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T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01967823
Recruitment Status : Completed
First Posted : October 23, 2013
Last Update Posted : July 2, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE October 18, 2013
First Posted Date  ICMJE October 23, 2013
Last Update Posted Date July 2, 2020
Actual Study Start Date  ICMJE October 24, 2013
Actual Primary Completion Date April 6, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2020)
Response Rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2, then per PI discretion ]
Percentage of patients who have a clinical response to treatment (objective tumor regression)
Original Primary Outcome Measures  ICMJE
 (submitted: October 18, 2013)
Determine whether administration of anti-ESO mTCR-engineered PBL plus highdose Il-2 following a nonmyeloablative lymphoid depleting preparative regimen may result in objective tumor regression in patients with metastatic cancers that express ESO... [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2018)
  • In vivo survival of TCR gene-engineered cells [ Time Frame: 3 and 6 months, and 1 year post cell administration ]
    TCR and vector presence will be quantitated in PBMC samples using established PCR techniques
  • Frequency severity of treatment-related adverse events [ Time Frame: 6 weeks following administration of cell product ]
    Aggregate of all adverse events and their frequency and severity
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer
Official Title  ICMJE Phase II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Anti-NY ESO-1 Murine TCR-Gene Engineered Lymphocytes
Brief Summary


The NCI Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying them, and then giving the cells back to the patient. In a previous study the NCI Surgery Branch used the anti-ESO-1 gene and a type of virus (retrovirus) to make these tumor fighting cells (anti-ESO-1 cells). About half of the patients who received this treatment experienced shrinking of their tumors. In this study, we are using a slightly different method of producing the anti-ESO-1 cells which we hope will be better in making the tumors shrink.


The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their surface can cause tumors to shrink and to see if this treatment is safe.


- Patients 15 years old and older with cancer that has the ESO-1 molecule on their tumors.


  • Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
  • Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti ESO-1 cells. {Leukapheresis is a common procedure which removes only the white blood cells from the patient.}
  • Treatment: Once their cells have grown the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-ESO-1 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
  • Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.
Detailed Description



  • We have constructed a single retroviral vector that contains both and <= chains of a murine T cell receptor (mTCR) that recognizes the NY-ESO-1 (ESO) tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
  • In co-cultures with HLA-A2 and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted significant amounts of IFN- >= with high specificity.

Primary objective:

- To determine whether the administration of anti-ESO mTCR-engineered peripheral blood lymphocytes (PBL) plus high-dose aldesleukin following a non-myeloablative lymphoid depleting preparative regimen may result in objective tumor regression in patients with metastatic cancers including melanoma expressing the ESO antigen.


  • Age greater than or equal to 15 years and less than or equal to 70 years. Patients aged 15-17 years must weigh at least 50 kg.
  • HLA-A*0201 positive
  • Metastatic cancer including melanoma whose tumors express the ESO antigen
  • Previously received and have been a non-responder to or recurred after receiving standard care for metastatic disease
  • No contraindications for high-dose aldesleukin administration


  • Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin to stimulate T-cell growth.
  • Transduction is initiated by exposure of cells to retroviral vector supernatant containing the anti- ESO mTCR genes. This mTCR targets the exact same epitope as the hTCR.
  • All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.
  • On day 0 patients will receive anti-ESO mTCR gene-transduced PBMC and then begin high dose aldesleukin.
  • A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks) following the administration of the cell product.
  • The study will be conducted using a phase II optimal design (Simon R, Controlled Clinical Trials 10:1-10, 1989). The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-ESO TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).
  • A total of up to 43 patients may be enrolled (41, plus allowing for up to 2 non-evaluable patients).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Meningioma
  • Breast Cancer
  • Non-Small Cell Lung Cancer
  • Hepatocellular Cancer
Intervention  ICMJE
  • Biological: Anti-NY ESO-1 mTCR PBL
    Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.
  • Drug: Cyclophosphamide
    Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
  • Drug: Fludarabine
    Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.
  • Drug: Aldesleukin
    Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Study Arms  ICMJE Experimental: 1/Experimental Therapy
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-ESO murine TCR transduced PBL + high-dose aldesleukin
  • Biological: Anti-NY ESO-1 mTCR PBL
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Drug: Aldesleukin
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 7, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: October 18, 2013)
Actual Study Completion Date  ICMJE April 6, 2020
Actual Primary Completion Date April 6, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • Measurable (per RECIST v1.0 criteria) metastatic cancer or locally advanced refractory/recurrent malignancy including melanoma that expresses ESO as assessed by one of the following methods: RT-PCR on tumor tissue, immunohistochemistry of resected tissue, or serum antibody reactive with ESO.
  • Confirmation of diagnosis of metastatic cancer including melanoma by the NCI Laboratory of Pathology.
  • Patients must have previously received first-line standard therapy (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
  • Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible.Patients with surgically resected brain metastases are eligible.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to grade 1 or less.

Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.


- Histologically proven recurrent meningioma or aggressive meningioma.

Note: Confirmation of ESO expression and pathology is not required in patients with definitive radiologic evidence of meningioma who are unresectable, and in whom radiation therapy without biopsy is the standard treatment.

  • Recurrent disease/progression after receiving all standard treatments, which must include the following:

    • Surgical resection, if possible.
    • Definitive radiation therapy for unresectable meningioma, or for recurrent meningioma after resection.
  • At least 4 weeks post-surgery, and must be at least 3 months post-radiation therapy, with resolution of related toxicities.
  • Measurable disease on MRI scan.
  • No history of intracranial hemorrhage.
  • Patients with a history of neurofibromatosis (NF) may have other stable CNS tumors, such as schwannoma, acoustic neuroma, or ependymoma only if those lesions have been stable for the past 6 months.
  • Patients must be on stable dose of steroids for at least 5 days prior to baseline imaging.


  • Age greater than or equal to 15 years and less than or equal to 70 years.
  • Patient, or their parent(s)/legal guardian(s) (if the patient is < 18 years of age), is able to understand and willing to sign a written informed consent. Written assent will be obtained for participants under the age of 18 as appropriate.
  • All participants greater than or equal to 18 years of age must be willing to sign a durable power of attorney.
  • Clinical performance status of ECOG 0 or 1.
  • Patients aged 15-17 years weigh greater than or equal to 50 kg.
  • HLA-A*0201 positive.
  • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  • Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  • Serology

    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  • Hematology

    • ANC greater than 1000/mm(3) without the support of filgrastim
    • WBC greater than or equal to 3000/mm(3)
    • Platelet count greater than or equal to 100,000/mm(3)
    • Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.
  • Chemistry:

    • Serum ALT/AST less than or equal to 2.5 times the upper limit of normal
    • Serum creatinine less than or equal to 1.6 mg/dl
    • Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.
  • Subjects must be co-enrolled in protocol 03-C-0277.


  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  • Concurrent systemic steroid therapy.
  • History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
  • History of coronary revascularization or ischemic symptoms.
  • Documented LVEF less than or equal to 45% tested in patients:

    • Age greater than or equal to 65 years
    • With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block or have a history of ischemic heart disease and/or chest pain.
  • Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history, with cessation within the past two years).
    • Symptoms of respiratory dysfunction.
  • Patients who are receiving any other investigational agents.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01967823
Other Study ID Numbers  ICMJE 130214
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date June 16, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP