Trastuzumab, Cyclophosphamide, and Vaccine Therapy in Treating Patients With High-Risk or Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vaccines made from gene-modified tumor cells may help the body build an immune response to kill tumor cells. Giving trastuzumab together with cyclophosphamide and vaccine therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects of giving trastuzumab together with cyclophosphamide and vaccine therapy in treating patients with high-risk or metastatic breast cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To evaluate the safety of allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine in combination with trastuzumab (Herceptin®) and cyclophosphamide in patients with high-risk or metastatic HER2/neu-overexpressing breast cancer. To measure the HER2/neu-specific CD4+ T-cell response by delayed-type hypersensitivity. To measure the magnitude of HER2/neu-specific CD8+ T-cell responses by ELISPOT. Secondary To assess the impact of trastuzumab on immune priming in vivo by IHC. To measure the impact of cyclophosphamide pretreatment on CD4+CD25+ regulatory T cells by flow cytometry. To determine the time to disease progression. Tertiary To develop the tandem tetramer/CD107a cytotoxicity assay for HER2/neu-specific CD8+ T cells. To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination. OUTLINE: Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day -1 of the first course of vaccination and continuing until the completion of the last course of vaccination. Patients also receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine intradermally on day 0. Treatment with cyclophosphamide and the vaccine repeats every 27-42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth course of cyclophosphamide and vaccine approximately 6-8 months after the first course. Patients undergo delayed-type hypersensitivity testing and blood sample collection at baseline and periodically during study for immunologic laboratory studies. Blood samples are analyzed for serum GM-CSF levels by pharmacokinetic studies and for immune monitoring by ELISPOT and flow cytometry. Skin punch biopsies are also performed periodically and analyzed by IHC. After completion of study treatment, patients are followed periodically.

Official Title
-----------------
A Safety and Bioactivity Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-Secreting Breast Tumor Vaccine for the Treatment of Patients With High Risk/ Metastatic HER-2/Neu- Overexpressing Breast Cancer With No Evidence of Disease

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Biological: allogeneic GM-CSF-secreting breast cancer vaccine
* Biological: trastuzumab
* Drug: cyclophosphamide
* Other: flow cytometry
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast, meeting one of the following criteria: Metastatic disease High-risk disease, defined as early-stage disease with pathologic involvement of locoregional lymph nodes Patients who are/will be receiving standard adjuvant trastuzumab [Herceptin®] for high-risk disease will participate in this study during the single-agent trastuzumab portion of their therapy No clinical or radiographical evidence of active disease Not eligible for therapy of known curative potential for metastatic breast cancer HER2/neu-overexpressing disease, defined as HER2/neu positive by IHC 3+ staining or by FISH+ amplification Stable CNS disease allowed provided it has been adequately treated and is not under active treatment Hormone receptor status not specified PATIENT CHARACTERISTICS: Menopausal status not specified ECOG performance status 0-1 ANC > 1,000/mm^3 Platelet count > 100,000/mm^3 Serum creatinine < 2.0 mg/dL Serum bilirubin ≤ 2.0 mg/dL (unless elevation is due to known Gilbert's syndrome) AST/ALT ≤ 2 times upper limit of normal (ULN) Alkaline phosphatase ≤ 5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Cardiac ejection fraction normal by MUGA OR ≥ 45% by ECHO No other malignancies within the past 5 years, except for carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer No prior or currently active autoimmune disease* requiring management with systemic immunosuppression, including any of the following: Inflammatory bowel disease Systemic vasculitis Scleroderma Psoriasis Multiple sclerosis Hemolytic anemia or immune-mediated thrombocytopenia Rheumatoid arthritis Systemic lupus erythematosus Sjögren syndrome Sarcoidosis Other rheumatologic disease No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest HIV-negative No evidence of active acute or chronic infection No uncontrolled medical problems No active major medical or psychosocial problems that could be complicated by study participation No corn allergy No known severe hypersensitivity to trastuzumab (except for mild to moderate infusion reactions that are easily managed and do not recur) NOTE: *Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed PRIOR CONCURRENT THERAPY: Any number of prior chemotherapy regimens for metastatic breast cancer allowed Prior or concurrent trastuzumab in the adjuvant or metastatic setting allowed More than 28 days since prior and no concurrent systemic oral steroids Topical, ocular, or nasal steroids allowed More than 28 days since prior and no concurrent chemotherapy, radiotherapy, or biologic therapy (except trastuzumab) More than 28 days since prior and no concurrent participation in another investigational clinical trial involving a new drug Concurrent endocrine therapy or bisphosphonates allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine<br>Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine | Biological: allogeneic GM-CSF-secreting breast cancer vaccine<br>* Day 0 : Allogeneic GM-CSF-secreting Breast Cancer Vaccine administered as: 12 intradermal injections of a divided total dose of 5 x108 cells.<br>Biological: trastuzumab<br>* Patient HAS received prior Trastuzumab within the last two weeks, give Trastuzumab 2 mg/kg weekly on Day -1 for 5 weeks. Patient has NOT received Trastuzumab within the last two weeks, give On Cycle 1, Day -1 ONLY, Loading dose 4 mg/kg<br>* Other names: Herceptin;Drug: cyclophosphamide<br>* Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide.<br>* Other names: Cytoxan;Other: flow cytometry<br>* Samples will be analyzed by flow cytometry using Cell Quest software<br>Other: immunoenzyme technique<br> <br> Other: immunohistochemistry staining method<br>* Measuring Immune Priming In Vivo By Vaccine Site Biopsies<br>Other: laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> Procedure: biopsy<br>* skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Assessed by Number of Participants Experiencing Toxicity | Safety as assessed by number of participants who experienced drug-related local and systemic toxicity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) in response to CY-modulated immunization with a novel breast cancer vaccine in the setting of weekly Trastuzumab therapy. | 4 years | 
| Number of Participants With Immunologic Response as Determined by Delayed-type Hypersensitivity (DTH) Response to HER2/Neu-derived Peptides |  | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit as Assessed by Number of Participants With Progression-free Survival | Number of participants without evidence of disease progression. | 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
male breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, HER2-positive breast cancer