Phase 2 Anastrozole and Vandetanib (ZD6474) in Neoadjuvant Treatment of Postmenopausal Hormone Receptor-Positive Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Vandetanib; Anastrozole
Intervention description: 300 mg daily; 1 mg daily
Intervention MeSH terms: Anastrozole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      In this 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.
    

Eligibility criteria:

        Inclusion Criteria:

        Histologically confirmed invasive, hormone receptor-positive (ER and/or PR positive) breast
        cancer

          -  Stage I-III breast cancer including any primary tumor ≥ 1 cm 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
             lymphadenopathy)

          -  Evaluation by a surgeon to determine eligibility for breast conservation

          -  Postmenopausal status (age ≥ 60 yo; or < 60 yo and FSH and estradiol in the
             postmenopausal range, prior bilateral oophorectomy)

          -  Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance > 50
             mL/minute (calculated by Cockcroft-Gault formula.)

          -  Serum bilirubin < 1.5 x ULN

          -  Serum potassium ≥ 4 mmol/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 excluded.

          -  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
             treatment

          -  Previous enrollment or randomization of treatment in the present study