Letrozole and Lapatinib Followed by Everolimus in Women With Advanced Breast Cancer

This is a single-institution clinical trial. Patients will be stratified according to the
HER2 status:

Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue

In the first part of the study, all of the patients will receive the combination of lapatinib
1,500 mg/day and letrozole 2.5 mg/day. We do not expect any significant toxicity from this
combination since the previous study of lapatinib and letrozole showed that this combination
is safe with no grade 3-4 toxicities observed. Restaging scans (CT scan, MRI, or bone scan)
will be obtained after every 12 weeks of treatment. In those patients who progress from any
group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250
mg/day as per the SWOG phase I study of lapatinib and everolimus. The outcome of each group
will continue to be assessed separately. We do not expect to see additional serious toxicity
from adding everolimus to the combination of lapatinib and letrozole. All of the treatment
will be continued until disease progression.

Inclusion Criteria:

- Female greater than or equal to 18 years.

- Histologically confirmed breast adenocarcinoma with incurable progressing
local-regional or metastatic.

- ER and/or PR positivity of primary and/or secondary tumor.

- Patients must have measurable or evaluable disease.

- Evidence of disease progression or relapse while on or less than 6 months off
aromatase inhibitors or tamoxifen either in adjuvant or first line metastatic setting.

- Postmenopausal

- Patients may have received up to one prior chemotherapy regimen for stage IV breast
cancer. Prior chemotherapy in the adjuvant and/or neoadjuvant setting is permitted.
Chemotherapy must be finished at least 2 weeks prior to enrollment.

- ECOG performance status <2

- Fasting cholesterol ≤300 mg/dL OR ≤7.75 mmol/LAND fasting triglycerides ≤ 2.5 x ULN
despite appropriate treatment.

- Patients must have adequate organ function as defined by the protocol.

- Stratification 1:

- HER2 positive in the primary or secondary tumor tissue

- Prior trastuzumab therapy is allowed but NOT required. However, trastuzumab
should be discontinued at least 3 weeks prior to enrollment.

- Stratification 2:

- HER2 negative in the primary or secondary tumor tissue

Exclusion Criteria:

- Patients receiving any other investigational agents.

- Prior exposure to lapatinib, everolimus, or other mTOR inhibitors.

- History of allergic reactions or hypersensitivity to compounds similar to everolimus,
lapatinib, or letrozole.

- Patients who have any severe and/or uncontrolled medical conditions that could affect
their participation such as:

- Left ventricular ejection fraction (LVEF) < 50%

- Unstable angina, symptomatic congestive heart failure, myocardial infarction
within 6 months, serious uncontrolled cardiac arrhythmia or any other clinically
significant cardiac disease.

- Severely impaired lung function as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or O2 saturation that is ≤ 88% at rest on room
air.

- Uncontrolled diabetes

- Active or uncontrolled severe infection

- Patients with QTc interval > 0.47 seconds.

- Significant chronic or acute gastrointestinal disorder with diarrhea as a major
symptom.

- Prior exposure to more than 360 mg/m2 doxorubicin, more than 120 mg/m2mitoxantrone, or
more than 90 mg/m2idarubicin, or elevated baseline cardiac troponin I.

- Patients with active CNS metastasis and/or carcinomatous meningtitis. However,
patients with CNS metastasis who have completed a therapy and are clinically stable
for 3 weeks as defined as: (1) no evidence of new or enlarging CNS metastasis and (2)
off steroids and/or anticonvulsants.

- Patient is known to be HIV, Hepatitis B, or Hepatitis C-positive (these tests are not
required).

- Patients with current active hepatic or biliary disease (with exception of patients
with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic
liver disease).

- Patients with INR ≥ 2 or PTT ≥ 2 x upper normal limit.

- Previous or current systemic malignancy other than breast cancer within the past 3
years other than carcinoma in situ of the cervix or basal/squamous carcinoma of the
skin.