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
- 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
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.
Allocation: Randomized, Primary Purpose: Treatment
Neelima Denduluri, MD
National Cancer Institute (NCI)
United States: Food and Drug Administration
|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|