Safety Study of Bevacizumab to Treat Women With a History of Breast Cancer and Suffering From Upper Extremity Lymphedema

Lymphedema occurs with varying frequency in patients with cancer but approximately 10-15% of
all breast cancer patients will develop lymphedema following breast cancer treatment.
Lymphedema in breast cancer patients following axillary lymph node dissection is caused by
the interruption of the axillary lymphatic system by surgery or radiation therapy, which
causes an accumulation of fluid in the subcutaneous tissue of the arm, with decreased
distensibility of tissue around the joints and increased weight of the extremity. The
primary current therapy employed involves complete decongestive therapy (CDT) which
encompasses the use of manual lymphatic drainage (MLD) and compression bandaging (CB) to the
affected limb.

The specific contribution of the vascular system to the development of lymphedema is
unclear. Vascular permeability is a complex process which is primarily controlled by the
interaction of the ligand vascular endothelial growth factor (VEGF). As a result of the
understanding of the biology of VEGF and the anecdotal appreciation of women with lymphedema
who have noted improvement in their lymphedema while on VEGF inhibitor therapy, it is
hypothesized that the reduction in vascular permeability resulting from the use of a VEGF
inhibitor either alone or in conjunction with standard decongestive lymphedema therapy may
significantly improve the outcome for patients with this post-operative complication.

Bevacizumab is a recombinant humanized monoclonal antibody directed against VEGF.
Bevacizumab blocks the development of new blood vessels in cancer and it is approved by the
FDA for the treatment of colon cancer in combination with chemotherapy. While bevacizumab
has been administered to thousands of patients with cancer, there is only limited
information about the use of bevacizumab in subjects without active cancer.

This study will evaluate the safety profile of escalating doses of bevacizumab administered
intravenously alone for 4 weeks followed by 4 weeks of therapy in combination with manual
lymph drainage (MLD) and compression bandaging (CB) to patients with moderate to severe
unilateral upper extremity lymphedema due to prior breast cancer therapy.

Inclusion Criteria:

- Women with a history of breast cancer status post (s/p) prior surgical resection
(i.e., either lumpectomy and radiation, modified radical mastectomy or radical
mastectomy) with lymphedema defined as a difference in limb volume of at least 500 ml
by perometric assessment

- Lymphedema may be newly diagnosed or previously treated as long as it is Stage I
(pitting) or II (fibrosis) at the time of study entry.

- No known evidence of recurrent or active metastatic breast cancer

- No prior chemotherapy within 6 months of study entry and has recovered to grade 1 or
less from the toxicity of all prior chemotherapy or radiation therapy (with the
exception of alopecia); ongoing anti-estrogen therapy for post-menopausal survivors
is permissible.

- Normal end organ function defined as: serum creatinine < 1.5 mg/dl or a calculated
creatinine clearance > 50 ml/min; SGOT and SGPT < 2.5 X upper limit of normal (ULN);
total bilirubin < 1.5 X ULN; absolute neutrophil count (ANC) > 1,500 cells/µl;
hemoglobin > 10 g/dl (without transfusions); platelet count > 100,000/µl; serum
albumin within normal limits (WNL).

Exclusion Criteria:

- Stage III (lymphostatic elephantiasis) lymphedema

- Clinical evidence of bilateral lymphedema. Those patients who have undergone
bilateral breast cancer surgery or prophylactic mastectomy on the non-cancerous
breast will be excluded.

- Any prior history of deep venous thrombosis (DVT) or pulmonary embolus (with the
exception of prior line-related thrombotic events) or myocardial infarction (MI),
cerebrovascular accident (CVA) or any other arterial thromboembolic event (i.e.,
transient ischemic attack [TIA], reversible ischemic neurologic deficit [RIND],
history of angina pectoris, clinically significant peripheral vascular disease with
claudication, etc.)

- Patients with problems with wound healing (e.g., diabetic ulcers), gastrointestinal
fistula

- Patients receiving therapeutic anti-coagulation including full dose aspirin or
non-steroidal anti-inflammatory agents known to inhibit platelet function (low dose
coumadin for port prophylaxis and low dose aspirin are allowed)

- Untreated hypertension with a baseline systolic blood pressure (SBP) of > 150 mmHg or
a diastolic blood pressure (DBP) >100 mmHg will be excluded (stable treated
hypertension with values less than those noted will be eligible).

- A history of infectious complications of the involved arm or those with any
contraindication to MLD + CB [e.g., congestive heart failure (CHF), DVT, acute or
chronic renal failure] will be excluded.

- Women with a history of CHF [New York Heart Association (NYHA) Class II or greater]
will be excluded.

- Pregnant or breast-feeding

- Unwilling to use an appropriate form of barrier contraception for the duration of the
study and for three months following the last dose of bevacizumab

- Those patients who are actively undergoing MLD and/or CB at the time of study entry
and for up to 4 weeks prior to entry

- Unable to provide written informed consent or to comply with study procedures

- Baseline urine protein : creatinine ratio > 1.0

- Known evidence of a bleeding diathesis or coagulopathy