Phase II Study With Trastuzumab + Paclitaxel in Locally Advanced HER2+ Tumors or Epirubicin + Taxotere in HER2- Tumors

Primary Objective: to determine the pathological complete response (pCR) and correlation with immune response.

Secondary Objectives:

• to determine the progression free survival (PFS) and overall survival (OS);
• to evaluate the safety of the treatment with particular attention to cardiac safety.

Inclusion Criteria:

• Histologically proven breast carcinoma evaluated for HER 2 status and immune status
• Locally advanced carcinoma (UICC stage II-III)
• Age < 70 years
• measurable lesions
• ECOG Performance Status 0-2
• Life expectancy > 3 months
• Adequate bone marrow and hepatic functions
• Creatinine Clearance > 40 ml/min
• Written informed consent
• Patients must be accessible for treatment and follow up

Exclusion criteria:

• Prior chemotherapy or hormonal treatments
• Brain metastases.
• Past or current history of neoplasm other than curatively treated.
• Concurrent treatment with other experimental drugs.
• Left Ventricular Ejection Fraction (LVEF) <50 %
• History of significant neurological or psychiatric disorders.

Treatment HER2 positive (defined as 3+ at Herceptest or FISH/CISH positive) Herceptin 4mg/kg first time, then 2 mg/kg weekly with concomitant paclitaxel 80 mg/mq weekly (one cycle corresponding to 4 weeks) for 12 weeks (3 cycles). Clinical and instrumental evaluation, in responding patients continue for additional 12 weeks (total 6 cycles), then surgical excision

HER2 negative:

Epirubicin 90 mg/mq and docetaxel 75 mg/mq every 3 weeks for 4 cycles. Clinical and instrumental evaluation, in responding patients continue for additional 12 weeks (total 8 cycles), then surgical excision.

Main Parameters of Activity:

• Complete Remission (CR): complete disappearance of all previously detectable disease for a period of at least 28 days, and no new lesions.
• Partial Remission (PR): more than 30% reduction in the longest diameter of target lesions, and no new lesions.
• Stable Disease (SD): less than 30% reduction and less than 20% increase in the longest diameter of target lesions and no new lesions.
• Progressive Disease (PD): an increase in size of more than 20% of at least one lesion of previously documented disease. Or the appearance of disease at any site.
• Progression Free Survival (PFS) will be measured from the first day of the treatment until the first observation of disease progression or death due to any cause or the last date the patient was known to be progression free and alive.
• Overall Survival (OS) will be computed as the time between the first day of treatment and the date of death or the last date the patient was known to be alive.

Main Parameters of Safety:

• Adverse events, laboratory parameters.
• All toxicity will be graded using the NCI common toxicity criteria (Appendix II). Cardiac events (CHF) will be graded according to NYHA

Study procedure:

• At Baseline:
• Complete medical history, ECOG PS, physical examination (including a neurological examination, height, weight,),
• ECG
• Left ventricular ejection fraction evaluation (LVEF, evaluated by echocardiography).
• Blood chemistry (fasting blood sugar, transaminases, serum alkaline phosphatase, total bilirubin, total protein, albumin, creatinine, PT, fìbrinogen)
• Complete blood count and differential
• Calculated Creatinine Clearance/24 h
• Chest X- ray
• Abdomen computer tomography (CT) or ultrasound
• Bone scan and X-ray (if appropriate)
• Written informed consent.
• During Treatment - Every Cycle:
• Blood chemistry
• Complete blood count and differential
• Toxicity evaluation
• Physical examination
• During Treatment - Every 12 weeks (3-4 cycles):
• Breast ultrasound
• Surgical and medical evaluation
• Left ventricular ejection fraction evaluation (LVEF) evaluated by echocardiography
• ECOG PS
• Before surgery:
• Mammography, Ultrasound and Magnetic resonance
• Long term Follow up - Every 3 months for the first 2 years, every 6 months years 3-5 then yearly
• Survival

Statistical Considerations:

The aim of this phase II clinical trial is to detect 20% improvement in the pCR (i.e., from 25% to 54%). Simon's methods will be used to calculate sample size. Accrual of 46 patients has been planned considering a 80% of power to detect a 20% difference (two-sided type I error =0.05). The Chi-square test and Fisher's exact test will be used for qualitative parameters.