Fulvestrant and/or Trastuzumab as First-Line Therapy in Treating Postmenopausal Women With Stage IV Breast Cancer

OBJECTIVES:

Primary

- Compare the overall objective response rate in postmenopausal women with estrogen
receptor (ER)- and/or progesterone receptor (PR)-positive, HER2/neu-overexpressing stage
IV breast cancer treated with first-line therapy comprising fulvestrant and/or
trastuzumab (Herceptin®).

Secondary

- Compare the duration of response in patients treated with these regimens.

- Compare overall survival of patients treated with these regimens.

- Compare the antitumor activity of these regimens, in terms of time to disease
progression, in these patients.

- Compare the clinical benefit of these regimens in these patients.

- Determine the safety and toxicity of these regimens in these patients.

- Correlate HER2/neu expression and ER and/or PR expression with response in patients
treated with these regimens.

OUTLINE: This is a randomized, controlled, open-label, multicenter study. Patients are
stratified according to prior adjuvant endocrine therapy (yes vs no). Patients are randomized
to 1 of 3 treatment arms.

- Arm I: Patients receive fulvestrant intramuscularly on days 1 and 15 of course 1 and
then on day 1 only in all subsequent courses.

- Arm II: Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes on days 1, 8,
15, and 22.

- Arm III: Patients receive fulvestrant as in arm I in combination with trastuzumab as in
arm II.

In all arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed every 8 weeks.

PROJECTED ACCRUAL: A total of 120 patients (40 per treatment arm) will be accrued for this
study.

Inclusion Criteria:

- Female patient, postmenopausal, defined as a woman fulfilling any one of the following
criteria:

- Age 60 years or older

- Age 45 years or older with amenorrhea for > 12 months with an intact uterus

- Follicle-stimulating hormone and estradiol levels within post-menopausal range

- Having undergone a bilateral oophorectomy

- Histologically or cytologically proven adenocarcinoma of the breast

- Subjects must have archived rumor tissue available to compare the clinical response
with tumor expression of biomarkers, such as HER-2, ER and PR; archived tissue will be
used to confirm HER-2, ER and PR status, but results will not be used to determine
subject eligibility for the study

- HER2-positive disease

- ER-positive and/or PR-positive disease

- ECOG performance status 0-2

- Life expectancy > 24 weeks

- Left ventricular ejection fraction > lower limit of normal

- No prior chemotherapy, endocrine therapy, Herceptin, or other biologic or
investigational therapy for metastatic breast cancer

- No more than two prior endocrine agents in the adjuvant setting as single- or
sequential-therapy is permitted, but no prior Faslodex therapy is permitted. A 1-month
treatment-free period is required prior to receiving the first dose of trial
treatments

- Prior adjuvant chemotherapy is permitted

- Prior adjuvant Herceptin permitted

- At least 1 month since prior surgery, radiotherapy, or endocrine therapy, with
complete recovery from the effects of these interventions

- Patients must have ended any hormone replacement therapy at least 1 month prior to
receiving the first dose of trial therapy

- Patients treated with bisphosphonates may enroll, with heir bone lesions only
assessable for disease progression

- Patient is accessible and willing to comply with treatment and follow-up

- Patient is willing to provide written informed consent prior to the performance of any
study-related procedures

- Required laboratory values:

- Absolute neutrophil count > 1.5 x 10^9/L

- Hemoglobin > 10g/dL

- Platelet count > 100 x 10^9/L

- Creatinine < 2.0 mg/dL

- Total bilirubin < 1.5 x upper limit of normal

- AST and ALT < 2.5 x ULN

Exclusion Criteria:

- Prior chemotherapy, hormonal therapy, Herceptin or other investigational therapy for
metastatic breast cancer

- Prior treatment with Faslodex

- Concurrent therapy with any other non-protocol anti-cancer therapy

- Current or prior history of brain metastases

- History of any other malignancy within the past 5 years, with the exception of
non-melanoma skin cancer or carcinoma-in-situ of the cervix

- Clinically significant cardiovascular disease, New York Heart Association Class II or
greater congestive heart failure, or serious cardiac arrhythmia requiring medication

- Prior exposure of > 360 mg/m2 doxorubicin or liposomal doxorubicin, > 120 mg/m2
mitoxantrone, > 90 mg/m2 idarubicin, or > 720 mg/m2 epirubicin

- Active, uncontrolled infection requiring parenteral antimicrobials

- The presence of any other medical or psychiatric disorder that, in the opinion of the
treating physician, would contraindicate the use of the drugs in this protocol or
place the subject at undue risk for treatment complications

- Inability to comply with the study protocol or follow-up procedures

- Known hypersensitivity to any of the drugs used in this protocol or to active or
inactive excipients of Faslodex

- History of bleeding diasthesis

- Long-term anticoagulant therapy other than anti-platelet therapy, such as with
warfarin