A Study to Develop Predictive and Prognostic Tools for Optimizing Therapy With Bevacizumab Frontline Cancer Therapy in Participants With HER 2-Negative Aggressive Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This multicenter, observational, prospective study will identify a powerful and easy predictive/prognostic marker to use with participants under bevacizumab.

Official Title
-----------------
Observational and Prospective Study to Develop Predictive and Prognostic Tools for Optimizing Therapy With Bevacizumab Frontline Cancer Therapy in Patients With Metastatic HER 2-Negative and Aggressive Disease Criteria

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Drug: Paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants with HER2-negative metastatic breast cancer. Mandatory to have the HER2/estrogen receptor (ER)/progesterone receptor (PR) status Participant who met criteria for first-line treatment with chemotherapy plus bevacizumab (standard doses) by local, regional or national guidelines or authorities Participants with measurable disease (RECIST criteria v1.1) or participants with no measurable but assessable disease Molecular phenotype as triple negative metastatic breast cancer; and ER-positive tumors need to fulfill at least one of the two clinical criteria: metastatic relapse on adjuvant endocrine therapy or progression to at least one prior line of endocrine therapy for advanced disease; or aggressive disease criteria (at least two criteria): taxane based regimen in the (neo) adjuvant setting; metastatic relapse within 2 years from the end of chemotherapy for early breast cancer; liver metastasis; three or more organs with metastatic involvement; symptomatic visceral disease Eastern Cooperative Oncology Group (ECOG) 0-2 Exclusion Criteria: Participant has received prior chemotherapy for metastatic disease Participant requiring major/minor surgery within 3 weeks prior to administration of the first dose of study treatment Participant has received an investigational therapy within 4 weeks prior to study entry Participant has known symptomatic brain metastases Participant with non-measurable or assessable disease: exclusive blastic bone disease; pleural, pericardial or abdominal effusion as only evidence of disease Participant in chronic daily treatment with corticosteroids (doses greater than [>]10 milligrams per day [mg/day] of methylprednisolone or equivalent), except inhaled steroids Pregnant or breastfeeding participant Women of childbearing potential who are not using hormonal contraceptives or highly effective birth control during the study Participant has an active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy Participant with significant renal, hematological or liver function alteration according to investigator's criteria Participant has serious medical risk factors involving any of the major organ systems

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

Sexes Eligible for Study
-----------------
All

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

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

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants With Metastatic Breast Cancer<br>Participants with metastatic breast cancer receiving bevacizumab in combination with paclitaxel, will be observed for treatment responses for up to 18 months from the start of treatment. | Drug: Bevacizumab<br>* Bevacizumab will be administered as per local clinical practice and local labeling.<br>Drug: Paclitaxel<br>* Paclitaxel will be administered as per local clinical practice and local labeling.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Benefit | Clinical benefit was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Clinical benefit is defined as partial or complete response as well as tumor stabilization for up to 24 weeks. Results for clinical benefit were reported for 2 groups based on Circulating Tumor Cells (CTC) Levels. The Sensitive group had CTC levels <5 (<5 CTCs in one of the two determinations) and Resistant group had CTC ≥5 (≥ 5 CTCs in the two determinations). | During follow-up (up to 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response as Assessed Using RECIST v1.1 | Overall response = Complete Response (CR) + Partial Response (PR). Overall response was evaluated for the Sensitive group (CTC <5) and Resistant group (CTC ≥5). | From Baseline up to end of study (up to 18 months) | 
| Progression Free Survival (PFS) as Assessed Using RECIST v1.1 | PFS was evaluated for the Sensitive group (CTC <5) and Resistant group (CTC ≥5). | From Baseline up to end of study (up to 18 months) | 
| Overall Survival | OS was evaluated for the Sensitive group (CTC <5) and Resistant group (CTC ≥5). | From Baseline up to end of study (up to 18 months) | 
| Percentage of Participants With Adverse Events of Toxicity Grading 3 and/or 4 | Adverse events (AEs) will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v 4.0). Any AEs that are not specifically listed in the NCI CTCAE follow the logic - Grade 3) Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living; Grade 4: Life-threatening consequences or urgent intervention indicated. | From Baseline up to end of study (up to 18 months) | 
| Optimal Cut-off for Clinical Benefit | Clinical benefit was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Clinical benefit is defined as partial or complete response as well as tumor stabilization for up to 24 weeks. The optimal cut-off for clinical benefit was calculated from a Receiver Operating Curve (ROC) based on CTC level and used to define the prognostic factors that could better predict clinical outcomes. | Baseline (within 21 days prior to Day 1 Cycle 1), 7 days prior to Day 1 Cycle 3 (Cycle length = 28 days) | 
| Percentage of Participants With Overall Response (OR) as Assessed Using RECIST v1. in Prognostic Groups | Overall response = CR + PR. An optimal cut-off point for the CTC count of 0.5 after 2 cycles of treatment was used to define the prognostic groups. | Baseline (within 21 days prior to Day 1 Cycle 1), 7 days prior to Day 1 Cycle 3 (Cycle length = 28 days) | 
| PFS as Assessed Using RECIST v1. in Prognostic Groups | An optimal cut-off point for the CTC count of 0.5 after 2 cycles of treatment was used to define the prognostic groups. | From Baseline up to end of study (up to 18 months) | 
| Mean CTC Count Levels | CTC and CEA levels were compared to determine any correlation between the two. Both CTC count at baseline and at cycle 2 were considered. | Baseline (within 21 days prior to Day 1 Cycle 1 [Cycle length = 28 days]) | 
| Mean Carcinoembryonic Antigen (CEA) Levels |  | Baseline (within 21 days prior to Day 1 Cycle 1 [Cycle length = 28 days]) | 
| Mean Biomarker Cancer Antigen 15.3 (CA 15.3) Level | CTC and CA 15.3 levels were compared to determine any correlation between the two. Both CTC count at baseline and at cycle 2 were considered. | Baseline (within 21 days prior to Day 1 Cycle 1 [Cycle length = 28 days]) |