Clinical Trials /

NY-ESO-1ᶜ²⁵⁹T for Advanced NSCLC

NCT02588612

Description:

This study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for human leukocyte antigen (HLA)-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 protein and a tumor test positive for NY-ESO-1 expression. The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. Subjects will be seen frequently by the Study Physician right after receiving their T cells back. Subjects will then be entered into a long-term follow up in order to monitor the subject. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: NY-ESO-1ᶜ²⁵⁹T for Advanced NSCLC
  • Official Title: A Pilot Open-Label Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Subjects With Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: 208749
  • SECONDARY ID: ADP-0011-004
  • SECONDARY ID: 2016-002517-21
  • NCT ID: NCT02588612

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
CyclophosphamideAutologous Genetically modified T cells, NY-ESO-1ᶜ²⁵⁹T
FludarabineAutologous Genetically modified T cells, NY-ESO-1ᶜ²⁵⁹T

Purpose

This study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for human leukocyte antigen (HLA)-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 protein and a tumor test positive for NY-ESO-1 expression. The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. Subjects will be seen frequently by the Study Physician right after receiving their T cells back. Subjects will then be entered into a long-term follow up in order to monitor the subject. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years.

Detailed Description

      This is a single-arm study of genetically engineered NY-ESO-1ᶜ²⁵⁹T cells in HLA-A*02:01,
      HLA-A*02:05 and/or HLA-A*02:06 positive subjects with advanced (Stage IIIb or IV) NSCLC.
      Subjects with measurable disease will be screened for general health, performance status and
      disease stage. Following screening, subjects meeting all eligibility will undergo a
      large-volume leukapheresis to obtain cells for the manufacture of autologous NY-ESO-1ᶜ²⁵⁹ TCR
      bearing T cells. When the NY-ESO-1ᶜ²⁵⁹T cells are available, subjects will receive
      lymphodepleting chemotherapy with cyclophosphamide and fludarabine . Subjects will visit the
      clinic for safety and efficacy assessments daily from T cell infusion (Day 1) through Day 5,
      Days 8, 10, 12, and then weekly until week 6 and then at 8, 10, 12, 16, 20 and 24 weeks, and
      every 3 months until 2 years and then every 6 months until progression of their disease (or
      withdrawal of consent for the interventional portion of the study). Subjects who have a
      confirmed response (or have stable disease for >4 months) but subsequent disease progression
      following the initial infusion and whose tumor continues to express the appropriate antigen
      target may be eligible for a second infusion. All subjects, completing or withdrawing from
      the interventional portion of the study, will enter a 15-year long-term follow-up phase for
      observation of delayed adverse events. All subjects will continue to be followed for overall
      survival during the long-term follow-up phase.
    

Trial Arms

NameTypeDescriptionInterventions
Autologous Genetically modified T cells, NY-ESO-1ᶜ²⁵⁹TExperimentalAfter Screening, eligible subjects will enter a leukapheresis phase, followed by lymphodepletion phase where they will be administered fludarabine and cyclophosphamide. On Day 1, subjects will be administered a single dose of NY-ESO-1ᶜ²⁵⁹T cell infusion. Subjects who have a confirmed response (or have stable disease for >4 months) but subsequent disease progression following the initial infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion.
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Subject has voluntarily agreed to participate by giving written informed consent in
             accordance with International Conference on Harmonization Good Clinical Practice (ICH
             GCP) Guidelines and applicable local regulations.

          -  Subject has agreed to abide by all protocol required procedures including study
             related assessments, and management by the treating institution for the duration of
             the study and long-term follow up.

          -  Subject is >=18 years of age on the day of signing informed consent.

          -  Subject has a diagnosis of histologically or cytologically confirmed advanced
             non-small cell lung cancer (Stage IIIB or IV) or recurrent disease.

          -  Subjects with known epidermal growth factor receptor (EGFR) mutations or ALK or ROS1
             gene rearrangements must have failed (disease progression [PD] or unacceptable
             toxicity) prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively (PD or
             unacceptable toxicity). There is no limit to lines of prior anti-cancer therapy.

          -  Subject has measurable disease according RECIST v1.1 criteria.

          -  Subject is HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 positive.

          -  Subject's tumor (either an archival specimen or a fresh biopsy if archival tissue is
             unavailable) has been pathologically reviewed by an Adaptimmune- / GSK-designated
             central laboratory confirming NY-ESO-1 and/or LAGE-1a expression.

          -  Subject has Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 10.
             Subject has an anticipated life expectancy >3 months.

          -  Subject has left ventricular ejection fraction >=50%.

