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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

NCT03709706

Description:

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.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pilot Immunotherapy 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 plus pembrolizumab
PembrolizumabSubjects receiving GSK3377794 plus pembrolizumab

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). Approximately 44 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

Eligibility Criteria

        Inclusion Criteria:

        Screening:

          -  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.

          -  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).

          -  Have measurable disease per RECIST 1.1 as assessed by investigator.

          -  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, LAGE1a.

        Leukapheresis:

          -  Subjects who have successfully completed screening. Subject is HLA-A*02:01,
             HLA-A*02:05 and/or HLA-A*02:06 positive.

          -  In the Investigator's opinion, the subject is suitable for leukapheresis, for:
             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 1st and 2nd line therapies; after
             the first 3 cycles of prior chemotherapy; During prior 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; At any time during first or second line tyrosine kinase
             inhibitor (TKI) therapy; after radiotherapy; pending approval of Medical Monitor (or
             designee), if prior standard of care (SoC) therapy is refused by the subject.

          -  A SoC line of therapy between leukapheresis and treatment is allowed if: it is based
             on risk/benefit assessment and/or local regulatory requirements and following
             agreement with Sponsor's Medical Monitor (or designee); it is performed at the same
             site and staff where the subject has enrolled to this study;and treatments, AEs, and
             other clinical observations are reported in this study..

        Lymphodepletion/Treatment:

          -  Prior to lymphodepleting chemotherapy, subjects must meet all the criteria for
             screening and Leukapheresis.

          -  Must have received or are receiving at least 1 line of prior systemic therapy:
             Subjects with epidermal growth factor receptor (EGFR) mutations , anaplastic lymphoma
             kinase (ALK) rearrangement, receptor tyrosine kinase which is encoded by the gene ROS1
             (ROS1) rearrangement, or BRAF V600E mutation must have received or are receiving a
             targeted therapy regimen with or without cytotoxic therapy; Subjects who received or
             are receiving a PD-1/PD-L1 checkpoint blocker alone or in combination with other
             therapies; subjects who received or are receiving any other systemic regimen; 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.

          -  Following treatment with therapies other than PD-1/PD-L1 checkpoint blockade,
             progression is defined by RECIST 1.1. Alternatively, lymphodepleting regimen may start
             after clinical AND/OR radiographic disease progression without second confirmatory
             imaging, based upon risk/benefit evaluation in agreement with the Medical Monitor (or
             designee);

          -  Have at least 2 lesions, 1 measurable as a target lesion and the other 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 risk-benefit 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;

          -  A SoC line of therapy between leukapheresis and treatment is allowed based on
             risk/benefit assessment and/or local regulatory requirements and following agreement
             with Sponsor's Medical Monitor (or designee), performed at the same site and staff
             where the subject has enrolled to this study and treatments, AEs, and other clinical
             observations are reported in this study.

          -  A biopsy of tumor tissue obtained following cessation of the last line of treatment
             for NSCLC but prior to initiating lymphodepleting chemotherapy is mandatory if
             feasible.

          -  Male subjects are eligible to participate if they agree to the following: 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 as detailed:)
             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 f >=1.5 x 10^9 cells/L for absolute neutrophil
             count, >=9 g/L or >=5.6 millimoles (mmol)/L for Hemoglobin, >=100 x 10^9/L for
             Platelets, >=2.5 grams/deciliter (g/dL) for albumin, <=1.5 x upper limit of normal
             (ULN) (isolated bilirubin <=1.5 x ULN is acceptable if bilirubin is fractionated and
             direct bilirubin <35%) for total bilirubin, <=2.5 x ULN (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.

        Anti-PD1 Rescue with Pembrolizumab (Arm A only):

          -  Subjects who have received GSK3377794 on 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:

          -  The subject (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

          -  Radiographically confirmed progressive disease following treatment with GSK3377794.

          -  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., peripheral neuropathy) can be enrolled on a case-by-case basis
             with prior consultation and agreement with the Sponsor's Medical Monitor (or
             designee).

          -  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:

          -  Has received >=3 lines of prior systemic therapy.

          -  Prior 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.

          -  Has severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its
             excipients.

          -  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 >1; 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) >450 milliseconds (msec) or QTc >480 msec for subjects
             with Bundle Branch Block (BBB).

          -  There are further inclusion /exclusion criteria within the protocol that need to be
             adhered to prior leukapharesis and lymphodepletion.

        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)
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:Not yet recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

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

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