Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Lapatinib; Letrozole; Trastuzumab
Intervention description: 1000 mg of Lapatinib by mouth daily; Letrozole, 2.5 mg by mouth daily (for hormone receptor positive participants only); 6 mg/kg intravenously, every 3 weeks
Intervention MeSH terms: Trastuzumab; Letrozole; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 128.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Locally Advanced Breast Cancer Neoadjuvant Endocrine

Summary:

      Breast cancer is the most common malignancy in the U.S. Targeted therapies such as tamoxifen
      have been revolutionary in reducing tumor recurrences and mortality in early breast cancer.
      Using this successful paradigm, there has been a continued search for other targeted biologic
      therapies directed at receptors with known potential for promoting tumor growth.

      The estrogen receptor (ER) and/or the HER signaling pathways are the dominant drivers of cell
      proliferation and survival in the majority of human breast cancers. Molecular targets of
      these pathways provide the most effective therapies in appropriately selected patients.
      However, de novo and acquired resistance remain major obstacles to successful treatment, and
      understanding the molecular pathways responsible for this resistance would enable the
      discovery of new strategies to overcome it.

      The superiority of multi-drug HER2-targeted therapy over single agent therapy has been
      demonstrated in the preclinical setting using mouse xenografts. Trastuzumab, pertuzumab,
      lapatinib, and gefitinib, represent a group of therapeutic agents that target the HER family
      by different molecular mechanisms. Used as single agents in the MCF7/HER2-18 xenograft model,
      these drugs restored or enhanced sensitivity to tamoxifen. However, tumor growth inhibition
      lasted only 2-3 months before resistance to treatments occurred. However, when gefitinib, a
      HER1 inhibitor, was added to the two-antibody (T+P) regimen to block signals from HER1
      dimers, a complete disappearance of nearly all xenograft tumors was observed; moreover, there
      was evidence of complete tumor eradication in 50% of the mice. The combination of lapatinib +
      trastuzumab was also highly effective in eradication of tumor burden, with no evidence of
      re-growth after 200 days. These xenograft models demonstrate that multi-drug HER2-targeted
      therapy more effectively induces apoptosis and inhibits proliferation, thereby resulting in
      tumor regression. Furthermore, HER2 combination therapy appears to more effectively reduce
      levels of phosphorylated pAKT and MAPK, thus resulting in sustained tumor inhibition.
    

Eligibility criteria:

        Inclusion Criteria:

          1. All patients must be female and at least 18 years of age.

          2. Signed informed consent.

          3. Locally advanced breast cancers are eligible. Locally advanced cancers must be of
             clinical and/or radiologic size >3 cm, or >2 cm with clinical evidence of axillary
             nodal involvement*. (If tumors are less than 3 cm, we will use the radiologically
             measured tumor size to determine if the tumor meets the minimal size requirements.)

          4. Patients must have histologically confirmed invasive mammary carcinoma that is HER2
             overexpressing, defined as 3+ by immunohistochemistry, or a FISH/CEP ratio greater
             than 2.

          5. Negative serum pregnancy test (HCG) within 7 days of starting study drug, if of
             child-bearing potential.

          6. Kidney and liver function tests - all within 1.5 times the institutional upper limit
             of normal.

          7. Performance status (WHO/ECOG scale) 0-1 and life expectancy >6 months.

          8. No evidence of brain or leptomeningeal disease, or any other Stage IV disease.

          9. No previous or current malignancies at other sites within the last 5 years, with
             exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri
             and basal or squamous cell carcinoma of the skin.

        Exclusion Criteria:

          1. Patients with bilateral breast cancer.

          2. Pregnancy or unwillingness to use a reliable contraceptive method in women of
             child-bearing potential.

          3. Severe underlying chronic illness or disease.

          4. Cardiomyopathy or baseline LVEF less than 50%.

          5. Other investigational drugs while on study.

          6. Severe or uncontrolled hypertension, history of congestive heart failure or severe
             coronary arterial disease.

          7. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel. Subjects with ulcerative colitis are also
             excluded

          8. Taking any lapatinib prohibited medication(s)

          9. Inability or unwillingness to comply with, or follow study procedures.

         10. Patients who have received any form of treatment for breast cancer within the past
             five years, including surgical resection, chemotherapy, endocrine therapy, or biologic
             therapy.

         11. Patients with a prior history of ipsilateral invasive breast cancer or carcinoma in
             situ who present with a new primary.

         12. Patients with known active, infectious Hepatitis B, Hepatitis C, or HIV.