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

• Status: Terminated
• Trial end date: 2013-12-01
• Target enrollment: 0
• Participant gender: Female

Summary

Target Population: female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy.

The study rationale is based on the potentiality of reversing endocrine-resistance by Lapatinib

• Activity on compensatory-adaptive mechanisms of hyperactivity of signals generated by HER2 family

• Modulation of energy balance and signals associated to survival through AMPK activation (via Calmodulin) Metformin

• Indirect mechanism, through reduced insulin receptors and IGFR stimulation, with reduces proliferative effects downstream

• Direct mechanism, through AMPK activation (via LKB1), with reduced protein synthesis (mTOR inhibition) and increased availability of intracellular energy Lapatinib and Metformin

• AMPK "Double"activation, through different potentially additional mechanisms.

• Inhibition of proliferative mechanisms for interference on various intracellular target

• IR (A e/o B); IGFR

• EGFR; HER2

Primary objectives :

1. To assess the rate of patients free from disease progression at 3 months from randomization

Secondary objectives :

1. To assess the overall response rate

2. To assess the duration of response

3. To assess 3-years overall survival rate

4. To assess tolerability of each proposed treatment Female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy will randomized to receive: hormonal therapy + lapatinib or hormonal therapy + metformin or hormonal therapy + metformin + lapatinib with a ratio 1:1:1.

For each arm of the study the following sample size is required:

• First step: 23 patients, for a total of 69 patients in all 3 arms

• Second step: further 33 patients, for a total of 168 patients in all 3 arms.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fondazione Michelangelo
• Treatments: Lapatinib; Metformin

Criteria

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