A Phase II Study of Letrozole in Combination With Bevacizumab in Patients With Estrogen Receptor- and/or Progesterone Receptor-Positive Unresectable Locally Advanced and/or Metastatic (Stage IV) Breast Cancer
A Phase II Study of Letrozole in Combination With Bevacizumab in Patients With Estrogen Receptor- and/or Progesterone Receptor-Positive Unresectable Locally Advanced and/or Metastatic (Stage IV) Breast Cancer
RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. Giving bevacizumab together with letrozole may be an effective treatment for locally advanced or metastatic breast cancer.
PURPOSE: This phase II trial is studying how well giving bevacizumab together with letrozole works in treating postmenopausal women with locally advanced or metastatic breast cancer that cannot be removed by surgery.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study.
Patients receive bevacizumab IV over 30-90 minutes on day 1 and oral letrozole once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed carcinoma of the breast
Measurable or nonmeasurable disease
May have had stable or progressive disease after ≤ 2 prior conventional chemotherapy regimens for treatment of locally advanced or metastatic breast cancer
May have had stable or responding disease on prior nonsteroidal aromatase inhibitors (e.g., letrozole, anastrozole, or aminogluthemide)
May have had disease progression on other prior hormonal therapy (e.g., selective estrogen receptor modulators [SERMs], receptor downregulators [SERDs], or ovarian suppression) in the adjuvant or metastatic setting
No history or evidence of primary brain tumor or brain metastases by CT scan or MRI
Must have estrogen receptor- and/or progesterone receptor-positive tumor
PATIENT CHARACTERISTICS:
Rendered postmenopausal with ovarian suppression (ovarian suppression with a depot LH-RH agonist allowed) prior to the start of study treatment OR is already postmenopausal, as defined by 1 of the criteria:
No spontaneous menses for ≥ 12 months if the patient is ≥ 50 years old
Amenorrheic for ≥ 12 months if the patient is < 50 years old, with serum estradiol and follicle-stimulating hormone (FSH) levels within the institutional postmenopausal range
Bilateral oophorectomy
Patients who have had prior hysterectomy but intact ovaries must be ≥ 55 years old, or have serum estradiol and FSH levels within the postmenopausal range
Ongoing ovarian suppression with a depot LH-RH agonist
ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
Life expectancy > 3 months
Female only
Absolute neutrophil count ≥ 1,000/mm^3
Platelet count ≥ 75,000/mm^3
WBC ≥ 2,500/mm^3
AST and ALT ≤ 2.5 times upper limit of normal
Bilirubin normal
Creatinine normal OR creatinine clearance ≥ 60 mL/min
No proteinuria at baseline
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No presence of bleeding diathesis or coagulopathy
No history of allergic reaction to compounds of similar chemical or biologic composition to letrozole or bevacizumab
No serious, nonhealing wound, ulcer, or bone fracture
No unstable angina pectoris
No serious cardiac arrhythmia requiring medication
No uncontrolled hypertension
No myocardial infarction
No New York Heart Association class II-IV congestive heart failure
No peripheral vascular disease ≥ grade II within the past year
No other clinically significant cardiovascular disease
No history or evidence of other CNS disease by CT scan or MRI, including seizures not controlled with standard medical therapy or stroke
No gastrointestinal tract disease resulting in an inability to take oral medication
No requirement for IV alimentation
No significant traumatic injury within the past 28 days
No psychiatric illness or social situation that would preclude study compliance
No other uncontrolled intercurrent illness
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
No prior steroidal aromatase inhibitors (e.g., exemestane) unless administered in the adjuvant setting (not for metastatic disease) and ≥ 12 months have elapsed since last treatment
Any number of prior immunotherapies (e.g., trastuzumab [Herceptin^®] or vaccines) in the adjuvant or metastatic setting allowed
More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
More than 3 weeks since prior radiotherapy
More than 3 weeks since prior immunotherapy
More than 3 weeks since prior investigational therapy
More than 2 weeks since prior hormonal therapy except letrozole therapy or a luteinizing hormone-releasing hormone (LH-RH) agonist for ovarian suppression
No prior surgical procedures affecting absorption
More than 28 days since prior major surgery or open biopsy
At least 24 hours since prior placement of indwelling catheters
At least 10 days since prior and no concurrent full-dose oral or parenteral anticoagulants or thrombolytic agents except as required to maintain patency of preexisting, permanent indwelling IV catheters
No prior bevacizumab
No other prior KDR inhibitors (e.g., vascular endothelial growth factor [VEGF] Trap, SU5416, SU6668, ZD6474, vatalanib, AEE788, or IMC-1CII)
No other concurrent investigational agent
No concurrent chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory medications known to inhibit platelet function (e.g., cyclooxygenase-1 inhibitors)
Concurrent bisphosphonates (e.g., zoledronate or pamidronate) or growth factors allowed
No other concurrent anticancer agents or therapies