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
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
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.
OBJECTIVES:
Primary
Secondary
Tertiary
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.
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
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:
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
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