Study to Evaluate Markers of Response in Locally Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to compare the association between image and certain molecular markers with complete response in patients with locally advanced breast cancer, treated with neoadjuvant chemotherapy composed of Bevacizumab, Docetaxel and Doxorubicin.

Detailed Description
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This is a pharmacogenomic phase II, multicenter, prospective clinical trial whose main objective is to evaluate the association of molecular and imaging markers with the response to bevacizumab administration in combination with docetaxel and doxorubicin as neoadjuvant chemotherapy in patients diagnose with locally advanced breast cancer.

Official Title
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A Multicenter Phase II Study, to Evaluate the Predictive Markers of Response in Locally Advanced Breast Cancer, Treated With Bevacizumab Combined With Neoadjuvant Chemotherapy

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Other: Bevacizumab, docetaxel and doxorubicin followed by surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Signed Informed consent form Ages between 18 and 70 12 months of life expectancy at least Histologically confirmed breast cancer No previous treatment for locally advanced breast cancer Her2+ o Her2- Disease measurable by PET and/or MRI ECOG 0-1 Adequate organic function Negative pregnancy test; fertile women must use anticonceptive methods after ICF and 30 days after last study drug administration Enough capability to follow the procedures and follow-up test included in the protocol Exclusion Criteria: Metastatic disease Inadequate health to receive the study chemotherapy Previous breast cancer treatment Pregnant or lactating women Major surgery or significative traumatic injure in the 28 days previous to inclusion, or during treatment. Minor surgery 24 hours before first bevacizumab infusion Concomitant or recent aspirin(>325mg/day)or clopidogrel(>75mg/day) treatment Concomitant or recent oral anticoagulant treatment History or evidence or bleeding diathesis or hereditary coagulopathy with bleeding risk Uncontrolled arterial hypertension Clinical significative heart disease, or uncontrolled severe arrhythmia disorder Unhealed wounds, peptic ulcer or bone fracture History of abdominal fistula, gastrointestinal perforation or intrabdominal abscess, 6 months before inclusion Evidence of any other disease, neurological or metabolical disorder or physical examination or laboratory finding related with any disease that makes the subjet ineligible for the study treatment or that put the subject in risk because of the study treatment. Psychiatric disorders that may prevent the subject to complete the study treatment Current participation in any other trial involving an investigational drug, or participation in any kind of trial 28 days before inclusion Chronical corticosteroid treatment Hypersensitivity reaction to bevacizumab or any of its components or any of the other study drugs or components Patients diagnosed with different neoplasms the previous 5 years excluding non melanoma skin cancer and resected cervical cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Bevacizumab, docetaxel and doxorubicin followed by surgery|The dosage form is Parenteral Injection (I/V) for all study drugs. Bevacizumab 15mg/kg in a single dose on day 1. Then 3 weeks later begin the cycles. On the day 1 of the cycle the patient receives Bevacizumab 15mg/kg, docetaxel 60mg/m2 and doxorubicin 50mg/m2. The cycles have a frequency of one every three weeks, and the protocol defines 4 cycles in total. The surgical procedure will be done 4-6 weeks after completion of chemotherapy.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of SNPs genotyping. | The analysis of genetic differences will be determined through analysis of single nucleotide polymorphisms. It will be assesed before starting the treatment using Affymetrix's Human Mapping 500k array set. | This evaluation will be performed within 14 days before start of treatment | 
| Assessment of tumoral response by Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) | The radiological interpretation of the images will evaluate size, shape, extent, distribution and kinetics of the lesons according to American College of Radiology Breast Imaging Reporting and Data System (ACR BIRADS- MRI (2003) guidelines). | This evaluation will be performed within 14 days before start of treatment (baseline assesment). | 
| Assessment of tumoral response by Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) | The radiological interpretation of the images will evaluate size, shape, extent, distribution and kinetics of the lesons according to American College of Radiology Breast Imaging Reporting and Data System (ACR BIRADS- MRI (2003) guidelines). | This evaluation will be performed within 12-19 days after first cycle | 
