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Randomized Phase II Trial of Anastrozole Combined With Novel Agent ZD6474 in the Neoadjuvant Treatment of Postmenopausal Patients With Hormone Receptor-Positive Breast Cancer

Phase 2
18 Years
Not Enrolling
Breast Cancer

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Trial Information

Randomized Phase II Trial of Anastrozole Combined With Novel Agent ZD6474 in the Neoadjuvant Treatment of Postmenopausal Patients With Hormone Receptor-Positive Breast Cancer

The use of adjuvant chemotherapy and endocrine therapy has had a significant impact on
breast cancer survival. However, not all patients will benefit from each of these therapies.
Increasing data suggests that patients with hormone receptor-positive breast cancer derive
marginal benefit from the addition of adjuvant chemotherapy. Identification and
characterization of cellular signaling pathways active in the pathogenesis of breast cancer
has lead to the development of multiple targeted therapies that hold enormous promise for
patients with less toxicity than conventional chemotherapy. Treatment strategies employing
neoadjuvant therapy have found that pCR is predictive for ultimate outcome. Due to this, the
use of neoadjuvant therapy has become an intense area of investigation in operable breast
cancer. In the IMPACT trial, the aromatase inhibitor anastrozole was found to improve
eligibility for breast conservation and was associated with a favorable clinical objective
response after 12 weeks of therapy.

In this proposed study, we plan to study the combination of ZD6474, a dual inhibitor of EGFR
and VEGFR-2, with anastrozole in the neoadjuvant setting for patients with Stage I-III
breast cancer. The aim is to overcome mechanisms of resistance and simultaneously block
multiple critical signaling pathways known to stimulate breast cancer. The two agents have
non-overlapping toxicities and are both administered orally, allowing for a more tolerable
treatment regimen. By using this combination in the neoadjuvant setting, we will target the
critical signaling pathways early and follow tumor responses during therapy, allowing for
prompt evaluation of the effectiveness of this treatment strategy. Pathologic tumor
specimens obtained at the time of definitive surgery will be evaluated for pathologic
complete response thus adding to the body of literature. By examining molecular markers such
as ER, PR, EGFR, and Ki-67 pre- and post-treatment, we hope to correlate modulations in
these biomarkers to response. Finally, using a novel second generation functional breast
MRI we will investigate the ability of MRI to predict response to antiangiogenic therapy.

Inclusion Criteria:

- Histologically confirmed invasive, hormone receptor-positive (ER
and/or PR positive) breast cancer

- Stage I-III breast cancer including any primary tumor >= 1cm by ultrasound

- Diagnosis by core needle biopsy with placement of metallic clip at tumor site

- Sentinel lymph node biopsy (US-guided FNA may be substituted if palpable axillary

- Evaluation by a surgeon to determine eligibility for breast conservation

- Postmenopausal status (age >= 60, age < 60 and FSH and estradiol in the
postmenopausal range, prior bilateral oophorectomy)

- Serum creatinine < 1.5 x ULN or creatinine clearance > 50 mL/minute (calculated by
Cockcroft-Gault formula.)

- Serum bilirubin < 1.5 x ULN

- Serum potassium must not be less than 4mmol/L (supplementation allowed)

- Serum calcium or magnesium within normal range (supplementation allowed)

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <= 2.5 x ULN or
alkaline phosphatase (ALP) <= 2.5 x ULN

- ECOG Performance Status 0,1,2

- ECG QTc < 480 msec

- Measurable disease

- Written, informed consent

Exclusion Criteria:- Inflammatory breast cancer

- Metastatic breast cancer excluding disease in regional lymph nodes

- Inoperable disease considered irreversible with neoadjuvant endocrine therapy

- HER2-overexpressed breast cancer

- Prior chemotherapy or radiotherapy for the treatment of the current breast cancer

- Prior hormonal therapy for the treatment of the current breast cancer

- Prior surgical biopsy, lumpectomy, mastectomy for the current breast cancer

- Any concurrent condition which in the Investigator's opinion makes it inappropriate
for the patient to participate in the trial or which would jeopardize compliance with
the protocol

- Currently active diarrhea that may affect the ability of the patient to absorb ZD6474
or tolerate diarrhea

- Clinically significant cardiac event such as myocardial infarction; New York Heart
Association (NYHA) classification of heart disease >2 within 3 months before entry;
or presence of cardiac disease that, in the opinion of the Investigator, increases
the risk of ventricular arrhythmia.

- History of arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia (VT) or uncontrolled atrial
fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or
asymptomatic sustained VT. Atrial fibrillation controlled on medication is not

- Previous history of QTc prolongation as a result of another medication that required
discontinuation of that medication.

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death <40
years of age.

- Presence of left bundle branch block (LBBB).

- QTc with Bazett's correction that is unmeasurable, or >= 480 msec on screening ECG.
If a patient has QTc > = 480 msec on screening ECG, the screen ECG may be repeated
twice (at least 24 hours apart). The average QTc from the three screening ECGs must
be < 480 msec in order for the patient to be eligible for the study.

- Use of any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes or induce CYP3A4 function.

- Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 mm Hg or diastolic blood pressure greater than 100 mm hg).

- Previous or current malignancies of other histologies within the last 5 years, with
the exception of cervical carcinoma in situ and adequately treated basal cell or
squamous cell carcinoma of the skin.

- Major surgery within 4 weeks or incompletely healed surgical incision before starting
study therapy.

- Receipt of any investigational agents within 30 days prior to commencing study

- Previous enrollment or randomization of treatment in the present study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Tumor Objective Response Rate by Ultrasound

Outcome Time Frame:


Safety Issue:


Principal Investigator

Dr. Ellie Guardino MD/PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Stanford University


United States: Institutional Review Board

Study ID:




Start Date:

January 2008

Completion Date:

December 2011

Related Keywords:

  • Breast Cancer
  • Breast Neoplasms



Stanford University School of Medicine Stanford, California  94305-5317