A Study of Liposomal Doxorubicin+Docetaxel+Trastuzumab+Metformin in Operable and Locally Advanced HER2 Positive Breast Cancer

Multi-center, open-label phase II trial to assess activity of this chemotherapy scheme evaluated by pathologic complete response rate (pCR).

Planned treatment are 6 cycles of chemotherapy.

At every cycle (every 21 days) will be administered:

Day 1: Liposome-encapsulated doxorubicin, 50 mg/m2 IV 1 hour infusion; Day 2 and 9: Docetaxel, 30 mg/m2 IV 1 hour infusion; Day 2, 9 and 16: Trastuzumab 4 mg/kg for the first infusion loading dose, then 2 mg/kg/week for subsequent injections Day -13 to 0: Metformin is administered as single agent. From day -13 to day -11, Metformin 1000 mg will be administered once a day; from day -10 Metformin 1000 mg will be administered twice a day continuously until end of the study treatment.

Total duration of the trial: 36 months Enrollment period: 24 months Treatment: maximum of 6 cycles (5 months) per patient Follow-up for recurrence: every six months for 5 years, than once a year until 10 years after surgery.It's necessary to recruit 46 patients for clinical objectives evaluation.

Inclusion criteria

• Patients must have histologically confirmed breast cancer
• HER2 overexpressing cancer
• Patients with operable breast cancer (T1c and cytologically N1-2, or cT2-3, N0-N2, M0) or locally advanced breast cancer (T4a-d, N0-N2, M0) (AJCC 7th edition 2010).
• No prior therapy for breast cancer
• Both sexes, age ≥ 18 years and < 75 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy > 3 months
• Neutrophil count ≥ 2 x 109/ L, leukocytes count ≥ 3 x 109/ L and platelet count ≥ 100 x 109/ L
• Total bilirubin ≤ 1 upper-normal limits (UNL) of the Institutional normal values and alanine aminotransferase (ASAT (GOT) and/or alanine aminotransferase ALAT (GPT) ≤ 2.5 UNL, alkaline phosphatase ≤ 5 UNL. Patients with ASAT and/or ALAT > 1.5 UNL and alkaline phosphatase > 2.5 UNL aren't eligible for the trial.
• Creatinine ≤ 1.5 mg/dL
• Left ventricular ejection fraction (LVEF) ≥ 50% (evaluated by echocardiogram or multiple gated acquisition scan (MUGA) scan -only one method must be employed for each patient)
• Written informed consent
• Homa Index calculated using the Matthews'formula

Exclusion criteria

• Prior chemotherapy or radiotherapy for breast cancer.
• History of prior malignancy in the last 10 years (other than non-melanoma skin cancer or excised cervical carcinoma in situ).
• Other serious illness or medical condition
• Congestive heart failure or angina pectoris even if medically controlled. Previous history of myocardial infarction, uncontrolled high risk hypertension or arrhythmia
• History of significant neurologic or psychiatric disorders including dementia or seizures
• Active infection
• Concurrent treatment with other experimental drugs.
• Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
• Geographic inaccessibility to treatment and followup
• Pregnant and lactating women
• Diabetes-insulin dependant and non-insulin dependant