low accrual

About a third of patients with breast cancer are usually treated by hormone pills called tamoxifen and aromatase inhibitors. Aromatase inhibitors are drugs that stop female hormone production. Female hormone or estrogen is an important hormone for the growth of breast cancer cells. Letrozole is one of the aromatase inhibitors that is approved by the FDA and has been used to treat breast cancer since 1997. However, hormone pills usually work for about 6-10 months in most patients. Later on, breast cancer will start to grow again. This condition when hormone pills or endocrine therapy no longer work is called "endocrine resistant" breast cancer. The scientists here at University of Maryland have discovered how these cancer cells can become resistant to hormone pills. In our laboratory tests, the investigators found that lapatinib and everolimus can reverse this resistance and make letrozole work again. However, it is not known if the drugs can reverse the resistance in humans.

The purpose of this study is to find out whether the combination of letrozole, lapatinib, and everolimus is effective in women with breast cancer when hormone pills no longer work.

Lapatinib is an anti-cancer drug that is already approved by the Food and Drug Administration (FDA). It is the standard of care for the treatment of a particular type of breast cancer called human epithelial growth factor receptor 2 (HER2)-positive breast cancer. HER2 is a protein involved in the growth of some cancer cells. This study will also include patients with HER2-negative breast cancer. This means that the cancer cells in these patients do not depend on the HER2 protein. The use of lapatinib in these patients is considered experimental.

Everolimus is also an anti-cancer drug that is approved by the FDA for kidney cancer. Initial studies in mice and later studies in women with breast cancer have shown that everolimus may also slow the growth of breast cancer. The use of everolimus is experimental in this study.

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.

Adverse events including serious adverse events (SAEs) were collected from the start of study until 30 days after completion of last study drug dose on all study patients (7), but only 4 severe adverse events were noted as reported previously.

The trial was terminated due to low accrual.

No masking was done