Randomized, Double Blind Multicenter Phase II Study of Time to Progression on Fulvestrant in Combination With Erlotinib or Placebo in Hormone Receptor-Positive Metastatic Breast Cancer (MBC) Subjects Who Progressed on First Line Hormonal Therapy

This is a multicenter, randomized, double-blind study of fulvestrant plus erlotinib versus
fulvestrant plus placebo for subjects with metastatic breast cancer whose disease progressed
after first line hormonal therapy.

- Total number of subjects planned for the trial is 130 subjects, that is, approximately
65 subjects in each arm.

- Subjects will be randomized to receive fulvestrant/erlotinib (arm A) or
fulvestrant/placebo (arm B) and stratified based on accrual center.

- The study is a parallel-arm double-blind study, with fulvestrant + placebo on the
monotherapy arm, and fulvestrant + erlotinib on the combination arm.

- The primary variable outcome is time to progression.

- Subjects whose metastatic disease was diagnosed more than 12 months after completing
adjuvant hormonal therapy are eligible to this study if their breast cancer is
hormone-receptor-positive and after disease progression on first line hormonal therapy
in the metastatic setting. Subjects may have received no more than one line of
chemotherapy. While receiving one line of hormonal therapy in the metastatic setting is
a requirement, receiving chemotherapy is not, and one line of chemotherapy in the
metastatic setting would not exclude these subjects from the trial. Subjects who had a
recurrence while on adjuvant hormonal treatment or within 12 months of completion of the
adjuvant hormonal treatment are also eligible without the need to receive first line
hormonal therapy in the metastatic setting.

Inclusion Criteria:

1. Subjects must sign a written consent.

2. Subjects must have estrogen- and/or progesterone-receptor-positive histologically
confirmed adenocarcinoma of the breast with recurrent or metastatic carcinoma of the
breast.

3. Baseline measurements and evaluations of involved sites should be performed as close
as possible to study entry, but must be within 4 weeks prior to randomization.

4. Subjects fulfilling one of the following criteria are eligible to participate in the
study: Subjects with measurable disease as per RECIST criteria. This is defined as at
least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded) as over 20 mm with conventional technique or as over 10 mm
with spiral CT scan or MRI. Subjects with bone lesions, lytic or mixed (lytic +
sclerotic), in the absence of measurable disease as defined by RECIST criteria. The
lytic component of at least one bone lesion should measure 20 mm with conventional
techniques or 10 mm with spiral CT scan or MRI. At least one bone lesion satisfying
these criteria must be outside any previously irradiated area.

5. All subjects must be postmenopausal females defined by:

Prior bilateral oophorectomy OR No menstrual period for 12 months or longer. If age 55
years or less and on tamoxifen within the prior 6 months, must have an estradiol level in
the postmenopausal range.

Exclusion Criteria:

1. Subjects must not have had more than 1 prior chemotherapy regimen for metastatic disease
and no chemotherapy within 3 weeks prior to randomization. 2. No concurrent chemotherapy is
allowed while on protocol therapy. Subjects whose adjuvant hormonal therapy was
discontinued more than 12 months ago must have had only 1 prior hormonal therapy for
metastatic disease. Subjects who relapsed while receiving adjuvant hormonal therapy or less
than 12 months after completing adjuvant hormonal therapy may be enrolled directly in the
trial.

3. No prior therapy with an estrogen receptor down-regulator (e.g. fulvestrant).
Non-protocol concurrent hormonal therapy is not allowed. Subjects must not have had prior
therapy with agents that target EGFR. Previous, but not concomitant, therapy with
trastuzumab (Herceptin) is allowed. Subjects must not receive trastuzumab (Herceptin)
within 3 weeks prior to randomization.

4. Subjects must have ECOG performance status of 0, 1, or 2. 5. Subjects must have adequate
hematologic, hepatic, and renal function defined by the following within 4 weeks prior to
randomization: Neutrophils > 1500/mm3 and platelets over 100,000/mm3 Total Bilirubin under
1.25 x Institutional upper limit of normal SGPT (ALT) and SGOT (AST) under 2.5 x
Institutional upper limit of normal if no demonstrable liver metastases or under 5 x
Institutional upper limit of normal in the presence of liver metastases Calculated
creatinine clearance over 30ml/min using the following formula: Ccr = (140 - age in years)
times (weight in kgs) times 0.085 72 x serum creatinine in mg/dL INR, PT and PTT under 1.5
x Institutional upper limit of normal.

6. Subjects must not be receiving therapy with anticoagulants or have other
contraindication to IM injections.

7. Subjects must be age over 18 years. 8. Subjects must not have a history of central
nervous system metastasis. 9. Subjects may receive concurrent radiation therapy to painful
sites of bony disease or areas of impending fracture as long as the radiation therapy is
initiated prior to study entry and sites of measurable disease outside the radiation
therapy port are available to follow.

10. Subjects must not take the following medications while enrolled in this trial:
ketoconazole, erythromycin, verapamil.

11. Subjects age less than 55 years must not be receiving LHRH agonists or antagonists
within 3 months prior to randomization.

12. Subjects who have an ocular inflammation or infection should be fully treated before
entry into the trial.

13. Subjects with a neuropathic keratopathy or diabetes or those with anterior basement
membrane disease must be advised of the need for frequent ophthalmologic exams.

14. Subjects who continue to wear contact lenses must be advised that they have an
increased risk of ocular events. The decision to wear contact lenses should be discussed
with the patient's treating oncologist and ophthalmologist.

15. Subjects must not suffer from medical or psychiatric conditions that would interfere
with protocol compliance, the ability to provide informed consent, or assessment of
response or anticipated toxicities.

16. Subjects must be disease-free of prior invasive malignancies for over 5 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix.