RATIONALE: Monoclonal antibodies such as bevacizumab and trastuzumab can block tumor growth in different ways. Some monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Others may stop the growth of tumor cells by stopping blood flow to the tumor. Combining bevacizumab with trastuzumab may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of combining bevacizumab with trastuzumab in treating women who have relapsed or metastatic breast cancer.

Condition	Treatment or Intervention	Phase
recurrent breast cancer stage IIIC breast cancer stage IV breast cancer stage IIIB breast cancer	Drug: bevacizumab  Drug: trastuzumab  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: growth factor antagonist therapy  Procedure: monoclonal antibody therapy	Phase I Phase II

OBJECTIVES: Primary

• Determine the maximum tolerated dose or recommended phase II dose of bevacizumab when combined with trastuzumab (Herceptin®) in women with relapsed or metastatic HER2/neu-overexpressing adenocarcinoma of the breast. (Phase I)
• Determine the feasibility and safety of this regimen in these patients. (Phase I)
• Determine the pharmacokinetics and pharmacodynamics of this regimen in these patients. (Phase I)
• Determine the clinical efficacy of this regimen, in terms of the objective response rate, time to tumor progression, prolonged disease stabilization (> 6 months), and overall survival, in these patients. (Phase II)

Secondary

• Determine the clinical safety and toxic effects of this regimen in these patients.
• Determine the efficacy of this regimen, in terms of clinical activity, in these patients.

OUTLINE: This is a phase I, dose-escalation study of bevacizumab followed by a non-randomized, open-label, multicenter phase II study.

• Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day 1 and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on day 8. Treatment continues for up to 2 years in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
• Phase II: Patients receive trastuzumab (Herceptin®) and bevacizumab as in phase I at the MTD. Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-74 patients (3-24 for phase I and 37-50 for phase II) will be accrued for this study.

Ages Eligible for Study:  18 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast
• Locally or regionally relapsed and surgically unresectable OR metastatic disease
• No newly diagnosed untreated stage IIIB breast cancer
• HER2/neu gene amplification by fluorescence in situ hybridization
• Bidimensionally measurable disease
• Site of measurable disease must be completely outside radiotherapy port OR there must be proof of progressive disease (i.e., new lesion[s] OR ≥ 25% increase in an index lesion)
• No more than 3 different metastatic sites (e.g., lung, breast, skin, liver)
• No more than 50% liver involvement by metastasis
• No symptomatic pulmonary metastasis
• No history or evidence of CNS disease (e.g., primary brain tumor or any brain metastases) by physical examination
• Hormone receptor status:
• Not specified

PATIENT CHARACTERISTICS: Age

• 18 to 75

Sex

• Female

Menopausal status

• Not specified

Performance status

• ECOG 0-2

Life expectancy

• More than 3 months

Hematopoietic

• WBC > 3,000/mm^3
• Platelet count > 75,000/mm^3
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
• No bleeding diathesis or coagulopathy

Hepatic

• Bilirubin ≤ 2.0 mg/dL
• AST or ALT ≤ 2.5 times upper limit of normal (ULN) (< 5 times ULN if liver metastases are present)

Renal

• Creatinine ≤ 2.0 mg/dL
• No proteinuria OR < 500 mg of protein on 24-hour urine collection

Cardiovascular

• LVEF normal by MUGA or echocardiogram
• No uncontrolled hypertension
• No myocardial infarction
• No unstable angina
• No New York Heart Association class II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No peripheral vascular disease ≥ grade 2 within the past year
• No other clinically significant cardiovascular disease

Pulmonary

• Oxygen saturation ≥ 90% on room air by pulse oximetry or arterial blood gas

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3-6 months after study participation
• No serious nonhealing wound, ulcer, or bone fracture
• No active infection requiring parenteral antibiotics
• No significant traumatic injury within the past 4 weeks
• No uncontrolled seizures
• No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that would preclude study participation
• No other invasive malignancy within the past 5 years except basal cell skin cancer

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior trastuzumab (Herceptin®) in the adjuvant or metastatic setting (phase II)
• Prior trastuzumab in the adjuvant or metastatic setting allowed for patients enrolled in the phase I portion of the study
• No prior bevacizumab
• No concurrent routine prophylactic hematopoietic colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or interleukin-11)
• No other concurrent biologic therapy

Chemotherapy

• Recovered from prior chemotherapy
• No prior chemotherapy in the metastatic setting (phase II)
• Prior chemotherapy in the metastatic setting allowed for patients enrolled in the phase I portion of the study
• No concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy

Surgery

• At least 4 weeks since prior major surgical procedure or open biopsy and recovered
• More than 7 days since prior fine needle aspiration
• More than 7 days since prior portacath placement
• No concurrent major surgical procedure

Other

• More than 10 days since prior and no concurrent oral or parenteral anticoagulants except to maintain patency of pre-existing permanent indwelling IV catheters
• More than 10 days since prior and no concurrent aspirin > 325 mg/day
• More than 4 weeks since prior and no concurrent participation in another experimental drug study
• No other concurrent anticancer therapy

California
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States; Recruiting

Study chairs or principal investigators

Mark D. Pegram, MD,  Study Chair,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000389159; UCLA-0109030-03
Record last reviewed:  September 2004
Record first received:  October 6, 2004
ClinicalTrials.gov Identifier:  NCT00093535
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-05