Vaccine Therapy in Treating Patients With Stage IV Breast Cancer

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects of escalating doses of adoptive T cell therapy in treating patients with stage IV breast cancer. Vaccines are given to patient prior the expansion of a person's white blood cells may help the body build an effective immune response to kill tumor cells that overexpress human epidermal growth factor receptor 2 (HER2)

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of infusing escalating doses of HER2 specific T cells into patients with advanced HER2+ breast cancer using ex vivo expanded autologous T cells. SECONDARY OBJECTIVES: I. To investigate to what extent HER2 specific T cell immunity can be boosted or generated in individuals after infusion of HER2 specific T cells. II. To evaluate how long T cell immune augmentation persists in vivo after adoptive transfer of HER2 specific T cells and subsequent booster immunizations. III. To determine the development of cluster of differentiation (CD)4+ and CD8+ epitope spreading after adoptive transfer of HER2 specific T cells. TERTIARY OBJECTIVES: I. To investigate the potential anti-tumor effects of HER2 specific T cells in patients with advanced HER2+ breast cancer. II. To determine whether indium-labeled HER-2 specific T-cells traffic to sites of metastatic disease once adoptively transferred using SPECT or SPECT-CT imaging. III. To assess whether adoptively transferred HER-2 specific T-cells induce acute inflammation at metastatic sites of disease by assessing the development of tumor inflammation after the second or third infusion of cells using PET-CT imaging. OUTLINE: This is a phase I/II, dose-escalation study of ex vivo-expanded HER2-specific autologous T cells. Patients receive HER2/neu peptide vaccine admixed with sargramostim (GM-CSF) intradermally (ID) on days 1, 8, and 15. Beginning 2 weeks later, patients undergo leukapheresis to isolate and collect peripheral blood mononuclear cells for T-cell expansion. Patients receive cyclophosphamide intravenously (IV) once on day -1 and autologous ex vivo-expanded HER2-specific T cell IV over 30 minutes on day 1. Treatment repeats every 7-10 days for up to three treatments. Patients receive a booster HER2/neu peptide vaccine 1 month after the final T-cell infusion, followed by 2 additional booster vaccines at 2-month intervals. While on the study, patients may continue their standard-of-care (non-research) treatment with trastuzumab and/or lapatinib IV weekly or every 3 weeks, except for 7 days before the cyclophosphamide dose, treatment 1 and treatment 2 and at least 7 days after receiving the second T cell vaccine. (Trastuzumab and lapatinib are not required or provided in this study). Before the third T cell treatment of HER2 specific T-cells we will label a small sample of the patient's T-cells with indium-111. Prior to the final infusion of T-cells, patients will have FDG PET-CT performed. This scan will be repeated 48 hours after T-cell infusion. In addition, patients would then undergo SPECT or SPECT-CT imaging at 4, 24, 48, and 72 hours (+/- 3 hours) after labeled cells have been infused. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for the following year, and then twice a year thereafter. This consists of blood collection and contact with patients physician.

Official Title
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Phase I/II Study of Adoptive T Cell Therapy Following In Vivo Priming With a HER-2/Neu (HER2) Intracellular Domain (ICD) Peptide-Based Vaccine in Patients With Advanced Stage HER2 Overexpressing Breast Cancer

