Letrozole and Lapatinib Followed by Everolimus in Women With Advanced Breast Cancer
Condition: Breast Neoplasms; Endocrine Breast Diseases; Neoplasm Metastasis
MeSH terms: Neoplasms; Neoplasm Metastasis; Breast Neoplasms; Breast Diseases
Intervention: letrozole; lapatinib; everolimus
Intervention description: Drug is are to be taken orally. 2.5 mg once daily; Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression); Drug is to be taken orally. 5 mg once daily.
Intervention MeSH terms: Everolimus; Letrozole; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: sequential treatment assignment, no masking is done
Masking: None (Open Label)
Masking description: No masking was done
Enrollment: 7.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: endocrine resistant; everolimus; lapatinib; letrozole

Summary:

      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.
    

Eligibility criteria:

        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.