A2-ESO-1 TCR-Engineered T Cells for Relapsed/Refractory Advanced or Metastatic NY-ESO-1 Overexpression Positive Triple Negative Breast Cancer

Study Overview
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Brief Summary
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This phase Ib trial tests the safety, side effects and best dose of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-T cells) in treating patients with NY-ESO-1 overexpression positive triple negative breast cancer (TNBC) that has come back after a period of improvement (relapsed/recurrent) or that does not respond to treatment (refractory), and that may have spread from where it first started (primary site) to nearby tissue, lymph nodes (advanced) or to other places in the body (metastatic). NY-ESO-1 is an antigen found on the surface of many different types of tumor cells including TNBC. Antigens make it possible for immune cells to recognize and kill germ cells that invade the body, however, it is more difficult for immune cells to recognize antigens on tumor cells. T cells are a special type of immune cell in the blood. These T cells may be trained to recognize the NY-ESO-1 antigen on tumor cells, allowing the T cells to attack and kill those tumor cells. The A2-ESO-1 TCR-T cells are T cells that have been removed from the patient's blood through a process called leukapheresis and then changed in the laboratory to recognize NY-ESO-1 on tumor cells. When given back to the patient, these A2-ESO-1 TCR-T cells find and attack tumor cells that express NY-ESO-1. Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They are given before the T cells to support optimum activity of the A2-ESO-1 TCR-T cells. IL-2 (aldesleukin) is in a class of drugs known as cytokines. It is a man-made version of a naturally occurring protein that stimulates the body to produce other chemicals which increase the body's ability to fight cancer. A2-ESO-1 TCR-T cells may kill more tumor cells in patients with recurrent or refractory advanced or metastatic TNBC that overexpresses NY-ESO-1.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of anti-HLA-A2/NY-ESO-1 TCR-transduced autologous T lymphocytes (A2-ESO-1 TCR-engineered T cells) in patients with relapsed/refractory locally advanced or metastatic TNBC that overexpresses NY-ESO-1 by using the Bayesian optimal interval (BOIN) design. II. To determine the dose-limiting toxicities (DLTs) of A2-ESO-1 TCR-engineered T cells in patients with relapsed/refractory locally advanced or metastatic TNBC that overexpresses NY-ESO-1, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v)5.0. SECONDARY OBJECTIVES: I. To evaluate the antitumor activity of A2-ESO-1 TCR-engineered T cells, as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. II. To evaluate the immunological activity (i.e., persistence, function) of A2-ESO-1 TCR-engineered T cells. EXPLORATORY OBJECTIVE: I. To evaluate the correlative markers of A2-ESO-1 TCR-engineered T cells, including but not limited to PD-L1 expression and immune cell populations such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). OUTLINE: This is a dose-escalation study of A2-ESO-1 TCR-T cells. Patients undergo leukapheresis on day -28 then receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6 followed by fludarabine IV over 30 minutes on days -5 to -1. Patients then receive A2-ESO-1 TCR-T cells IV over 30 minutes on day 0 followed by aldesleukin IV over 15 minutes on days 0 to 2. Patients also undergo blood sample collection and computed tomography (CT) scans throughout the study. Additionally, patients may undergo a breast biopsy, a mammogram, breast magnetic resonance imaging (MRI), and breast ultrasound (US) at screening and follow up, and echocardiography (ECHO) or multi-gated acquisition scan (MUGA) at screening. After completion of study treatment, patients are followed up at 3, 6, and 12 months and then yearly for up to 15 years or until disease progression, voluntary study withdrawal or study discontinuation, whichever occurs first.

Official Title
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Phase Ib Clinical Trial of Autologous Anti-NY-ESO-1 TCR-Engineered T Cells in Patients With Relapsed/Refractory Locally Advanced or Metastatic NY-ESO-1-Expressing Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: Anti-HLA-A2/NY-ESO-1 TCR-transduced Autologous T Lymphocytes
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Drug: Cyclophosphamide
* Procedure: Echocardiography
* Drug: Fludarabine
* Procedure: Leukapheresis
* Procedure: Magnetic Resonance Imaging
* Procedure: Mammogram
* Procedure: Multigated Acquisition Scan
* Procedure: Ultrasound Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged >= 18 years Histologically confirmed advanced or metastatic TNBC that have relapsed on or are refractory to 2 or more lines of standard-of-care therapy including immune checkpoint inhibitors, chemotherapy, trastuzumab deruxtecan (TDX-d) and poly-ADP ribose polymerase (PARP) inhibitors if indicated, but less than 4 lines of total therapies. TNBC is defined as estrogen receptor (ER) and progesterone receptor negative (< 10% immunohistochemistry [IHC] staining) and HER2 negative (IHC 1+ or 0 AND/OR in situ hybridization negative based on: Single-probe average HER2 copy number < 4.0 signals/cell Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell) HLA-A2+ and tumoral overexpression of NY-ESO-1 (2 to 3+ IHC staining in > 50% of cells) Have measurable disease based on RECIST 1.1 Life expectancy >= 6 months Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Hemoglobin >= 9.0 g/dL (transfusions permitted) Absolute neutrophil count (ANC) >= 1500/mm^3 Platelet count >= 100,000/mm^3 Creatinine (Cr) < 2 x upper limit of normal (ULN), and Cr clearance (CrCl) >= 50 mL/min by Cockcroft