A Study of Bevacizumab (Avastin) in Combination With Neoadjuvant Treatment Regimens in Participants With Primary Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the effect of bevacizumab in combination with chemotherapy or endocrine therapy, as preoperative treatment, in participants with HER2 negative breast cancer. Participants will be randomized to receive either chemotherapy (FEC100: Epirubicine 100 milligrams per square meter [mg/m^2], 5-fluorouracil 600 mg/m^2, and cyclophosphamide 600 mg/m^2] for 12 weeks followed by taxane (paclitaxel/docetaxel) for 12 weeks or endocrine therapy (an aromatase inhibitor] daily for 24 weeks) with or without bevacizumab (15 milligrams per kilogram [mg/kg] as intravenous [IV] infusion every 3 weeks up 24 weeks).

Official Title
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A Multicenter, Randomized, Phase II Clinical Trial to Evaluate the Effect of Avastin in Combination With Neoadjuvant Treatment Regimens on the Molecular and Metabolic Characteristics and Changes in the Primary Tumors With Reference to the Obtained Responses in Patients With Large Primary HER2 Negative Breast Cancers

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Aromatase Inhibitor
* Drug: Bevacizumab
* Drug: Epirubicine
* Drug: 5-Fluorouracil (5FU)
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, HER2-negative, men or pre- or post-menopausal women with primary operable adenocarcinoma of the breast, greater than or equal to (>=) 2.5 centimeters (cm) in size Eastern Cooperative Oncology Group (ECOG)/world health organization (WHO) performance status less than or equal to (</=) 2 Normal baseline cardiac function (Left Ventricular Ejection Fraction [LVEF]) Exclusion Criteria: Stage IV (metastatic) disease Previous treatment for localized breast cancer less than (<) 24 months from diagnosis of present breast cancer Other previous or current cancer except for basal cell cancer or in situ cervical cancer Current or recent use of aspirin (greater than [>] 325 milligrams per day) Clinically significant cardiovascular disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chemotherapy<br>Participants will receive epirubicine, 5-fluorouracil, and cyclophosphamide (FEC 100) for 12 weeks followed by taxane therapy (paclitaxel or docetaxel) for next 12 weeks. | Drug: Epirubicine<br>* Participants will receive epirubicine at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: 5-Fluorouracil (5FU)<br>* Participants will receive 5FU at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: Paclitaxel<br>* Participants will receive paclitaxel at a dose of 80 mg/m^2 as IV infusion every week for 12 weeks.<br>Drug: Docetaxel<br>* Participants will receive docetaxel at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>|
| Experimental: Chemotherapy and Bevacizumab<br>Participants will receive epirubicine, 5-fluorouracil, and cyclophosphamide (FEC 100) for 12 weeks followed by taxane therapy (paclitaxel or docetaxel) for next 12 weeks. Participants will also receive concurrent treatment with bevacizumab every 3 weeks for 24 weeks. | Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg as IV infusion every 3 weeks (or 10 mg/kg every other week in participants receiving weekly paclitaxel), for 24 weeks.<br>* Other names: Avastin;Drug: Epirubicine<br>* Participants will receive epirubicine at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: 5-Fluorouracil (5FU)<br>* Participants will receive 5FU at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: Cyclophosphamide<br>* Participants will receive cyclophosphamide at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>Drug: Paclitaxel<br>* Participants will receive paclitaxel at a dose of 80 mg/m^2 as IV infusion every week for 12 weeks.<br>Drug: Docetaxel<br>* Participants will receive docetaxel at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.<br>|
| Active Comparator: Endocrine Therapy<br>Participants will receive aromatase inhibitor therapy at discretion of the investigator for a period of 24 weeks. | Drug: Aromatase Inhibitor<br>* Participants will receive aromatase inhibitor therapy, at a dose per investigator discretion, once daily for 24 weeks.<br>|
| Experimental: Endocrine Therapy and Bevacizumab<br>Participants will receive aromatase inhibitor therapy at discretion of the investigator and concurrent treatment with bevacizumab for a period of 24 weeks. | Drug: Aromatase Inhibitor<br>* Participants will receive aromatase inhibitor therapy, at a dose per investigator discretion, once daily for 24 weeks.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg as IV infusion every 3 weeks (or 10 mg/kg every other week in participants receiving weekly paclitaxel), for 24 weeks.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Messenger Ribonucleic Acid (mRNA) Markers of Pathological Complete Response, as Assessed by Magnetic Resonance Imaging (MRI) |  | Baseline up to end of study treatment (approximately 24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Pathological Complete Response, as Assessed by Clinical Assessment |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Type of Surgery | Percentage of participants with different surgery types (for example, Mastectomy, Tumorectomy/Breast conserving therapy (BCT), and Tumorectomy followed by mastectomy) will be reported. | At Surgery (Between Weeks 24 and 25) | 
| Percentage of Participants With Axillary Lymph Node Dissection Performed |  | At Surgery (Between Weeks 24 and 25) | 
| Pathological Tumor Size, as Assessed by Histopathological Examination |  | At Surgery (Between Weeks 24 and 25) | 
| Percentage of Participants With Presence of Tumor Cells Close to Resection Margin |  | At Surgery (Between Weeks 24 and 25) | 
| Percentage of Participants With Tumor Deposit in Other Body Parts |  | At Surgery (Between Weeks 24 and 25) | 
| Tumor Free Resection Margin |  | At Surgery (Between Weeks 24 and 25) | 
| Pathological Tumor Size as Measure Using Caliper |  | Cycles 1 to 10 (cycle length=21 days), and Week 25 | 
| Pathological Tumor Size as Measure Using MRI |  | Baseline, Weeks 12 and 25 | 
| Pathological Tumor Size as Measure Using Mamography |  | Baseline, Weeks 12 and 25 | 
| Pathological Breast Tumor Size as Measure Using Ultrasound |  | Baseline, Weeks 12 and 25 | 
| Pathological Axilla Tumor Size as Measure Using Ultrasound |  | Baseline, Weeks 12 and 25 | 
| Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status |  | Screening, Cycles 1 to 10 (cycle length=21 days), and Week 25 | 
| Percentage of Participants With Lymph Node Involvement |  | Cycles 1 to 10 (cycle length=21 days), and Week 25 | 
| Percentage of Participants With Objective Tumor Response, as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) |  | Weeks 12 and 25 | 
| Percentage of Participants With New Lesions |  | Weeks 12 and 25 | 
| Percentage of Participants With Molecular Changes in Protein Kinase Expression |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Molecular Changes in Messenger Ribonucleic Acid (mRNA)/microRNA(miRNA) |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Molecular Changes in Protein Expression |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Single Nucleotide Polymorphism (SNP) Profiles Predicting Treatment Response |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Treatment-Induced Changes in Tumor Cells as Determined by Number of Disseminated Tumor Cells in Bone Marrow |  | Baseline up to end of study treatment (approximately 24 weeks) | 
| Percentage of Participants With Treatment-Induced Changes in Tumor Cells as Determined by Number of Circulating Tumor Cells in Peripheral Blood |  | Baseline up to end of study treatment (approximately 24 weeks) |