Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer

Inclusion Criteria:

1. Female patients with a histologically or cytologically confirmed adenocarcinoma of the breast progressing from prior hormonal therapy
2. Receptor positive disease (ER+ and/or PgR+)
3. HER2 negative
4. Pre- and post-menopausal status
5. Documented disease progression after first-line hormone therapy
6. Age ≥18 years.
7. Measurable or evaluable metastatic disease
8. Life expectancy > 3 months
9. ECOG Performance Status < 1

10. Adequate bone marrow, liver, and renal function as assessed by the following parameters:

    • Hemoglobin > 9.0 g/dl
    • Leucocytes count ≥ 3,000/mL
    • Absolute neutrophil count (ANC) ≥ 1.500/mL
    • Platelet count ≥ 100,000/mL
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement)
    • Albumine and total bilirubin ≤ 1.5 x ULN
    • Prothrombin Time (PT) < 70 %
    • Serum creatinine < 1.4 mg/ml, creatinine clearance > 70 ml/min
11. Normal Respiratory Function and Saturation level ≥ 90%
12. New York Hearth Association (NYHA) Classification ≤ 2 and baseline left ventricular ejection fraction (LVEF)≥ 50%
13. Patients must be willing and able to sign a written informed consent.

Exclusion Criteria:

1. Previous or concomitant treatment with lapatinib and/or metformin
2. More than one line of prior hormone therapy for metastatic breast cancer.
3. More than two lines of prior chemotherapy for metastatic breast cancer
4. Unique location of disease local-regionally treated (surgery, radiotherapy , other)
5. Disease progression not documented or less than 30%
6. Metastatic disease defined as aggressive at investigator's judgement (e.g. visceral disease more than >1/3 of involved parenchyma, symptomatic disease requiring intensive supportive measures or therapies not allowed by protocol)
7. Patients with brain metastasis
8. Osteosclerotic bone metastasis as unique disease site
9. Pathological tumor markers as unique sign of progressive disease
10. Concomitant treatment with any other anticancer drugs (biphosphonates are permitted)
11. Serious, not solved or unstable toxicity from previous treatment
12. Diabetes mellitus Type I and Type II
13. Renal insufficiency (creatinine ≥ 1.4 mg/ml)
14. Malabsorption syndrome or diseases that significantly may alter gastroenteric functions
15. Other serious illness or medical conditions judged by the investigator to be clinically significant that may adversely affect patient's participation in the trial or interfere with safety profile
16. Active clinically significant or uncontrolled infections (bacterial or viral)
17. Known history of unstable angina (angina symptoms at rest), cardiac ventricular arrhythmias clinically significant, myocardial infarction, stroke or congestive heart failure within 12 months prior to randomization
18. History of lactic acidosis
19. Evidence or symptoms of hepatic insufficiency
20. Chronic alcoholism
21. Concomitant treatment with amiodarone or any other agent that could interfere with study drugs
22. Known or suspected hypersensitivity or allergy to lapatinib, metformin or used excipients
23. Women who are pregnant or lactating
24. History of previous cancer, unless at low risk of relapse per investigator's judgement