Carboplatin, Paclitaxel, and Bevacizumab in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving carboplatin and paclitaxel together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving carboplatin and paclitaxel together with bevacizumab works in treating patients with locally recurrent or metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary To determine the progression-free survival of patients with locally recurrent or metastatic breast cancer treated with carboplatin, paclitaxel albumin-stabilized nanoparticle formulation, and bevacizumab as first-line therapy. Secondary To determine the response rate in these patients. To determine the overall survival of these patients. To evaluate the toxicity profile of this regimen in these patients. OUTLINE: Patients receive carboplatin IV over 1 hour and bevacizumab IV on days 1, 22 and 43. Patients also receive paclitaxel albumin-bound nanoparticle formulation IV over 30 minutes on days 1, 8 ,15, 22, 29, 36, 43, and 50. Treatment continues in the absence of disease progression or unacceptable toxicity. Formalin-fixed paraffin-embedded archived tumor tissue samples are assessed by immunohistochemistry (IHC) for various biomarkers. Levels of Notch-1, Notch-4, cyclin A, cyclin B, Jagged-1, and DLL4 in tumor-associated endothelial cells are correlated with response in both estrogen- and progesterone-positive and negative tumors, and independently of p53 status. After completion of study treatment, patients are followed for up to 2 years.

Official Title
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A Phase II Study of Carboplatin, Nanoparticle Albumin-Bound Paclitaxel (ABI-007) and Avastin as the First Line Therapy in Metastatic Breast Cancer.

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: Carboplatin
* Drug: ABI-007


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed primary adenocarcinoma of the breast Locally recurrent or metastatic disease Must have HER-2-negative breast cancer or, if HER-2-positive, must be unable to receive trastuzumab (Herceptin®) or have previously received trastuzumab in the past Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by conventional techniques or as > 10 mm by spiral CT scan. No known CNS disease Hormone receptor status not specified PATIENT CHARACTERISTICS: Inclusion criteria: Postmenopausal status not specified ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100% Life expectancy > 12 weeks WBC ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Total bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN (unless bone metastasis is present in the absence of liver metastasis) Creatinine ≤ 1.5 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other concurrent malignancies within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix Exclusion criteria: Pre-existing neuropathy ≥ grade 1 Uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Serious, non-healing wound, ulcer, or bone fracture Psychiatric illness/social situations that would limit compliance with study requirements Inadequately controlled hypertension (defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications) History of hypertensive crisis or hypertensive encephalopathy New York Heart Association class II-IV congestive heart failure History of myocardial infarction or unstable angina within the past 6 months History of stroke or transient ischemic attack within the past 6 months Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Significant traumatic injury within the past 28 days History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months Proteinuria, as demonstrated by either urine protein:creatinine ratio ≥ 1.0 OR urine dipstick for proteinuria ≥ 2+ Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline must demonstrate 24-hour urine protein ≤ 1g History of allergy or hypersensitivity to paclitaxel albumin-stabilized nanoparticle formulation, paclitaxel, bevacizumab, carboplatin, albumin, drug product excipients, or chemically similar agents PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from all prior therapy No prior chemotherapy for locally recurrent or metastatic disease Prior neoadjuvant or adjuvant chemotherapy allowed More than 1 week since prior core biopsy or other minor surgical procedure, excluding placement of a vascular access device More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy More than 4 weeks since prior radiotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) At least 1 year since prior taxane regimen No other concurrent investigational agents Concurrent anticoagulation allowed, provided the following criteria are met: Stable dose of warfarin or low molecular weight heparin INR within desired range (2-3) No evidence of active bleeding or coagulopathy No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent radiotherapy, chemotherapy, immunotherapy, or antitumor hormonal therapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carboplatin, ABI-007 and Bevacizumab<br>Participants will receive combination carboplatin, nanoparticle albumin-bound paclitaxel (ABI-007-Abraxane), and bevacizumab (Avastin) | Biological: bevacizumab<br>* Participants will receive bevacizumab 15 mg/kg on days 1,22, and 43.<br>* Other names: Avastin;Drug: Carboplatin<br>* Participants will receive a standard carboplatin dose according to their area under the plasma drug concentration-time curve (AUC-6) on days 1, 22, and 43.<br>* Other names: Paraplatin;Drug: ABI-007<br>* Participants will receive ABI-007 (Abraxane) 100mg/m2 on days 1,8, 15, 22, 29, 36,43,and 50.<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was measured from treatment initiation to 30 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 30 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate at End of Treatment | Response to treatment was recorded 30 months following treatment initiation. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions . | 30 Months | 
| Overall Survival | Overall survival was measured from treatment initiation to 80 months | 80 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage III breast cancer, stage IV breast cancer