Sunitinib in Treating Patients With Newly Diagnosed Stage II or Stage III Breast Cancer That Can Be Removed by Surgery

OBJECTIVES:

Primary

• Determine the feasibility of neoadjuvant sunitinib malate in patients with newly diagnosed, resectable stage II-IIIA breast cancer.

Secondary

• Determine the nature, severity, and frequency of adverse events in patients treated with this drug.
• Determine the response rate in patients treated with this drug.
• Evaluate markers of angiogenesis (e.g., VEGF receptor, platelet-derived growth factor receptor, circulating plasma VEGF, sVEGFR-2, sVEGFR-3, sKIT, and tumor vascularity) both pre- and post-treatment.
• Examine the role of both host- and tumor-specific genes pertaining to response and toxicity.
• Compare tumor vascular parameters pre- and post-treatment using DCE-MRI.
• Compare cell death and tumor microcirculation pre- and post-treatment using contrast-enhanced spectroscopic and microbubble contrast-enhanced ultrasound.
• Compare tumor metabolic activity pre- and post-treatment using fludeoxyglucose F 18-PET.

OUTLINE: This is a multicenter study.

Patients receive oral sunitinib malate once daily for 14-21 days in the absence of disease progression or unacceptable toxicity.

Tissue samples are obtained by needle biopsy at baseline and once between days 14-21. Blood samples are collected at baseline, once between days 14-21, and at 4 weeks post-treatment for pharmacodynamic and other studies. Markers of angiogenesis (VEGF receptors, platelet-derived growth factor receptor, VEGF, sKIT, and tumor vascularity) are detected by immunohistochemistry. DCE-MRI and fludeoxyglucose F 18-PET are conducted for research studies at baseline and once between days 14-21.

After completion of study treatment, patients are followed at 4 weeks.

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer

• Newly diagnosed disease
• Stage II-IIIA (T1c, T2, or T3) disease
• Unifocal disease
• Resectable disease
• Tumor must be suitable for multiple biopsies and imaging
• No prior breast cancer
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Male or female
• Menopausal status not specified
• ECOG performance status 0-1
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine normal
• Calcium ≤ 3 mmol/L
• Bilirubin normal
• ALT and AST ≤ 2.5 times upper limit of normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
• No QTc prolongation (defined as a QTc interval ≥ 500 msec) or other significant ECG abnormalities
• No history of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No prior or concurrent NYHA class II-IV cardiovascular disease
• No inadequately controlled hypertension (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg)
• No myocardial infarction, cardiac arrhythmia, stable or unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within the past 12 months
• No pulmonary embolism within the past 12 months
• No cerebrovascular accident or transient ischemic attack within the past 12 months
• No serious illness or medical condition that would preclude study compliance including, but not limited to, the following:

• History of significant neurologic or psychiatric disorder
• Active uncontrolled infection
• Serious or nonhealing wound, ulcer, or bone fracture
• No medical condition that could interfere with oral medication intake (e.g., frequent vomiting, malabsorption)
• No history of allergic reactions attributed to compounds with similar chemical composition to sunitinib malate
• No preexisting hypothyroidism unless patient is euthyroid on medication

PRIOR CONCURRENT THERAPY:

• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including the following:

• Azole antifungals (ketoconazole, miconazole)
• Verapamil
• Clarithromycin
• HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir)
• Erythromycin
• Delavirdine
• Diltiazem
• At least 12 days since prior and no concurrent CYP3A4 inducers, including the following:

• Rifampin
• Phenytoin
• Rifabutin
• Hypericum perforatum (St. John's wort)
• Carbamazepine
• Efavirenz
• Pentobarbital
• Tipranavir
• Phenobarbital
• No prior protein tyrosine kinase inhibitor
• No prior antiangiogenic agent
• No prior hormonal therapy, radiotherapy, chemotherapy, surgery, investigational therapy, or other therapy for breast cancer
• At least 12 days since prior and no concurrent cyclooxygenase-2 inhibitors (e.g., etoricoxib, valdecoxib, celecoxib, dual cyclooxygenase/lipid oxidation, and lumiracoxib)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent agents with proarrhythmic potential (e.g., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide)
• No other concurrent treatment for breast cancer
• No concurrent coumadin-derivative anticoagulants (e.g., warfarin)

• Anticoagulants at ≤ 2 mg/day for prophylaxis of thrombosis allowed
• Low molecular weight heparin allowed provided INR ≤ 1.5