Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for the Treatment of HER-2/Neu-Overexpressing Metastatic Breast Cancer
Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for the Treatment of HER-2/Neu-Overexpressing Metastatic Breast Cancer
This is a feasibility study to examine combination therapy with Trastuzumab (T),
 Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine in
 patients with Stage IV HER-2/neu-overexpressing breast cancer. The main purposes of this
 study are to test the safety, clinical benefit, and bioactivity of vaccine therapy in
 combination with Cyclophosphamide and Trastuzumab in patients with HER-2/neu-overexpressing
 Stage IV breast cancer. This study will also to test whether the Cyclophosphamide can
 eliminate the suppressive influence of regulatory T cells, and whether Trastuzumab can
 increase antigen processing and presentation. These drug activities may make the immune
 system react better and enhance the effects of the vaccine in treating breast cancer. The
 vaccine consists of two irradiated allogeneic mammary carcinoma cell lines genetically
 modified to secrete human granulocyte-macrophage colony stimulating factor (GM-CSF). This
 open label, single arm study is designed to recruit up to 40 subjects to identify 20 research
 subjects with HER-2/neu-overexpressing Stage IV breast cancer eligible for study treatment.
Breast cancer ranks second among cancer deaths in women. In the year 2005, the American
 Cancer Society has estimated that 212,240 new invasive cases of breast cancer will be
 diagnosed, and predicts 40,410 deaths will result from breast cancer. While 80% of patients
 present with locoregional disease involving the breast and/or axillary lymph nodes, about
 half develop disseminated disease and ultimately die from it. Stage IV breast cancer is
 typically managed with hormonal agents or conventional cytotoxic drugs. Tumors quickly become
 resistant to these treatments. Immunotherapy is a particularly attractive strategy for
 overcoming drug resistance and can be integrated with existing therapeutic modalities in an
 additive or synergistic fashion. Immunotherapy is a type of treatment for cancer based on the
 idea that the immune system can be activated to destroy cancer cells that might be resistant
 to hormonal therapy and chemotherapy. A vaccine is a kind of immunotherapy that delivers an
 antigen (something that activates the immune system) so that the immune system recognizes
 cells with that antigen as foreign and destroys any cells that display that antigen.

 The allogeneic breast tumor cell vaccine consists of two types of breast tumor cells
 developed from the tumor cells of patients with breast cancer. The human
 granulocyte-macrophage colony-stimulating factor (GM-CSF) gene was used to genetically modify
 the breast tumor cells to secrete GM-CSF. GM-CSF is a substance made by the body that helps
 the immune system recognize a tumor and destroy it. The vaccine cells were irradiated to
 prevent them from growing or dividing. The cells themselves are not radioactive. The cells
 are stored frozen until the day of vaccination. The total number of cells in each vaccine
 will be 500,000,000, divided into twelve injections given in the thighs and arms. The choice
 of twelve injections for each vaccine is based on the volume of the vaccine and a finding
 that the body has a better chance to respond to the vaccine if it is injected into a number
 of different areas.

 We propose to test the safety and bioactivity of an allogeneic GM-CSF-secreting breast cancer
 vaccine when given in a specifically timed sequence with Cyclophosphamide and Trastuzumab,
 two drugs commonly used to treat breast cancer. In this study the Cyclophosphamide is used at
 lower doses than usual to help the vaccine to activate the patient's immune system.
 Trastuzumab will be given at doses that are commonly used to treat breast cancer and it may
 also increase the immune response. The dose and scheduling of Cyclophosphamide and
 Trastuzumab used are based on testing the drugs with a GM-CSF-secreting vaccine in mice that
 get breast cancer, and are the ones that enabled the vaccine to induce the most potent
 anti-tumor immunity. The dose of vaccine cells is based on the safety of the same dose of a
 similar GM-CSF-secreting vaccine for pancreatic cancer. This breast cancer vaccine has also
 been given to people with breast cancer by itself, and with Cyclophosphamide and another
 chemotherapy drug, Doxorubicin. To date, people have had no vaccine-related serious side
 effects, but not enough people have received the vaccine to know if it treats breast cancer.
 The vaccine is experimental and has not been approved by the U.S. Food and Drug
 Administration (FDA). However, the FDA has permitted its use in this research study. This is
 the second study of this breast cancer vaccine and the first study to test this vaccine with
 Trastuzumab.

 The main purposes of this study are to test the safety, clinical benefit, and bioactivity of
 vaccine therapy in combination with Cyclophosphamide and Trastuzumab in patients with
 HER-2/neu-overexpressing Stage IV breast cancer. This study will also to test whether the
 Cyclophosphamide can eliminate the suppressive influence of regulatory T cells, and whether
 Trastuzumab can increase antigen processing and presentation. These drug activities may make
 the immune system react better and enhance the effects of the vaccine in treating breast
 cancer.

 The study is open to men and women with HER-2/neu-overexpressing metastatic breast cancer.
 Concurrent hormone therapy and/or bisphosphonates (standard breast cancer therapy that is not
 chemotherapy or other investigational therapy) is allowed. Patients may have received
 Trastuzumab in the past or continue on it while participating in this study. About 40 people
 with HER-2/neu positive breast cancer will enter in the study. About 20 will pass the
 screening tests and receive the vaccine.

 Research subjects will receive a fixed dose of the allogeneic breast tumor vaccine consisting
 of two irradiated allogeneic breast cancer cell lines transfected with the GM-CSF gene in a
 specifically timed sequence with a low dose of Cyclophosphamide and Trastuzumab. Patients
 will receive 300 mg/m2 of Cyclophosphamide on day -1, and the vaccine on day 0. Weekly
 Trastuzumab will be timed to coincide with Cyclophosphamide administration. Research subjects
 will receive three monthly vaccination cycles, with a fourth and final (boost) vaccination
 cycle three months from the third cycle.

