AZD2171 and Combination Chemotherapy in Treating Women With Locally Advanced Breast Cancer

OBJECTIVES:

Primary

• Determine the overall pathologic complete response rate in women with previously untreated, locally advanced breast cancer treated with neoadjuvant AZD2171, doxorubicin hydrochloride, cyclophosphamide, and docetaxel.

Secondary

• Compare changes in pretreatment levels of pKDR after 1 course of AZD2171 vs no medication.
• Determine the number of patients who respond to combination therapy beginning with the second course of therapy.
• Determine the clinical response rate in patients treated with this regimen.
• Determine the safety of this regimen in these patients.
• Determine the changes in tumor proliferation (Ki67) in these patients.
• Determine the pharmacokinetics and pharmacogenetics of this regimen in these patients.
• Correlate angiogenic parameters with tumor response in these patients.
• Determine tumor vascularity and permeability before and after treatment as seen on dynamic contrast-enhanced MRI and initial area under the gadolinium curve.
• Determine tumor choline levels before and after treatment as measured by quantitative single-voxel MR spectroscopy and correlate with response.

OUTLINE: This is a multicenter, randomized, pilot study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral AZD2171 once daily on days 1-7* during course 1. During the second and subsequent courses, patients receive oral AZD2171 once daily on days 1-21, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SC) on days 2-11 or pegfilgrastim SC on day 2. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

NOTE: *If biopsy cannot be scheduled prior to day 7 or 8 of course 1, AZD2171 alone can be continued for up to 14 days.

• Arm II (control): Beginning during the second course, patients receive AZD2171, doxorubicin hydrochloride, cyclophosphamide, docetaxel, and G-CSF or pegfilgrastim as in arm I.

All patients undergo tumor biopsiesat at baseline, before courses 2 and 4, and 3 weels after completion of study treatment. Tissue is examined for various biomarkers (phosphorylated-KDR, -MAPK, and -Akt, Ki67, VEGF, and p53) and for DNA ploidy analysis**.

NOTE: **Patients also undergo dynamic contrast-enhanced MRI and quantitative magnetic resonance spectroscopy 1 week before beginning therapy, 24 hours after starting therapy, prior to courses 2, 4, and 6, and 3 weeks after completion of study treatment.

After completion of AZD2171 and chemotherapy, patients undergo surgical resection.

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

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer, meeting 1 of the following criteria:

• Previously untreated disease
• Inflammatory disease
• Locally advanced breast cancer (stage IIIA, IIIB, or IIIC disease)
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion (longest diameter) ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan or breast MRI
• Accessible tumor tissue for serial biopsy
• No overexpression of HER2
• No known brain metastases secondary to breast cancer
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Karnofsky performance status 60-100%
• Life expectancy > 3 months
• Female only
• Menopausal status not specified
• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 8 g/dL
• Bilirubin normal (≤ 2 times upper limit of normal [ULN] if evidence of Gilbert's disease and elevated bilirubin not related to tumor or other liver disease)
• AST and ALT ≤ 2.5 ULN
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Proteinurea ≤ +1 on 2 consecutive dipsticks at least 1 week apart
• INR ≤ 1.5
• LVEF ≥ 50% by MUGA or echocardiogram without clinical symptoms or signs of heart failure
• Fertile patients must use effective contraception
• Not pregnant or nursing
• Negative pregnancy test
• No peripheral neuropathy ≥ grade 2
• No known CNS disease, including history of stroke or seizures not controlled by standard medical therapy
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel, doxorubicin hydrochloride, or cyclophosphamide
• No uncontrolled intercurrent illness including, but not limited to, any of the following:

• Hypertension
• Ongoing or active infection requiring IV antibiotics
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Peripheral vascular disease ≥ grade II
• Psychiatric illness/social situation that would preclude study treatment
• No nonhealing wounds or bone fractures within the past 28 days
• No history of an active malignancy except carcinoma in situ of the cervix or nonmelanomatous skin cancer in the past 5 years

PRIOR CONCURRENT THERAPY:

• No prior surgery, chemotherapy, or hormonal therapy for breast cancer
• No concurrent medication that may affect renal function (e.g., amphotericin B or pentamidine)
• No full-dose oral or parenteral anticoagulants or chronic daily treatment with aspirin (dose > 325 mg/day) within the past 10 days
• No other concurrent investigational agents
• No other concurrent commercially available drugs for this cancer
• No concurrent antiretroviral therapy for known HIV infection
• No major surgery within the past 28 days