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Pilot Immunotherapy Study With Autologous T-cells Specific for NY-ESO-1/ LAGE-1a-positive Advanced NSCLC Either Alone or in Combination With Pembrolizumab

NCT03709706

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pilot Immunotherapy Study With Autologous T-cells Specific for New York Esophageal Antigen-1 (NY-ESO-1)/ Cancer-testis Antigen-2 (LAGE-1a)-Positive Advanced Non-small Cell Lung Cancer (NSCLC) Either Alone or in Combination With Pembrolizumab
  • Official Title: A Phase 1b/2a Pilot Randomized 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

Clinical Trial IDs

  • ORG STUDY ID: 208471
  • NCT ID: NCT03709706

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
GSK3377794Subjects receiving GSK3377794 monotherapy
PembrolizumabSubjects receiving GSK3377794 monotherapy

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Subjects receiving GSK3377794 monotherapyExperimentalSubjects will receive GSK3377794 monotherapy, administered as a single IV infusion of 1 to 6 x10^9 transduced cells. Subjects who subsequently progress will be offered anti-PD-1 rescue therapy with pembrolizumab 200 milligrams Q3W.
  • GSK3377794
  • Pembrolizumab
Subjects receiving GSK3377794 plus pembrolizumabExperimentalSubjects will receive a single IV infusion of GSK3377794 on Day 1 followed by pembrolizumab 200 milligrams on Day 22 and thereafter Q3W.
  • GSK3377794
  • Pembrolizumab
Subjects receiving GSK3377794 with pembrolizumabExperimentalSubjects will receive a single IV infusion of GSK3377794 on Day 1 followed by pembrolizumab 200 milligrams on Day 22 and thereafter Q3W.
  • GSK3377794

Eligibility Criteria

        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
             investigator/radiology.

          -  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
             guidelines.

          -  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
             available, LAGE-1a.

        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
             lymphodepletion.

          -  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
             systemic chemotherapy).

          -  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
             pregnant.

          -  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
             Monitor.

          -  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
             designee).

          -  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
             compression.

          -  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
             excipients.

          -  Subject has an active autoimmune disease that has required systemic treatment in past
             2 years.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects with adverse events (AE) and serious adverse events (SAE) in subjects who received GSK3377794 alone or in combination with pembrolizumab
Time Frame:Up to 106 weeks
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity,is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Up to 106 weeks
Safety Issue:
Description:PFS is defined as the time from the date of T-cell infusion until the earliest date of disease progression as assessed by the Investigator per RECIST 1.1, or death due to any cause.
Measure:Disease Control Rate (DCR)
Time Frame:Up to 106 weeks
Safety Issue:
Description:DCR is defined as the percentage of subjects with a confirmed CR, PR, or stable disease (SD) for at least 6 months as per RECIST 1.1.
Measure:Duration of Response (DoR)
Time Frame:Up to 106 weeks
Safety Issue:
Description:DoR is defined as, in the subset of subjects who show a confirmed CR or PR, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.
Measure:Time to Response (TTR)
Time Frame:Up to 106 weeks
Safety Issue:
Description:TTR is the time from the date of T-cell infusion and the first documented evidence of response (PR or better) in the subset of subjects who achieved a confirmed PR or CR as assessed by the Investigator.
Measure:Maximum observed concentration (Cmax) following administration of monotherapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 12 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis.
Measure:Cmax following administration of combination therapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 3 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis.
Measure:Time to Cmax (Tmax) following administration of monotherapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 12 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis
Measure:Tmax following administration of combination therapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 3 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis.
Measure:Area under the time curve from zero to time t (AUC [0 to t]) following administration of monotherapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 12 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis.
Measure:AUC (0 to t) following administration of combination therapy of GSK3377794
Time Frame:Pre-dose, Day 1, Day 2, Day 4, Week 2, Week 3, Week 4, Week 7 and every 3 weeks from Week 23 to Week 106 post-dose
Safety Issue:
Description:Blood samples will be collected for pharmacokinetic analysis.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • GSK3377794
  • Pembrolizumab
  • T Cell Receptors
  • Adoptive T-cell therapy
  • Non-Small Cell Lung Cancer

Last Updated

October 7, 2019