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
N/A
Female
Breast Cancer
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
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.
Inclusion Criteria
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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Primary Purpose: Treatment
Principal Investigator
Neelima Denduluri, MD
Investigator Role:
Study Chair
Investigator Affiliation:
National Cancer Institute (NCI)
Authority:
United States: Food and Drug Administration
Study ID:
CDR0000466185
NCT ID:
NCT00310089
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
Name | Location |
|---|---|
| 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 |
