Vaccine Therapy, Trastuzumab, and Vinorelbine in Treating Women With Locally Recurrent or Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Vaccines may make the body build an immune response to kill tumor cells. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining vaccine therapy with monoclonal antibody therapy and chemotherapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving vaccine therapy together with trastuzumab and vinorelbine works in treating women with locally recurrent or metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of multiepitope autologous dendritic cell vaccine, trastuzumab (Herceptin^®), and vinorelbine by measuring the change in the largest dimension of metastatic lesions, in women with locally recurrent or metastatic breast cancer that does not overexpress human epidermal growth factor receptor 2 (HER2)/neu. Secondary Determine the ability of this regimen to induce functional antigen-specific T cells in these patients by measuring ex-vivo antigen-specific T-cell activity against peptide-pulsed dendritic cells and tumor targets by tetramer staining and intracellular cytokine assays. OUTLINE: Autologous dendritic cell mobilization and harvest: All patients undergo autologous dendritic cell mobilization with filgrastim (G-CSF) and/or sargramostim (GM-CSF) subcutaneously daily for 4 days followed by apheresis. Mobilized peripheral blood is processed for the production of dendritic cells by cluster of differentiation (CD)34-positive cell selection. The dendritic cells are expanded and then pulsed with E75 and E90 peptides. Treatment: Patients receive vinorelbine IV over 6-10 minutes and trastuzumab (Herceptin ^®) IV over 90 minutes on day 1. Patients also receive autologous dendritic cells pulsed with E75 and E90 peptides subcutaneously over 2-5 minutes on day 1*. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Note: *If treatment is given locally, the vaccine therapy will be given at University of North Carolina (UNC) -Chapel Hill the following day. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 17-37 patients will be accrued for this study.

Official Title
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Phase II Trial Evaluating The Efficacy Of A Multiepitope Dendritic Cell Vaccine Given With Trastuzumab And Vinorelbine For The Treatment Of Women With Metastatic Breast Cancer That Express HLA-A0201

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: therapeutic autologous dendritic cells
* Biological: trastuzumab
* Drug: vinorelbine ditartrate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Locally recurrent or metastatic disease HLA-A0201 positive by DNA genotyping HER2/neu expression at least 1+ by immunohistochemistry of tumor sample Central Nervous System (CNS) metastases allowed provided on therapy for 3 months and stable Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 18 and over Sex Female Menopausal status Not specified Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 Hematocrit > 33% Hepatic Transaminases ≤ 3 times upper limit of normal Bilirubin ≤ 2 times normal Hepatitis B surface antigen negative Renal Creatinine < 2.0 mg/dL Cardiovascular Ejection fraction > 45% by multigated acquisition scan (MUGA) OR Left ventricular function normal by echocardiogram No serious cardiac condition that would preclude study participation or compliance Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No serious medical or psychiatric condition that would preclude study participation or compliance PRIOR CONCURRENT THERAPY: Biologic therapy Prior biologic therapy allowed Chemotherapy More than 30 days since prior cytotoxic chemotherapy No other concurrent chemotherapy Endocrine therapy More than 30 days since prior hormonal therapy No concurrent hormonal therapy No concurrent systemic steroids Radiotherapy Not specified Surgery Not specified Other Concurrent bisphosphonates for bone metastases allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Dendritic Cell Vaccine<br>Dendritic Cells: Dosage: 20 x 106 dendritic cells (DCs) given per treatment Vinorelbine:25 mg/m2 will be administered i.v biweekly Trastuzumab: 6mg/Kg administered by i.v. biweekly | Biological: therapeutic autologous dendritic cells<br>* 10 μg/kg subcutaneously (sc) each day for four days or g-CSF at 5 μg/kg sc each day for four days with GM-CSF 250 μg/m2 sc each day for four days. G-CSF and/or GM- CSF will be self-administered. On the fifth day patients will have two intravenous lines placed in the apheresis area of the Blood Bank and then undergo a 15 litre apheresis collection<br>Biological: trastuzumab<br>* 4 mg/kg intravenously, every 14 days<br>Drug: vinorelbine ditartrate<br>* Vinorelbine 25 mg/m2 will be administered intravenously, every 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response measured by Response Evaluation Criteria In Solid Tumors (RECIST), (Complete Response + Partial Response) Complete Response (CR)- Disappearance of all target lesions Partial Response (PR)-at least a 30% decrease in the longest diameters of target lesions, taking as reference the baseline longest diameter. | 6 months following treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Response | Measured by intracellular cytokine staining for Interferon-gamma (INFgamma) and cluster of differentiation (CD107) up regulation and tetramer. A fourfold increase in the number of cluster of differentiation (CD8+) tetramers comparing prevaccine with peak postvaccine values indicated an immune response to the therapy. | 3 months following treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer