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A Pilot Study to Evaluate The Effects of Neoadjuvant AZD2171, a VEGF Receptor Tyrosine Kinase Inhibitor With Docetaxel, Doxorubicin, and Cyclophosphamide Chemotherapy in Previously Untreated Locally Advanced Breast Cancer

18 Years
Not Enrolling
Breast Cancer

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Trial Information

A Pilot Study to Evaluate The Effects of Neoadjuvant AZD2171, a VEGF Receptor Tyrosine Kinase Inhibitor With Docetaxel, Doxorubicin, and Cyclophosphamide Chemotherapy in Previously Untreated Locally Advanced Breast Cancer



- 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.


- Compare changes in pretreatment levels of pKDR after 1 course of AZD2171 vs no

- 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.

Inclusion Criteria


- Histologically or cytologically confirmed breast cancer, meeting 1 of the following

- 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

- Accessible tumor tissue for serial biopsy

- No overexpression of HER2

- No known brain metastases secondary to breast cancer

- Hormone receptor status not specified


- 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

- 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

- 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


- No prior surgery, chemotherapy, or hormonal therapy for breast cancer

- No concurrent medication that may affect renal function (e.g., amphotericin B or

- 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

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Principal Investigator

Neelima Denduluri, MD

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Food and Drug Administration

Study ID:




Start Date:

January 2006

Completion Date:

July 2007

Related Keywords:

  • Breast Cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • inflammatory breast cancer
  • Breast Neoplasms



Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School New Brunswick, New Jersey  08903
Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support Bethesda, Maryland  20892-1182