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

Treatment Plan Patient will continue to be treated with the same hormone therapy at the same dose, route and schedule

Patients will be randomized to receive:

A: Lapatinib, 1250 mg/die, os B: Metformin, 1500 mg/die, os C: Lapatinib + Metformin, 1250 mg+1500 mg/die, os Patients will receive study treatment until disease progression is documented, extraordinary medical circumstances occur, intolerable toxicities occur, or the patient withdraws consent

Statistical consideration Randomization will be stratified according to the site of metastases: visceral versus non-visceral lesions. The primary objective of this study is to evaluate the rate of patients free of disease progression at 3 months from randomization. The final analysis of this objective will be conducted when a total of 168 patients are enrolled across the three arms. This is the number of patients needed for a test with an experiment-wise alpha = 0.05 and power = 80% to show a statistically significant increment of 10% to the rate of patients without disease progression at 3 months, assuming a rate of 5% for treatments without lapatinib and/or metformin (P0=5% and P1=15%). After having accrued a total of 23 evaluable patients in each arm, the trial design can proceed to step 2 randomizing additional patients to each arm only if two or more patients are free of disease progression at 3 months. Otherwise, the study arm with less than expected responses will be discontinued. In the second stage 33 additional patients will be enrolled in each study arm to reach a total of 56 total patients per arm. If less than 6 patients per arm will be free of disease progression then the increment of corresponding treatment will be considered not significant.

Procedures:

The study will consist of a screening period, a treatment period and follow up for survival Screening Phase

Within 4 weeks prior randomization:

A signed written, informed consent will be obtained prior to any study specific assessments are initiated. The following will be performed prior to randomization

• Radiographic complete assessment of disease status (chest Xray; liver ultrasound, bone scan and CT or MR of target lesions and involved sites)
• Hematology and biochemistry
• Pregnancy test for women of child-bearing potential
• Cardiac assessment with ECG, echocardiography or multi-gated scintigraphic scan (MUGA)
• Medical history, physical examination, vital signs, signs and symptoms of breast cancer lesions, weight, height, ECOG performance status

Treatment Phase:

MONTHLY up to 3 months since randomization

• Physical examination, including clinical disease assessment, ECOG performance status, vital signs
• Hematology and biochemistry
• Safety evaluation (i.e. routine collection of adverse events)
• Patient's compliance
• Concomitant therapy

EVERY 3 MONTHS after the first 3 months of treatment until disease progression is documented, intolerable toxicities occur, or the patient withdraws consent:

• Physical examination, including clinical disease assessment, ECOG performance status, vital signs
• Radiographic disease assessment (using the same methods at screening)
• Hematology and biochemistry
• Safety evaluation (i.e. routine collection of adverse events)
• Concomitant therapy
• Patient's compliance

EVERY 6 MONTHS until disease progression is documented, intolerable toxicities occur, or the patient withdraws consent:

• Complete radiographic assessment
• Assessment of the LVEF using the same method at screening

Afterwards:

EVERY 6 MONTHS after disease progression or trial discontinuation due to intolerable toxicities or other reasons. Patients may receive other therapy following study discontinuation. Patients will continue to be followed for survival for a minimum of 3 years.