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MelanomaPhase 2NCT01967823

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

A Phase 2 study testing Anti-NY ESO-1 mTCR PBL, Cyclophosphamide and Fludarabine in people with Melanoma and Meningioma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Background: The National Cancer Institute (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. Read more about this study

Who is it for?
Ages 15 to 70 years
Conditions the study is for
Melanoma, Meningioma, Breast Cancer
What is being tested?
Anti-NY ESO-1 mTCR PBL, Cyclophosphamide and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
1 siteUnited States
Study dates
24 Oct 2013to 6 Apr 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 15 to 70 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • Measurable disease on magnetic resonance imaging (MRI) scan.
  • No history of intracranial hemorrhage.
  • Patients with a history of neurofibromatosis (NF) may have other stable central nervous system (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 Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  • Patients aged 15-17 years weigh greater than or equal to 50 kg.
  • Human leukocyte antigen serotype within the HLA-A serotype group (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 human immunodeficiency virus (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 Hepatitis C Virus Ribonucleic acid(HCV RNA) negative.
  • Hematology
  • Absolute neutrophil count (ANC) greater than 1000/mm(3) without the support of filgrastim
  • White blood cells (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 alanine aminotransferase (ALT)/aspartate aminotransferase (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.

Who cannot join

  • 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 immune competence 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.
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  • History of coronary revascularization or ischemic symptoms.
  • Documented Left Ventricular Ejection Fraction (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 forced expiratory volume 1 (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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: 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

Background:

The National Cancer Institute (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.

Read more

Objectives:

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.

Eligibility:

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

Design:

  • Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (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.
Read the detailed description

PRECIS

Background:

  • We have constructed a single retroviral vector that contains both and <= chains of a murine T cell receptor (mTCR) that recognizes the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) (ESO) tumor antigen, which can be used to mediate genetic transfer of this T-cell receptor (TCR) with high efficiency.
  • In co-cultures with human leukocyte antigen serotype within the HLA-A serotype group (HLA-A2) and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted significant amounts of Interferons (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.

Eligibility:

  • 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

Design:

  • Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in the presence of anti-CD3 monoclonal antibody (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 human T-cell receptor (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% Partial Response (PR) + Complete Response (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).
Being tested
Anti-NY ESO-1 mTCR PBL, Cyclophosphamide, Fludarabine, Aldesleukin
Keywords
Metastatic Cancer, Gene Therapy, Immunotherapy, Tumor Regression, Melanoma
Medical subject headings
Melanoma, Meningioma, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Liver Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Anti-NY ESO-1 mTCR PBLBiological

    Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.

  • CyclophosphamideDrug

    Also called Cytoxan

    Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenously (IV) in 250 mL dextrose 5% in water (D5W) infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.

  • FludarabineDrug

    Also called Fludara

    Days -7 to -3: Fludarabine 25 mg /m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.

  • AldesleukinDrug

    Also called Proleukin

    Aldesleukin 720,000 IU/kg intravenously (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 groups in NCT01967823
Study groupRoleWhat they receive
1/Cyclophosphamide & Fludarabine + Anti-ESO murine TCR transduced PBL + HD AldesleukinExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-ESO murine T-cell receptor (TCR) transduced PBL + high-dose (HD) aldesleukin
Receives: Biological: Anti-NY ESO-1 mTCR PBL; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With a Response

    Percentage of patients who have a clinical response (complete response or partial response) to treatment (objective tumor regression). Response was determined entirely by radiographic imaging using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 to compare target lesions in centimeters. Complete Response is defined as disappearance of all target lesions. Partial Response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

    Measured: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2, then per principal investigator (PI) discretion, up to five years or disease progression.

Secondary outcomes (1)

  1. Percentage of T Cell Receptor (TCR) in Cluster of Differentiation 3 (CD3) + Cells

    T Cell Receptor (TCR) and vector presence will be quantitated in peripheral blood mononuclear cells (PBMC) samples using established polymerase chain reaction (PCR) techniques.

    Measured: 3 and 6 months, and 1 year post cell administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Oct 2013 (estimated)
  2. Study start24 Oct 2013
  3. Primary completion6 Apr 2020
  4. Study completion6 Apr 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01967823
Sponsor's protocol ID
130214
Other IDs
13-C-0214
Status last verified
Mar 2021
First submitted
18 Oct 2013
Last updated
24 Mar 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15.

    PubMed 21498393

  • Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008 Nov 10;26(32):5233-9. doi: 10.1200/JCO.2008.16.5449. Epub 2008 Sep 22.

    PubMed 18809613

  • Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011 Mar 1;29(7):917-24. doi: 10.1200/JCO.2010.32.2537. Epub 2011 Jan 31.

    PubMed 21282551

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Anti-NY ESO-1 mTCR PBL, Cyclophosphamide and Fludarabine in people with Melanoma and Meningioma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With a Response (time frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2, then per principal investigator (PI) discretion, up to five years or disease progression.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01967823, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2021.

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