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

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.