ZoNantax - Zolendronic Acid as Neoadjuvant Therapy Plus Anthracycline and Taxane in Locally Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the association of zoledronic acid with standard treatment with anthracycline followed taxane plus trastuzumab in locally advanced breast cancer HER 2 positive.

Detailed Description
-----------------
This trial combines zolendronic acid with anthracycline followed taxane plus trastuzumab for neoadjuvant treatment of HER 2 positive stage II/III breast cancer. Zoledronic acid (ZOL) has activity of anti-bone resorption and shows diverse anti-tumor effects in vitro. Some chemical and biological characteristics of ZOL indicate potential for inhibition of tumor growth in pre clinical studies The primary objective of the study is to evaluate the residual cancer burden (RCB) with the addition of zolendronic acid to standard neoadjuvant therapy. RCB is calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size). RCB index is a significant predictor of distant relapse-free survival, and can be used to define categories of near-complete response and chemotherapy resistance after neoadjuvant chemotherapy compared with currently used risk factors. Additionally, the study will collect tissue biopsies and blood before and after treatment in order to correlate clinical outcomes with gene expression and radiologic data to predictive response.

Official Title
-----------------
Phase II Clinical Trial of Neoadjuvant Treatment With Zolendronic Acid Plus Anthracycline and Taxane in Locally Advanced Breast Cancer

Conditions
-----------------
Breast Cancer, Breast Disease, Neoplasms, Neoplasms by Site

Intervention / Treatment
-----------------
* Drug: Zo-Nantax


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Stage IIA to IIIB HER-2 positive breast cancer ECOG performance ≤ 2 Adequate hematologic function with: Absolute neutrophil count (ANC)> 1500/mm³ Platelets ≥ 100.000/mm³ hemoglobin ≥ 9g/dL Adequate hepatic and renal function with: Serum bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤ 2.5 x the institutional upper limit of normal (ULN) Alkaline phosphatase )≤ 2.5 x the institutional upper limit of normal (ULN) Serum creatinine ≤ 1.5 x the institutional upper limit of normal (ULN) or calculated creatinine clearance > 50 mL/min Adequate cardiac function Left ventricular ejection fraction (LVEF)with institutional normal range Knowledge of the investigational nature of the study and ability to provide consent for study participation Exclusion Criteria: Previous diagnostic of breast or other cancer Pregnancy Metastatic breast cancer Bilateral, synchronous breast cancer Any other disease(s), psychiatric condition, metabolic dysfunction, that contraindicates the use of study drugs or that woud make the patient inappropriate for this study Neuropathy grade > 2 by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zometa neoadjuvant HER2 breast cancer<br>Zo-Nantax arm - Neoadjuvant chemotherapy with association of zoledronic acid and standard treatment with anthracycline followed taxane plus trastuzumab in locally advanced breast cancer HER2 positive HR positive/negative. Drug:Cyclophosphamide Drug:Adriamycin Drug:Docetaxel Drug:Trastuzumab Drug:Zolendronic acid | Drug: Zo-Nantax<br>* Experimental: AC,Docetaxel,Trastuzumab,Zolendronate Drug: AC Adriamycin 60mg/m2 IV plus cyclophosphamide 600mg/m2 every 21 days for 4 cycles Drug: Docetaxel Docetaxel 100 mg/m2 every 21 days for 4 cycles. Drug: Trastuzumab Trastuzumab 8mg/kg [loading dose] once then 6mg/kg IV every 21 days for 3 cycles plus docetaxel. Drug: zolendronic acid Zolendronic acid 4mg IV every 21 days for 8 cycles combine with chemotherapy<br>* Other names: Zometa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the residual cancer burden (RCB) | Use MD Anderson calculator to quantify the minimal residual disease | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessing the tolerance to standard neoadjuvant treatment plus zolendronic acid,according to the common toxicity criteria Terminology Criteria for Adverse Events version 3.0. | CTC 4.0 | 6 months | 
| Assessment of the difference in gene expression according to treatment response | Through microarray assays | 6 months | 
| Prediction of pathological response by MRI calculated from the sequence of apparent diffusion coefficient (ADC) | Make MRI before the start of chemotherapy, after the second cycle and before surgery, and evaluate the changes in the diffusion of water | 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoadjuvant therapy, Breast cancer HER2 positive, zolendronic acid