          -  Subject is fit for leukapheresis and has adequate venous access for the cell
             collection.

          -  Male or Female. 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: Male subjects are eligible to participate if they agree to the
             following during the intervention period starting at the first dose of chemotherapy
             for at least 12 months after receiving the T-cell infusion, or 4 months after there is
             no evidence of persistence/ gene modified cells in the subject's blood, whichever is
             longer. A) Refrain from donating sperm Plus either: B) 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 C) Must agree to use
             contraception/barrier. Female subjects: A female subject is eligible to participate if
             she is not pregnant or breastfeeding, and at least one of the following conditions
             applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP who will agree
             to use a barrier method (male condom) and use a contraceptive method that is highly
             effective during the intervention period and for at least 12 months after receiving
             the T-cell infusion, or 4 months after there is no evidence of persistence/ gene
             modified cells in the subject's blood, whichever is longer. WOCBP should also agree
             not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
             The Investigator should evaluate the effectiveness of the contraceptive method in
             relationship to the first dose of study intervention.

          -  Subject must have adequate organ function as indicated by the following laboratory
             values: a) Absolute Neutrophil count (ANC) >=1.0 x10^9 per liter (/L) (without G-CSF
             support); b) Platelets >= 75 x10^9/L; c) Hemoglobin >80 grams per deciliter (g/dL)
             (without transfusion support within 7 days from start of leukapheresis); d)
             Prothrombin Time or International Normalized Ratio (INR) <=1.5 times upper limit of
             normal (ULN) unless receiving therapeutic anticoagulation. e) Partial Thromboplastin
             Time (PTT) <=1.5 times upper limit of normal (ULN) unless receiving therapeutic
             anticoagulation. f) Calculated or measured creatinine clearance >=40 milliliters per
             minute (mL/min); g) Serum total bilirubin <=1.5 times ULN (unless subject had
             documented Gilbert's Syndrome); h) Alanine aminotransferase (ALT)/Serum Glutamic
             Pyruvic Transaminase (SGPT) <=2.5 times ULN.

        Exclusion Criteria:

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
             per Investigator assessment). Stable chronic liver disease should generally be defined
             by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal
             or gastric varices, persistent jaundice or cirrhosis.

          -  Subject who has had cytotoxic chemotherapy within 2 weeks prior to leukapheresis;
             Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors) or
             biological therapy with no wash-out times required; corticosteroids or any other
             immunosuppressive therapy within 2 weeks prior to leukapheresis; tyrosine kinase
             inhibitor (TKI) (e.g. erlotinib, gefitinib) and any other anti-cancer treatment within
             1 week prior to leukapheresis; Investigational treatment within 4 weeks prior to
             leukapheresis; Experimental anti-cancer vaccine within 2 months prior to leukapheresis
             in the absence of response or in the opinion of the Investigator is responding to an
             experimental vaccine given within 6 months prior to leukapheresis; Any prior gene
             therapy using an integrating vector.

          -  Toxicity from previous anti-cancer therapy that has not recovered to <=Grade 1 prior
             to enrollment (except for non-clinically significant toxicities, e.g., alopecia,
             vitiligo). Subjects with existing pneumonitis as a result of radiation are not
             excluded; however, subjects cannot be oxygen dependent.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cyclophosphamide, fludarabine, or other agents used in the study.

          -  Subject has central nervous system (CNS) metastases except if, on a case by case basis
             after risk-benefit evaluation in consultation with the Sponsor Medical Monitor or
             designee (all below points apply): Low CNS disease burden; Asymptomatic; Clinically
             stable; No history of bleeding within CNS metastases; No lesions in the brain stem;
             Not requiring escalating anti-epileptic treatment; Not requiring treatment with
             steroids; Not treated with whole brain radiotherapy within the prior 4 weeks; Not with
             leptomeningeal disease or carcinomatous meningitis. Note: Treatment with focal
             radiotherapy may be allowed (for example, gamma knife radiosurgery) with at least
             2-week wash-out period

          -  Subject has active brain metastases or leptomeningeal metastases. Subjects with prior
             history of brain metastasis who have undergone local therapy (i.e., metastatectomy
             and/or radiation) and show no evidence of local recurrence or progression over the
             past 3 months prior to Screening are eligible.

          -  Investigational treatment within 4 weeks prior to leukapheresis; experimental
             anti-cancer vaccine within 2 months prior to leukapheresis in the absence of response
             or in the opinion of the Investigator is responding to an experimental vaccine given
             within 6 months prior to leukapheresis; any prior gene therapy using an integrating
             vector.

          -  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.

