Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

Primary

• To evaluate the safety of cyclophosphamide-modulated vaccination with vs without trastuzumab in patients with breast cancer that does not overexpress HER-2/neu.
• To compare the clinical benefit of cyclophosphamide-modulated vaccination with vs without trastuzumab in these patients.
• To measure HER-2/neu-specific CD4+ and CD8+ T-cell immunity by delayed-type hypersensitivity (DTH) and ELISPOT.
• To measure the pharmacodynamics of CD4+CD25+ regulatory T cells by flow cytometry.

Secondary

• To assess the impact of trastuzumab on immune priming in vivo by immunohistochemistry of vaccine-site biopsies at day +3 and day +7 of courses 1 and 3 on the two study arms, comparing cellular infiltrates to those seen in previous preclinical and clinical models.
• To measure hTERT-specific CD8+ T-cell immunity by ELISPOT.
• To characterize the peripheral-memory T-cell pool.

Tertiary

• To determine baseline and change in vaccine site-draining lymph node immunohistology and gene expression profile.
• To develop the tandem tetramer/CD107a cytotoxicity assay for HER-2/neu-specific CD8+ T cells.
• To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.
• Arm II: Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.

Skin punch and lymph node biopsies are collected at baseline and on days +3 and +7 of courses 1 and 3 for biomarker analysis.

After completion of study treatment, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

• Does not overexpress HER-2/neu, defined as FISH negative or 0, 1+, or 2+ by IHC
• Stage IV disease
• Must not be eligible for therapy of known curative potential for metastatic breast cancer
• Measurable or evaluable disease
• Stable CNS disease allowed provided that it's adequately treated and 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
• Platelets > 100,000/mm^3
• Serum bilirubin < 2.0 mg/dL (unless due to Gilbert syndrome)
• AST and ALT < 2 times upper limit of normal (ULN)
• Alkaline phosphatase < 5 times ULN
• Serum creatinine < 2.0 mg/dL
• Ejection fraction normal by MUGA OR ≥ 50% by echocardiogram
• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed
• No prior or concurrent 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
• Sjogren syndrome
• Sarcoidosis
• Other rheumatologic disease
• No other malignancies within the past 5 years, except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, superficial bladder cancer, or tamoxifen-related endometrial cancer that has been adequately treated
• No active major medical or psychosocial problems that could be complicated by study participation
• No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
• No uncontrolled medical problems
• No evidence of active acute or chronic infection
• No known severe hypersensitivity to trastuzumab, except mild to moderate infusion reactions that are easily managed and do not recur
• No allergy to corn

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 28 days since prior and no other concurrent chemotherapy, radiation therapy, or biologic therapy (except trastuzumab)

• Concurrent endocrine therapy and supportive therapy with bisphosphonates allowed
• More than 28 days since prior and no other concurrent participation in an investigational new drug trial
• More than 28 days since prior and no other concurrent systemic oral steroids

• Topical, ocular, and nasal steroids allowed
• No prior vaccination with the allogeneic GM-CSF-secreting breast tumor vaccine