Bevacizumab and Doxorubicin Hydrochloride Liposome in Treating Women With Locally Recurrent or Metastatic Breast Cancer

OBJECTIVES:

Primary

• Determine the safety and tolerability of bevacizumab and doxorubicin hydrochloride liposome in women with locally recurrent or metastatic breast cancer.

Secondary

• Determine the efficacy of this regimen in these patients.
• Identify surrogate markers of angiogenesis, including vascular endothelial growth factor (VEGF), VEGF receptor 1, and matrix metalloproteinase 9, in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive bevacizumab IV over 30-90 minutes and doxorubicin hydrochloride liposome IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for up to 6 courses*. Patients then receive bevacizumab alone IV over 30-90 minutes on days 1 and 15. Courses with bevacizumab repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients may receive additional courses of doxorubicin hydrochloride liposome at the discretion of the primary investigator.

Blood samples are collected at baseline, on day 1 of course 3 and then once every 3 months during study treatment, and after completion of study treatment. Samples are analyzed by enzyme-linked immunosorbent assay to determine the level of circulating angiogenesis-related molecules, including serum vascular endothelial growth factor (VEGF), VEGF receptor 1, and matrix metalloproteinase 9.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Cytologically or histologically confirmed breast cancer

• Metastatic OR locally recurrent disease
• Unresectable disease
• Not amenable to radiotherapy
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan

• Measurable disease must be outside irradiated areas
• ErbB2-negative disease by immunohistochemistry (negative or 1+) or fluorescent in situ hybridization (FISH)
• No known CNS metastases, even if previously treated
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Female
• Menopausal status not specified
• WHO performance status 0-1
• LVEF ≥ 55%
• Hemoglobin ≥ 10.0 g/dL
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin < 2 times upper limit of normal (ULN)
• ALT ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
• Alkaline phosphatase (AP) ≤ 2.5 times ULN

• AP > 2.5 times ULN and ≤ 6 times ULN allowed if ALT ≤ 1.5 times ULN
• AP > 6 times ULN allowed if ALT normal
• Creatinine ≤ 1.5 times ULN
• Proteinuria < 2+ by dipstick OR protein ≤ 1 g/24hr-urine collection
• INR ≤ 1.5 OR Quick ≥ 70%
• aPTT ≤ 1.5 times ULN
• No peripheral neuropathy > grade 2
• No history or evidence of hereditary bleeding diathesis or coagulopathy with the risk of bleeding
• No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 100 mm Hg, measured repeatedly at > 2 visits despite adequate treatment with ≥ 2 different antihypertensive drugs
• No clinically significant cardiovascular disease, including the following:

• Cerebrovascular accident or stroke within the past 6 months
• Myocardial infarction within the past 6 months
• Unstable angina
• New York Heart Association class II-IV congestive heart failure
• Serious cardiac arrhythmia (e.g., ventricular arrhythmia, high-grade atrioventricular-block) not controlled by medication or requiring medication which might interfere with regularity of the study treatment
• No serious nonhealing wound, active peptic ulcer, nonhealing bone fracture, or bleeding skin metastases
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• No active infection requiring IV antibiotics
• No known hypersensitivity to any of the study drugs or excipients
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
• No evidence of any other disease that contraindicates the use of an investigational drug, that may affect patient compliance with study routines, or places the patient at high risk for treatment-related complications including, but not limited to, the following:

• Metabolic dysfunction
• Physical examination finding
• Psychological dysfunction
• Clinical laboratory finding giving reasonable suspicion of a disease or condition
• No known CNS disease unrelated to cancer (e.g., uncontrolled seizures), unless adequately treated with standard medical therapy
• No high-risk factors for bleeding, including the following:

• Coagulation parameters outside range
• Need for concurrent anticoagulant therapy
• Insufficient time gap after surgical procedures
• No other malignancy within the past 5 years except for adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
• No significant traumatic injury within the past 28 days
• No known HIV positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study therapy

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy for metastatic or inoperable locally recurrent breast cancer
• No prior bevacizumab or other anti-vascular endothelial growth factor drug therapy
• No prior radiotherapy involving the heart (usual irradiation dose to breast or chest wall allowed)
• More than 12 months since prior neoadjuvant or adjuvant chemotherapy
• No neoadjuvant or adjuvant doxorubicin hydrochloride with cumulative dose > 360 mg/m² or epirubicin hydrochloride with cumulative dose > 720 mg/m²
• More than 6 months since prior adjuvant radiotherapy
• More than 28 days since prior major surgical procedure with high risk of bleeding
• More than 24 hours since prior minor surgical procedures
• More than 10 days since prior acetylsalicylic acid (> 325 mg/day) or clopidogrel bisulfate (> 75 mg/day)
• More than 10 days since prior and no concurrent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes

• Prophylactic use of anticoagulants allowed (e.g., for maintenance of venous catheter)
• More than 30 days since prior investigational therapies or participation in other investigational studies
• No concurrent hormonal therapy
• No other concurrent antineoplastic or antitumor therapy
• No other concurrent investigational drugs
• No concurrent radiotherapy
• No concurrent nonsteroidal anti-inflammatory drugs with activity on platelets and gastric mucosa (e.g., dipyridamole, clopidogrel bisulfate, acetylsalicylic acid)
• No anticipated need for major surgery during the course of the study treatment