 1 second [FEV1], forced vital capacity [FVC], total lung capacity [TLC], Pulmonary
diffusing capacity for carbon monoxide [DLCO]); Interstitial lung disease (subjects
with existing pneumonitis as a result of radiation are not excluded; however,subjects
cannot be oxygen dependent).
- Current unstable liver or biliary disease per Investigator assessment .
- Subject has positive viral serology as defined in protocol.
- Subject is pregnant or breastfeeding.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study in the opinion of the Investigator and
Sponsor's Medical Monitor (or designee).
- Has known psychiatric or substance abuse disorders.
- Corrected QT interval (QTc)>480 milliseconds (msec).
Leukapheresis (Part 2):
- Toxicity from previous anti-cancer therapy that has not recovered to CTCAE v4.03 Grade
≤1 prior to enrollment (except for non-clinically significant toxicities,
e.g.,alopecia, vitiligo). Subjects with existing pneumonitis because of radiation are
not excluded; however, subjects cannot be oxygen-dependent. Subjects 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. Exceptions to this rule must be evaluated by the Investigator in
agreement with the Sponsor's Medical Monitor (or designee).
- Radiotherapy that involves the lung (V20 exceeding 30% lung volume), or >25% bone
marrow exposure, or mean heart dose >20Gy within 3 months.
Lymphodepletion/ Treatment (Part 3):
- Has been more than 3 years following randomization.
- Has received a live vaccine within 30 days prior to the first dose of study
drug.Examples of live vaccines include,measles,mumps, rubella, varicella/zoster
(chicken pox), yellow fever, rabies, BacillusCalmette-Guérin (BCG), typhoid vaccine.
There are further inclusion /exclusion criteria within the protocol that need to be adhered
to prior leukapharesis and lymphodepletion.
Major surgery >28 days before first dose of study treatment
For Anti-PD1 Rescue with Pembrolizumab (Arm A only):
- Persistence of toxicities such as Cytokine Release Syndrome (CRS) =>Grade 2 that
preclude treatment with pembrolizumab.