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

It is a multicenter, open-label, two stage phase II trial, to assess activity, safety and potential early predictors of response in neoadjuvant setting. 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) with overexpression or amplification of HER2 (AJCC 7th edition 2010) are included in the study.

The primary objective is to evaluate the pathological complete response rate (pCR).

The secondary objectives are:

* to evaluate the clinical response rate (RR).
* to evaluate the feasibility and systemic tolerance, with particular attention to cardiac toxicity.
* to evaluate the conservative surgery rate.

Total duration of the trial is 36 months; 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.

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.

Eligibility Criteria:
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