and Gault Alanine transaminase (ALT) and aspartate transaminase (AST) < 2 x ULN (Patients with liver metastases whose ALT/AST are < 5 x ULN are eligible for enrollment) Bilirubin < 2 x ULN White blood cell (WBC) count > 2500/uL and < 15000/uL Lymphocyte count >= 500/uL Cardiac ejection fraction >= 50% Negative serum pregnancy (human chorionic gonadotropin [beta-hCG]) test within 7 days of day 0 (leukapheresis) for women of childbearing potential (WOCBP). WOCBP must be willing to use a highly effective method of contraception for the course of the study through 90 days after A2-ESO-1 TCR-engineered T cell infusion Willing and able to provide written informed consent for the study Willing to provide biopsy tissues and blood samples as required by the study Exclusion Criteria: Radiation therapy, chemotherapy, or non-cytotoxic investigational agent within 2 weeks of day 0 (leukapheresis) Received cyclophosphamide within the past 4 months Evidence of New York Heart Association class III or greater cardiac disease History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within the past 12 months History of congenital QT prolongation Absolute QT interval of > 470 msec in the presence of > 4.0 mEq/L potassium and > 1.8 mg/dL magnesium Brain or leptomeningeal metastases Females who are pregnant or breastfeeding Hypersensitivity or intolerance to cyclophosphamide, fludarabine, or their components Alcoholic liver disease or other hepatic disease with the exception of liver metastases History of gastrointestinal bleeding, ulceration, or perforation Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study, such as severely impaired lung function, any active (acute or chronic) or uncontrolled infection/disorders, and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the study treatment Current use of medications that interact with or compromise the immune system such as steroid doses > 10 mg/day prednisone or equivalent daily within 2 weeks before leukapheresis History of immunodeficiency disease or autoimmune disease Concurrent use of any complementary or alternative medicines Unwilling or unable to comply with the study protocol Prior major surgery that requires general anesthesia must be completed at least 4 weeks before leukapheresis and surgery that requires local anesthesia (except for study tissue sample collection) must be completed at least 2 weeks before leukapheresis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (A2-ESO-1 TCR-T cells)<br>Patients undergo leukapheresis on day -28 then receive cyclophosphamide IV over 1 hour on days -7 and -6 followed by fludarabine IV over 30 minutes on days -5 to -1. Patients then receive A2-ESO-1 TCR-T cells IV over 30 minutes on day 0 followed by aldesleukin IV over 15 minutes on days 0 to 2. Patients also undergo blood sample collection and CT scans throughout the study. Additionally, patients may undergo a breast biopsy, a mammogram, breast MRI, and breast US at screening and follow up, and ECHO or MUGA at screening. | Biological: Aldesleukin<br>* Given IV<br>* Other names: Recombinant Human Interleukin-2;Biological: Anti-HLA-A2/NY-ESO-1 TCR-transduced Autologous T Lymphocytes<br>* Given IV<br>* Other names: Autologous HLA-A2/NY-ESO-1-specific TCR Gene-transduced T-lymphocytes;Procedure: Biopsy<br>* Undergo biopsy of breast tumor<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Procedure: Leukapheresis<br>* Undergo leukapheresis<br>* Other names: Therapeutic Leukopheresis;Procedure: Magnetic Resonance Imaging<br>* Undergo breast MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Mammogram<br>* Undergo mammogram<br>Procedure: Multigated Acquisition Scan<br>* Undergo MUGA scan<br>* Other names: Synchronized Multigated Acquisition Scanning;Procedure: Ultrasound Imaging<br>* Undergo ultrasound of breast<br>* Other names: US;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of anti-HLA-A2/NY-ESO-1 T-cell receptor (TCR)-transduced autologous T lymphocytes (A2-ESO-1 TCR-engineered T cells) | Will employ the Bayesian optimal interval to find the MTD. | Up to 8 weeks after A2-ESO-1 TCR-engineered T cell infusion | 
| Incidence of dose-limiting toxicities | Defined as any treatment-related death or any greater than or equal to grade 3 adverse event (AE) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. | Up to 8 weeks after A2 ESO-1 TCR-engineered T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity | Antitumor activity will be assessed by RECIST 1.1. Complete Response (CR) = disappearance of all target lesions, Partial Response (PR) = at least a 30% decrease in the sum of the longest diameter of target lesions, using the baseline sum longest diameter as a reference, Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD) using the smallest sum longest diameter since treatment start as reference, PD = At least a ≥20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | At pre-treatment and 6 months post-treatment | 
| Change in PD-1 expression on T cells | Levels of PD-1 expression on T cells will be monitored. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test. | At pre-treatment and 6 months post-treatment | 
| Change in NY-ESO-1-specific TCR-engineered T cells | Levels of NY-ESO-1-specific TCR-engineered T cells will be monitored to determine whether these T cells are persistent. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test. | At pre-treatment and 6 months post-treatment | 
| Change in regulatory T cells (Treg) | Because NY-ESO-1-specific TCR-engineered CD4+ T cells may differentiate into Treg cells, levels of Treg cells will be monitored. Post-treatment biomarker measurements will be compared to the pre-treatment values using a one-sided paired t-test and nonparametric Wilcoxon signed-rank test. | At pre-treatment and 6 months post-treatment |