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A Feasibility Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for HER-2/Neu-Overexpressing Metastatic Breast Cancer.

Phase 2
18 Years
Not Enrolling
Breast Neoplasms

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Trial Information

A Feasibility Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine for HER-2/Neu-Overexpressing Metastatic Breast Cancer.

Breast cancer ranks second among cancer deaths in women (American Cancer Society, 2005). 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

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 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

Inclusion Criteria:

1. Patients with histologically confirmed HER-2/neu-overexpressing adenocarcinoma of the
breast; this is defined as HER-2+ by IHC 3+ staining or 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 CNS disease that has been adequately treated and is not under active treatment

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

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 ANC > 1000 and platelets > 100,000.

12. Adequate renal function with serum creatinine < 2.0.

13. Adequate hepatic reserve with serum bilirubin < 2.0, AST/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

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

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).

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety will be evaluated by assessing toxicity related to the vaccine, CY, Trastuzumab, cardiac dysfunction, and the potential induction of autoimmunity.

Outcome Time Frame:

Until 30 days after intervention

Safety Issue:


Principal Investigator

Leisha A Emens, M.D.,Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

September 2006

Completion Date:

February 2010

Related Keywords:

  • Breast Neoplasms
  • Stage IV HER-2/neu overexpressing breast cancer
  • Breast Neoplasms
  • Neoplasms



The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231