Protocol Number: 01-C-0173

Title:

A Pilot Study to Evaluate Angiogenesis after Treatment with Bevacizumab (Anti-VEGF Humanized Monoclonal Antibody) in Previously Untreated Patients with Inflammatory Breast Cancer or Locally Advanced Breast Cancer

Number:

01-C-0173

Summary:

This study will evaluate the effectiveness of the drug bevacizumab, in combination with doxorubicin and docetaxel, in improving survival of patients with inflammatory breast cancer. This aggressive breast cancer, which often causes a red, swollen, tender breast, is associated with a poor prognosis. Bevacizumab blocks the growth of new blood vessels that supply oxygen and nutrients to tumors, and therefore, may kill cancer cells or stop their growth. Doxorubicin and docetaxel are approved drugs for treating breast cancer.

Patients 18 years of age or older with stage IIIB or stage IV inflammatory breast cancer who have not been treated with chemotherapy or radiation therapy may be eligible for this study. Candidates will undergo a medical history and physical examination, blood and urine tests, electrocardiogram and chest X-ray. A mammogram of both breasts, computed tomography (CT) of the head, chest, abdomen and pelvis, and a bone scan will be done to determine the extent of disease. Those enrolled will undergo the following procedures at various intervals before, during and/or after completing chemotherapy:

- Tumor and skin biopsies - A small piece of tumor tissue and a small piece of skin are removed under local anesthesia for microscopic study. The tumor tissue will be used to study the effects of bevacizumab on blood vessels and the biology of inflammatory breast cancer.

- Dynamic MRI - Magnetic resonance imaging of the breast will be used to examine changes in the blood vessels and breast cancer following bevacizumab treatment. Dynamic MRI involves injecting a contrast liquid into a vein before scanning. A standard MRI scan will also be done before the dynamic MRI.

- Blood tests will be done to 1) study clot formation and breakdown, 2) measure levels of VEGF and VCAM-1, a substance produced by cells lining blood vessel walls, and 3) check blood counts and liver and kidney function.

- MUGA or echocardiogram - MUGA is a nuclear medicine scan that checks the heart's pumping ability. An echocardiogram (ultrasound scan of the heart) can also be used to evaluate heart function.

- Blood pressure monitoring

- Urine tests

Patients will have a central venous line (plastic tube) placed into a major vein in the chest before beginning treatment. The line remains in the body during the entire treatment period and is used to give chemotherapy and other medications such as antibiotics, if needed, and to withdraw blood samples. The line is usually placed under local anesthesia in the radiology department or the operating room. All treatment will be given on a single day every 3 weeks. This constitutes one treatment cycle. Cycle 1 will be bevacizumab alone; cycles 2 through 7 will be bevacizumab with doxorubicin and docetaxel. During each cycle, patients will also receive ten injections under the skin of G-CSF, a drug that raises the number of infection-fighting white blood cells, which are often decreased as a side effect of chemotherapy. After cycle 7, patients may require surgery or radiation or radiation alone. After radiation treatment, bevacizumab will be re-started, given alone every 3 weeks for an additional eight cycles. Patients whose tumors are positive for estrogen or progesterone receptors will be advised to take the drug tamoxifen for 5 years to decrease the chances of disease recurrence. This would begin with cycle 8.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Patients must have inflammatory breast cancer or locally advanced breast cancer previously untreated with chemotherapy and/or radiation therapy. Inflammatory breast cancer is defined as histologically proven invasive adenocarcinoma of one breast with clinical inflammatory signs including onsent of erythema and brawny induration or edema of the skin with an erysipeloid edge with or without an underlying tumor mass. Dermal lymphatic involvement by tumor cells is not a requirement for diagnosis. We will define locally advanced breast cancer as stage IIB, IIIA, or IIIC breast cancer according to the 2002 AJCC staging guidelines. Patients must have tissue accessible for serial biopsies.

Age greater than or equal to 18 years.

ECOG performance status of 0, 1, or 2.

Patients must have a left ventricular ejection fraction of greater than or equal to 50% without clinical symptoms or signs of heart failure.

Patients must have adequate bone marrow, hepatic and renal function as defined by the following:

Absolute neutrophil count greater than or equal to 1500/mL; Platelets greater than or equal to 100,000/mL; Serum creatinine less than or equal to 1.5 mg/dL; AST, ALT less than or equal to 1.5 times the upper limit of normal; Alkaline phosphatase less than or equal to 2.5 times the upper limit of normal; Total bilirubin less than or equal to the upper limit of normal for institution. In patients with evidence of Gilbert's disease, elevated bilirubin should not be related to tumor or other liver diseases, and should be less than or equal to 2 times the upper limit of normal.

Women of childbearing potential must agree to use an accepted and effective method of contraception during their participation on the trial.

Patients must be able to provide informed consent.

EXCLUSION CRITERIA:

Evidence of carcinomatous meningitis or brain metastases or other CNS disease including history of stroke, primary brain tumor or seizures not controlled by standard medical therapy.

History of an active malignancy other than in situ carcinoma of the cervix, or non-melanomatous skin cancers in the last five years prior to Day 1 on study.

Patients with non-healing wounds, bone fractures, or major surgery within the previous 28 days..

Uncontrolled hypertension (sustained systolic blood pressure greater than 160 mmHg or diastolic blood pressure of greater than 100 mmHg).

Clinically significant cardiovascular disease (e.g., myocardial infarction, unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or Grade II or greater peripheral vascular disease within 12 months prior to Day 1 on study.

INR greater than 1.50. Prior history of bleeding diathesis or coagulopathy including deep venous thrombosis or pulmonary embolism. Recent (within last six months) or current history of gastrointerstinal bleeding.

Current use of full-dose or parenteral anticoagulants or chronic daily treatment with aspirin (greater than 325 mg/day) within 10 days prior to Day 1 on study.

Active infection requiring intravenous antibiotics on Day 1 on study.

Patients with 24 hour urine protein greater than or equal to 500 mg or a history of a primary renal disease (excluding infection).

Clinical grade greater than or equal to 2 peripheral neuropathy.

History of other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.

Pregnant or lactating women.

Patients who are receiving other investigational drugs.

Patients with a history of hypersensitivity reaction to products containing Polysorbate 80 (Tween 80).

Patients with a known hypersensitivity to E. coli derived products.

Patients with an arterial thromboembolic event (including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction) within 6 months.

Patients with clinically significant peripheral artery disease.

Special Instructions: Currently Not Provided

Keywords:

Endothelial Proliferation

Endothelial Apoptosis

VEGF

Magnetic Resonance Imaging

Molecular Targets

Recruitment Keywords:

Breast Cancer

Inflammatory Breast Cancer

IBC

Conditions:

Breast Cancer

Investigational Drug(s):

Bevacizumab

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

The biology of vascular endothelial growth factor

Tumor-related angiogenesis

What is the evidence that tumors are angiogenesis dependent?

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