| Assessment of tumoral response by Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) | The radiological interpretation of the images will evaluate size, shape, extent, distribution and kinetics of the lesons according to American College of Radiology Breast Imaging Reporting and Data System (ACR BIRADS- MRI (2003) guidelines). | This evaluation will be performed within 12-19 days aftet fifth cycle. | 
| Positron emission tomography (PET) scan | It will be determined the association between tissue:blood activity ratio and hypoxic tumor volume by 18F-fluoromisonidazole positron emission tomography (FMISO-PET). DNA synthesis, assesed by [18F]-fluoro-3'-deoxy-3'-L-fluorothymidine PET (FLT-PET), will be compared to quantitative kinetics data adquired through previously described DCE-MRI. Finally, these results will be correlated with the Risk Score obtained in the genomic analysis | This evaluation will be performed within 14 days before start of treatment (baseline assesment) | 
| Positron emission tomography (PET) scan | It will be determined the association between tissue:blood activity ratio and hypoxic tumor volume by 18F-fluoromisonidazole positron emission tomography (FMISO-PET). DNA synthesis, assesed by [18F]-fluoro-3'-deoxy-3'-L-fluorothymidine PET (FLT-PET), will be compared to quantitative kinetics data adquired through previously described DCE-MRI. Finally, these results will be correlated with the Risk Score obtained in the genomic analysis | This evaluation will be performed within 12-19 days after first cycle | 
| Positron emission tomography (PET) scan | It will be determined the association between tissue:blood activity ratio and hypoxic tumor volume by 18F-fluoromisonidazole positron emission tomography (FMISO-PET). DNA synthesis, assesed by [18F]-fluoro-3'-deoxy-3'-L-fluorothymidine PET (FLT-PET), will be compared to quantitative kinetics data adquired through previously described DCE-MRI. Finally, these results will be correlated with the Risk Score obtained in the genomic analysis | This evaluation will be performed within 12-19 days aftet fifth cycle | 
| Evaluation of Genomic tissular profile in a sample of biopsy | A correlative analysis will be performed between the expression profile of the sample obtained by Affymetrix 's GeneChip Human Genome U133 and its association with tumor response (based on the imaging markers described previously) on the proposed stages (baseline, before first cycle of treatment and after fifth cycle of treatment | This evaluation will be performed within 14 days before start of treatment (baseline assesment | 
| Evaluation of Genomic tissular profile in a sample of biopsy | A correlative analysis will be performed between the expression profile of the sample obtained by Affymetrix 's GeneChip Human Genome U133 and its association with tumor response (based on the imaging markers described previously) on the proposed stages (baseline, before first cycle of treatment and after fifth cycle of treatment | This evaluation will be performed within 12-19 days after first cycle | 
| Evaluation of Genomic tissular profile in a sample of biopsy | A correlative analysis will be performed between the expression profile of the sample obtained by Affymetrix 's GeneChip Human Genome U133 and its association with tumor response (based on the imaging markers described previously) on the proposed stages (baseline, before first cycle of treatment and after fifth cycle of treatment). | This evaluation will be performed within 12-19 days aftet fifth cycle | 
| Evaluation of Proteomic expression in blood serum | To determine the proteomic expression in blood serum, a ZeptoMARK Reverse Array assay will be performed according to manufacturer's instructions. | This evaluation will be performed within 14 days before start of treatment (baseline assesment) | 
| Evaluation of Proteomic expression in blood serum | To determine the proteomic expression in blood serum, a ZeptoMARK Reverse Array assay will be performed according to manufacturer's instructions. | This evaluation will be performed within 12-19 days after first cycle. Description: | 
| Evaluation of Proteomic expression in blood serum | To determine the proteomic expression in blood serum, a ZeptoMARK Reverse Array assay will be performed according to manufacturer's instructions. | This evaluation will be performed within 12-19 days aftet fifth cycle. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Complete pathological response in surgical piece | To determine if a patient has undergone complete pathological response, an anatomo-pathological study will be conducted on the surgical piece. The evaluation will follow the Miller and Payne criteria; a complete response will be considered just in the absence of invasive tumor cells in breast and lymphatic nodules. | This evaluation will be performed within 20-22 weeks after start of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast, cancer, Pharmacogenomics, bevacizumab