 Blood samples to measure GM-CSF levels will be taken on the day of vaccination, every day for
 4 days, and then on day 7 after vaccination. Blood samples to evaluate the safety of the
 vaccinations will be taken about once a week for one month following each vaccination. During
 studies of the breast vaccine and similar vaccines in renal cell cancer, prostate cancer,
 pancreatic cancer, and non-small cell lung cancer, local symptoms of swelling and redness
 developed at the vaccine site between 2 and 7 days after vaccination. In this study, if the
 subject's vaccination site shows swelling over 1 cm in diameter, a skin biopsy will be taken.
 The skin biopsy will be evaluated to determine to what types of cells are important to the
 immune response. Based on our previous preclinical and clinical data, the biopsy will be
 taken on day 3, and possibly on day 7, after the first and third vaccinations. Other tests
 and evaluations include history and physical examination, vital signs, CT of the chest,
 abdomen, and pelvis, nuclear medicine bone scan, pre-vaccination biopsy, blood for immune
 monitoring, and a skin test for delayed-type hypersensitivity (DTH) that is like a purified
 protein derivative (PPD) test and involves injecting pieces of a protein antigen (HER-2/neu)
 that is delivered by the breast cancer vaccine. The purpose of the DTH test is to evaluate
 whether the research subject has developed a systemic immune response to the breast cancer
 vaccine. Tumor core needle biopsies will be obtained at baseline, and on days 0 and +14 of
 vaccine cycle 1 only.

 Patients will be evaluated clinically and with laboratory testing for evidence of disease
 progression after each cycle or when otherwise clinically indicated. Computed tomography (CT
 scan) of the chest, abdomen, and pelvis and nuclear medicine bone scan will also be performed
 to evaluate disease status prior to starting the study, after vaccine cycle 3 and prior to
 and after vaccine cycle 4. About every three months cardiac function will be evaluated.
Inclusion Criteria:

 1. Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the
 breast; this is defined as HER-2+ by immunohistochemistry (IHC) 3+ staining or
 Fluorescence In-Situ Hybridization (FISH). Prior adjuvant Trastuzumab therapy is
 permitted. Patients must not be eligible for therapy of known curative potential for
 metastatic breast cancer if it is identified during the course of the study.

 2. Patients may have measurable or evaluable disease.

 3. Stable central nervous system (CNS) disease that has been adequately treated and is
 not under active treatment allowed.

 4. Age 18 years or older.

 5. Able to give informed consent.

 6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or
 1.

 7. No systemic oral steroids administered within 28 days prior to initiating treatment on
 protocol. Topical, ocular, and nasal steroids are allowed, as are those applied to
 mucus membranes.

 8. No prior or currently active autoimmune disease requiring management with systemic
 immunosuppression. This includes inflammatory bowel disease, systemic vasculitis,
 scleroderma, psoriasis, multiple sclerosis, hemolytic anemia or immune-mediated
 thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's
 syndrome, sarcoidosis, or other rheumatologic disease. Asthma or chronic obstructive
 pulmonary disease that does not require daily systemic corticosteroids is acceptable.

 9. Not pregnant, and on appropriate birth control if of child-bearing potential.

 10. No history of other malignancies within the prior five years (excluding a history of
 carcinoma in situ of the cervix, superficial non-melanoma skin cancer, and superficial
 bladder cancer).

 11. Adequate bone marrow reserve with absolute neutrophil count (ANC) > 1000 and platelets
 > 100,000.

 12. Adequate renal function with serum creatinine < 2.0.

 13. Adequate hepatic reserve with serum bilirubin < 2.0, aspartate transaminase (AST) and
 alanine aminotransferase (ALT) < 2X the upper limit of normal, and alkaline
 phosphatase < 5X the upper limit of normal. Serum bilirubin > 2.0 is acceptable in the
 setting of known Gilbert's syndrome.

 14. Adequate cardiac reserve with a cardiac ejection fraction within the lower limit of
 facility normal by MUGA, or 45% by echocardiogram.

 15. No active major medical or psychosocial problems that could be complicated by study
 participation.

 16. HIV negative.

 Exclusion Criteria:

 1. No histologic documentation of breast adenocarcinoma.

 2. Breast adenocarcinoma that is not amplified for HER-2/neu gene expression by at least
 2-fold by FISH analysis, or that is less than IHC 3+ when FISH negative.

 3. Cardiac dysfunction documented by an ejection fraction less than the lower limit of
 the facility normal by multi-gated acquisition (MUGA) scan, or 45% by echocardiogram.

 4. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs
 resulting in dyspnea at rest.

 5. History of autoimmune disease as detailed above.

 6. Systemic oral corticosteroid treatment within 28 days prior to initiating treatment on
 study.

 7. Uncontrolled medical problems.

 8. Evidence of active acute or chronic infection.

 9. Chemotherapy, radiation therapy, or biologic therapy (except Trastuzumab) within 28
 days prior to initiating treatment on study. Hormonal therapy and supportive therapy
 with bisphosphonates will be allowed.

 10. Participation in an investigational new drug trial within 28 days prior to initiating
 treatment on study.

 11. Pregnant or breast feeding.

 12. Hepatic, renal, or bone marrow dysfunction as detailed above.

 13. Concurrent malignancy or history of other malignancy within the last five years except
 as noted above.

 14. Corn allergy.

 15. Known severe hypersensitivity to Trastuzumab (excluding mild to moderate infusion
 reactions that are easily managed and do not recur).