          -  Subject has active brain metastases or leptomeningeal metastases. Subjects with prior
             history of brain metastasis who have undergone local therapy (i.e., metastasectomy
             and/or radiation) and show no evidence of local recurrence or progression over the
             past 3 months prior to Screening are eligible.

          -  Other active malignancies besides NSCLC within 3 years prior to Screening. Exceptions:
             adequately treated malignancies not likely to require therapy (e.g., completely
             resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma).
             Subjects must be in complete remission from prior malignancy in order to be eligible
             to enter the study.

          -  Unintended weight loss >10% in 6 months preceding study entry.

          -  Corrected QT interval (QTc) >450 milliseconds (msec) or QTc >480 msec for subjects
             with Bundle Branch Block (BBB).

          -  Uncontrolled intercurrent illness including, but not limited to: a) Ongoing or active
             infection; b) Clinically significant cardiac disease defined by chronic heart failure
             (CHF) New York Heart Association (NYHA) Class >1; uncontrolled clinically significant
             arrhythmia in last 6 months; Acute Coronary Syndrome (ACS) (angina or myocardial
             infarction [MI]) in last 6 months. c) Inadequate pulmonary function with mechanical
             parameters <40% predicted (forced expiratory volume in one second [FEV1], forced vital
             capacity [FVC], total lung capacity [TLC], diffusing capacity of the lungs for carbon
             monoxide [DLCO]). d) Interstitial lung disease (subjects with existing pneumonitis as
             a result of radiation are not excluded, however, subjects cannot be oxygen dependent).

          -  Subjects who in the opinion of the Investigator will be unlikely to fully comply with
             protocol requirements.

          -  Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV),
             hepatitis C virus (HCV) or human T-cell lymphotropic virus (HTLV) as minimally defined
             below: a) Positive serology for HIV. b) Active hepatitis B infection as determined by
             hepatitis B surface antigen. c) Active hepatitis C infection as determined by
             hepatitis C RNA; A subject who is HCV antibody positive will be screened for HCV
             ribonucleic acid (RNA) by any reverse transcriptase (RT) polymerase chain reaction
             (PCR) or bDNA assay. If HCV antibody is positive, eligibility will be determined based
             on a negative screening RNA value. d) Positive serology for HTLV 1 or 2.

          -  Subject is pregnant or breastfeeding. Furthermore and prior to lymphodepleting
             chemotherapy, a subject meeting the following criteria is not eligible for
             participation in the study: 1) Subject has received: Cytotoxic chemotherapy within 3
             weeks prior to lymphodepleting chemotherapy; Immune therapy (including monoclonal
             antibody therapy, checkpoint inhibitors) or biological therapy within 4 weeks prior
             lymphodepleting chemotherapy; Corticosteroids or any other immunosuppressive therapy
             within 2 weeks prior to lymphodepleting chemotherapy; Tyrosine kinase inhibitor (e.g.
             erlotinib, gefitinib) and any other anti-cancer treatment within 1 week prior to
             lymphodepleting chemotherapy; Major surgery within 4 weeks prior to lymphodepleting
             chemotherapy; subjects must have recovered from any surgical-related toxicities in the
             opinion of the Investigator; Radiotherapy that involves the lung or mediastinum within
             3 months prior to lymphodepleting chemotherapy; however, electron beam radiotherapy to
             superficial structures in the chest is permitted.
      
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), including serious adverse events (SAE)
Time Frame:24 months
Safety Issue:
Description:Determine if treatment with autologous genetically modified T cells, (NY-ESO-1ᶜ²⁵⁹T) is safe and tolerable through assessment of AEs, including SAEs.

Secondary Outcome Measures

Measure:Proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR)
Time Frame:24 months
Safety Issue:
Description:Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Measure:Interval between the date of first T cell infusion dose and first documented evidence of CR or PR
Time Frame:24 months
Safety Issue:
Description:Evaluation of the efficacy of the treatment by assessment of time to first response.
Measure:Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause
Time Frame:24 months
Safety Issue:
Description:Evaluation of the efficacy of the treatment by assessment of duration of response.
Measure:Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause
Time Frame:24 months
Safety Issue:
Description:Evaluation of the efficacy of the treatment by assessment of progression-free survival.
Measure:Disease control rate (DCR)
Time Frame:24 months
Safety Issue:
Description:Evaluation of the efficacy of the treatment according to DCR, defined as the percentage of subjects with a confirmed stable disease (SD) or better as the best overall response (BOR) (i.e., PR, CR, or SD >=12 weeks).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • Immuno-oncology
  • Cell Therapy
  • NY-ESO-1
  • T Cell Therapy
  • Previously Treated
  • T Cell Receptor

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