Conditions
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HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: HER-2/neu peptide vaccine
* Procedure: leukapheresis
* Biological: ex vivo-expanded HER2-specific T cells
* Drug: cyclophosphamide
* Biological: sargramostim
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with HER2+ Stage IV breast cancer that have been maximally treated and not achieved a complete remission Patients must have stable or slowly progressive disease state, measurable disease as: Extraskeletal disease that can be accurately measured >= 10 mm by standard imaging techniques that can include but not limited to computed tomography (CT), positron emission tomography (PET), PET/CT, magnetic resonance imaging (MRI); Skeletal or bone-only disease which is measurable by fludeoxyglucose (FDG) PET or PET/CT imaging will also be allowed Patients can be currently receiving trastuzumab and/or lapatinib and/or hormonal therapy and/or bisphosphonate therapy HER2 overexpression in the primary tumor or metastasis by immunohistochemistry (IHC) of 2+ or 3+, or documented gene amplification by fluorescence in situ hybridization (FISH) analysis; if overexpression is 2+ by IHC, then patients must have HER2 gene amplification documented by FISH Subjects must have a Performance Status Score (Southwest Oncology Group [SWOG]/Zubrod Scale) = 0, 1 or 2 Patients must be off all immunosuppressive treatments such as chemotherapy or systemic steroid therapy a minimum of 14 days prior to initiation of study (i.e. first vaccination) Patients on trastuzumab and/or lapatinib must have a baseline left ventricular ejection fraction (LVEF) measured by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) equal to or greater than the lower limit of normal for the facility within 90 days of eligibility determination Men and women of reproductive ability must agree to contraceptive use during the entire study period Patients must have an expected survival of 6 months White blood cell (WBC) >= 3000/mm^3 Absolute neutrophil count (ANC) >= 1000/mm^3 Hemoglobin (Hgb) >= 10 mg/dl Platelets >= 75,000/mm^3 Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 2.5 mg/dl Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 3 times upper limit of normal (ULN) Patients must be >= 18 years old Exclusion Criteria: Patients with any of the following cardiac conditions: Symptomatic restrictive cardiomyopathy; Unstable angina within 4 months prior to enrollment; New York Heart Association functional class III-IV heart failure on active treatment Patients with any contraindication to receiving rhuGM-CSF based products Patients with any clinically significant autoimmune disease uncontrolled with treatment Patients with a history of brain metastases must have a stable head imaging study within 30 days of eligibility determination; specifically, patients with active brain metastases will not be eligible for study Patients who are simultaneously enrolled in any other treatment study Pregnant or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 (vaccine therapy)<br>Patients receive HER2/neu peptide vaccine admixed with sargramostim (GM-CSF) ID on days 1, 8, and 15. Beginning 2 weeks later, patients undergo leukapheresis to isolate and collect peripheral blood mononuclear cells for T-cell expansion. Patients receive cyclophosphamide IV once on day -1 and autologous ex vivo-expanded HER2-specific T cell IV over 30 minutes on day 1. Treatment repeats every 7-10 days for up to three immunizations. Patients receive a booster HER2/neu peptide vaccine 1 month after the final T-cell infusion, followed by 2 additional booster vaccines at 2-month intervals. | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Procedure: leukapheresis<br>* Undergo leukapheresis<br>Biological: ex vivo-expanded HER2-specific T cells<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Biological: sargramostim<br>* Given ID<br>* Other names: Prokine;Other: laboratory biomarker analysis<br>* Correlative study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Toxicity of Infusing HER2-specific T Cells as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 | Patients are monitored for the development of end organ damage by assessing adverse events with serum chemistries, liver function studies, complete blood counts, urine analysis and physical exams. All adverse events for all systems are graded on a scale of 1-5 and attribution is assigned. There are DLT criteria. DLT is defined as any incidence of Grade 3 hematologic and non-hematologic toxicity (excluding: fever, hypoxia, and urticaria) Thus, if a subject develops a Grade 3 toxicity (excluding those listed in Table 4) will be considered excessive toxicity and no further dose escalations will occur. | Up to 4 months after first booster vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Whose T Cells Persist at a Level the Same or Greater as the Level After the Final T Cell Infusion and Subsequent Booster Immunizations as Assessed by IFN-gamma (IFN-g) ELISPOT |  | Up to 2 year following the last infusion | 
| Development of CD4+ and CD8+ Epitope Spreading | As assessed by the development of immunity to epitopes within the HER2 protein to which the patient was not vaccinated as well as the development of immunity to other breast cancer related tumor antigens. | Up to 2 years | 
| Response of Skeletal or Bone-only Disease by FDG-PET and According to European Organization for Research and Treatment for Cancer (EORTC) |  | Up to 2 years |